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[논문 읽기 2016년 9월]

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1. 조기위암 림프절 전이를 예측하기 위한 nomogram - CD44v6 포함 (국립암센터)

국립암센터 엄방울, 국명철 선생님 팀에서 림프절 전이 nomogram을 발표하였습니다 (Eom BW. PLoS One 2016). ESD 후 수술이 필요한 환자에서 보다 정확한 숫자를 제시하며 치료 계획을 논할 수 있다는 점에서 유용하다고 생각됩니다.

In previous studies, the seven biomarkers were proved to be associated to lymph node metastasis in gastric cancer. However, in this study, E-cadherin, α1 catenin, p53, EZH2 had no relationship with lymph node metastasis, and Annexin II and PRL-3 had little discrimination in the immunohistochemistry. CD44v6 was the only significant risk factor for lymph node metastasis, and its OR was very high similar to depth of invasion.

* 참고: EndoTODAY Incomplete resection

2. ESD 후 출혈의 위험인자

ESD 후 출혈 위험에 대한 최근 메타분석입니다 (Libanio D. Gastrointest Endosc 2016). "Procedure duration >60 minutes (OR 2.05) and the use of histamine-2 receptor antagonists instead of proton pump inhibitors (OR 2.13) were the procedural factors associated with PPB (post-procedure bleeding), whereas endoscopist experience and pre-procedural proton pump inhibitors were not. Second-look endoscopy was not associated with decreased PPB (OR 1.34; 95% CI, 0.85-2.12)."

그림에서 제시된 여러 인자 중 시술자가 어떻게 해 볼 수 있는 것은 단 한가지였습니다. ESD 후 H2RA 대신 PPI를 사용하는 것이지요. Second look endoscopy는 이번 분석에서도 유용하지 않은 것으로 다시 확인되었습니다.

* 참고 1: EndoTODAY ESD 후 출혈

* 참고 2: EndoTODAY SLE (second look endoscopy) after ESD

3. [2016-8-26. GI & Hepatology News] H. pylori’s relationship with gastric cancer? It’s complicated by MICHELE G. SULLIVAN

Does eradicating Helicobacter pylori prevent gastric cancer?

The answer is yes, sometimes, but it depends on where you live, and what other bacteria coexist in your gut microbiome.

The overall view is a positive one, Richard M. Peek Jr., MD, said at the at the meeting sponsored by the American Gastroenterological Association. A very large, recent meta-analysis confirms it (Lee YC. Gastroenterology 2016). Comprising 24 studies and 48,000 subjects, the meta-analysis determined that eradicating the bacteria in infected people cut gastric cancer incidence significantly. That’s great news - but there’s a big caveat, said Dr. Peek of Vanderbilt University, Nashville. “The benefit was dependent on what your baseline risk was. For those with a high baseline risk, the benefit was tremendous. For those with a low baseline risk, it was not statistically significant.”

There are long-term data suggesting that treating H. pylori sooner rather than later is the way to go. A 2005 study followed more than 700 patients with preneoplastic gastric lesions for 12 years. It found that the treatment effect was cumulative: The longer the patient was free of H. pylori, the more reliably healing occurred (Mera R. Gut 2005). At baseline, the patients were randomized to nutritional supplements or to a combination of amoxicillin, metronidazole, and bismuth subsalicylate. At 6 years, the trial was unblinded and all patients were offered treatment. Patients were followed for another 6 years. Those who were H. pylori negative at 12 years had 15% more regression and 14% less progression than subjects who were positive at 12 years. Among those who received anti-H. pylori treatment at the 6-year mark, the effect was smaller and nonsignificant. Perhaps surprisingly, though, the biggest bang for H. pylori treatment is seen in the antrum of the stomach, not in the corpus.

Another meta-analysis, this one of 16 studies, found very consistent reductions in the severity of intestinal metaplasia in the antrum after antibiotic treatment - but no difference at all in corpus metaplasia. The reason for that finding isn’t at all clear, the authors of that paper noted (Kong YJ. WJG 2014).

