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7 Sipponen P, Vauhkonen M, Helske T, Kaariainen I, Harkonen M. Low circulating levels of gastrin-17 in patients with Barrett’s esophagus. World J Gastroenterol 2005; 11:5988–5992. 8 Agréus L, Storskrubb T, Aro P, Ronkainen J, Talley NJ, Sipponen P. Clinical use of proton-pump inhibitors but not H2-blockers or antacid/alginates raises the serum levels of amidated gastrin-17, pepsinogen I and pepsinogen II in a random adult population. Scand J Gastroenterol 2009; 44:564–570.

Response to: Misleading results in the diagnosis of atrophic gastritis Adrian G. McNicholl and Javier P. Gisbert, University Hospital of ‘La Princesa’ and Health Research Institute Princesa, Center for Network Biomedical Research on Hepatic and Digestive Diseases, Madrid, Spain Correspondence to Adrian G. McNicholl, PhD, MSc, University Hospital of ‘La Princesa’ and Health Research Institute Princesa, Center for Network Biomedical Research on Hepatic and Digestive Diseases, 28006 Madrid, Spain Tel: +0034 913093911; fax: +0034 914022299; e-mail: [email protected] Received 5 November 2014 Accepted 6 November 2014

We wish to thank Professor Di Mario for his comments [1] on our published work on the accuracy of GastroPanel for the diagnosis of atrophic gastritis [2]. However, we would like to clarify for the readers, with reasoned arguments, some of his comments. First, we would like to clarify for Professor Di Mario that the ‘multicentre’ nature of a study, obviously, does not depend on the total number of patients included – much less the number per centre – but on the participation of various centres, as it is the case of our study. As Professor Di Mario seems to indicate in his letter, the sample size of our study is limited and cannot provide a definite answer to the potential usefulness of serology for the diagnosis of gastric atrophy for all settings, but it is enough to fulfil the aim of the study, the validation of GastroPanel in a routine clinical practice setting in Spain. Even Professor Di Mario cites as an acceptable reference the validation study by Rugge et al. [3], which included only three patients more than our study. Professor Di Mario’s letter criticizes the lack of evaluation of the severity of histological alterations; however, this is not the case of our study, in which a blinded expert pathologist evaluated the severity of alterations using the modified Sydney system. Concerns are also raised on the proton pump inhibitor treatment; we agree that antisecretory treatment may affect the usefulness of the serologic panel, but as discussed in our article, the usefulness of a method depends on its practicality on clinical routine, in which most upper-gastrointestinal endoscopy patients are under antisecretory treatment. In any case, only 5% of the study patients were under proton pump inhibitor treatment. It appears that Professor Di Mario’s main concern with our study is that our results contradict ‘all’ previously published literature. However, any updated bibliographic

search would show that this debate is not as clear or as finished as some would like us to believe. For example, even Rugge and colleagues, in the study mentioned by Professor Di Mario, only reaches sensitivities of 77 and 85% (with specificities of 67 and 80%), which means that ∼ 20–30% of patients would be misdiagnosed. Masci et al. [4] obtained similar results in another study (sensitivity of 83%), which led them to conclude that pepsinogen serology could not reflect the severity of lesions. Zhang et al. [5], on evaluating 282 individuals, concluded that the pepsinogen I/pepsinogen II ratio could not distinguish atrophic gastritis from both nonatrophic gastritis and early gastric cancer. Hosseini et al. [6], in their study, including 132 patients, obtained areas under the receiver operating characteristic curve below 0.65. Finally, Shafaghi et al. [7], evaluating a series of 1390 patients, could not achieve acceptable accuracies (area under the receiver operating characteristic curve < 0.70), and using the best cutoff points, only reached sensitivities of 82% (with an associated specificity of 64%). These are just some of the latest published studies questioning the validity of pepsinogen measurement for the diagnosis of histological alterations that any bibliographic search and critical reading would identify. In any case, contradiction of the previous literature is not, by itself, a sign of invalidity of results or conclusions; on the contrary, conflicting data and rejection of past theories are the basis of science. Moreover, a major bias in publication could be created if studies contradicting recommendations or previously published data were systematically negatively evaluated. Adding this bias to the already existing (and well demonstrated) bias towards ‘positive results publications’ would cause an image distortion of the real experience gained by research groups and science worldwide. We expect our study to increase debates on the subject, and allow the final recommendations on this subject to evaluate not only the biased positive results but the full picture.

Acknowledgements Conflicts of interest

There are no conflicts of interest.

References 1 2

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Di Mario F, Goni E. Misleading results in the diagnosis of atrophic gastritis. Eur J Gastroenterol Hepatol 2014; 26:1439–1440. McNicholl AG, Forné M, Barrio J, de la Coba C, González B, Rivera R, et al. Helicobacter pylori Study Group of Asociación Española de Gastroenterología (AEG). Accuracy of GastroPanel for the diagnosis of atrophic gastritis. Eur J Gastroenterol Hepatol 2014; 26:941–948. Rugge M, de Boni M, Pennelli G, de Bona M, Giacomelli L, Fassan M, et al. Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinicopathological follow-up study. Aliment Pharmacol Ther 2010; 31:1104–1111. Masci E, Pellicano R, Mangiavillano B, Luigiano C, Stelitano L, Morace C, et al. GastroPanel® test for non-invasive diagnosis of atrophic gastritis in patients with dyspepsia. Minerva Gastroenterol Dietol 2014; 60:79–83. Zhang XM, Li JX, Zhang GY, Li XH, Gu H. The value of serum pepsinogen levels for the diagnosis of gastric diseases in Chinese Han people in midsouth China. BMC Gastroenterol 2014; 14:3.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Letters to the Editor 105

Hosseini M, Amoueian S, Attaranzadeh A, Montazer M, Soltani G, Asadollahi K, Abangah G. Serum gastrin 17, pepsinogen I and pepsinogen II in atrophic gastritis patients living in North-East of Iran. J Res Med Sci 2013; 18:225–229. Shafaghi A, Mansour-Ghanaei F, Joukar F, Sharafkhah M, Mesbah A, Askari K, et al. Serum gastrin and the pepsinogen I/II ratio as markers for diagnosis of premalignant gastric lesions. Asian Pac J Cancer Prev 2013; 14:3931–3936.

thresholds have been proposed. As an example, Massarrat et al. [5] very recently obtained median PGI levels of 103 μg/l (interquartile range = 78–163) in a series of 107 patients with moderate or marked corpus atrophy. In this context our results are neither skewed nor impossible; in our study only one patient with atrophic gastritis (severe) showed PGI levels lower than 25 μg/l, and only two patients between 25 and 100 μg/l (one severe and one moderate).

Response to: Accuracy of GastroPanel test in detection of atrophic gastritis

As mentioned in