Kong YJ. WJG 2014

The bacteria-metaplasia cancer link gets even more complicated when H. pylori is viewed as a contributing member of society, rather than a hermit. The bacterium seems to be a bully in the neighborhood, radically altering the normal gastric microbiome, Dr. Peek said. In the absence of H. pylori, the gastric microbiome is much more diverse, consisting of about 50% Actinobacteria and 25% Firmicutes species. Bacteroides and Proteobacteria species make up the remainder, with a small population of Cyanobacteria as well. In its presence, Proteobacteria - a gram-negative genus that includes a wide variety of pathogens - almost completely subsume beneficial bacteria.

Researchers saw this change in action in 2011, when a group at the Massachusetts Institute of Technology, Cambridge, inoculated two mouse populations with H. pylori and followed them for gastric neoplasms (Lofgren JL. Gastroenterology 2011). All the mice were genetically engineered to overexpress human gastrin, a characteristic that invariably leads them to develop gastric cancers. One group comprised germ-free mice raised in sterile environments. The control group was free of pathogens, but lived in a conventional environment and so had normal gastric flora. Both groups were inoculated with H. pylori. By 11 months, the microbiome of the control group was strikingly different. It showed a significant increase in the number of Firmicutes bacteria in the stomach, with an associated decrease in the number and variety of other bacteria including Bacteroides. This was especially interesting when viewed in relation to the rate of gastric neoplasia, Dr. Peek said. These mice are programmed to develop gastric cancer by 6 months of age - and this is what happened in the control mice, which had H. pylori plus other gastric microbes. But the germ-free mice who were monoinfected with H. pylori showed a much different progression of disease. At 7 months, most showed only a mild hypergastrinemia. Conversely, at 7 months, all of the H. pylori-infected control mice had developed gastric intraepithelial neoplasia, 80% of it high grade. Only 10% of the monoinfected mice developed cancer, and all of it was low grade.

“It looks like there is active collaboration between H. pylori and other bacteria in the stomach,” resulting in this increased cancer risk, Dr. Peek said. It’s a collaboration that reaches deep into the tumors themselves, he said. “A very interesting study a couple of years ago searched cancer genomes for the presence of bacterial DNA, and found that gastric cancers incorporated the second-highest amount of microbial DNA into their cancer genomes. But it wasn’t just H. pylori. Many other species had integrated their DNA into these tumors.” That study, published in 2013, was the first to prove that bacterial DNA can impact carcinogenesis. Acute myeloid leukemia showed the highest integration of bacterial DNA, but gastric adenocarcinoma was a close second. Most of the species were of the Proteobacteria lineages (83%), with a third of that represented by Pseudomonas, particularly P. fluorescens and P. aeruginosa. Both of those species have been shown to promote gastric tumorigenesis in rats. All of the DNA integrations occurred in five genes; four of these are already known to be upregulated in gastric cancer (Riley DR. PLOS Comp Biol 2013).

Interestingly, only a few of the sample reads turned up DNA integration with H. pylori. This reduction in gastric microbial diversity could be an important key to H. pylori’s relation to gastric cancer, Dr. Peek said. He examined this in residents of two towns in Colombia, South America: Tumaco, where the risk of gastric cancer is low, and Tuquerres, where it’s 25 times higher (Ines Yang. Sci Rep 2016 What was different was the gastric microbiome of residents. Those living in low-risk Tumaco had much more microbial diversity: 361 varieties, compared with 194 in Tuquerres. And 16 of these groups - representative of what’s usually considered a healthy microbiome - were absent in the high-risk subjects. But Tuquerres residents had two bacteria that weren’t found in Tumaco residents, including Leptorichia wadei, which has been associated with necrotizing enterocolitis. There was no difference, however, in the prevalence of H. pylori between these high- and low-risk groups.

These new findings illustrate an increasingly complicated interplay of bacteria and gastric cancer, Dr. Peek said. But they also provide a new direction for research. “We have a framework now where we can move forward and try to understand how some of these other strains impact gastric cancer risk,” he said.

© 일원내시경교실 바른내시경연구소 이준행. EndoTODAY Endoscopy Learning Center. Lee Jun Haeng.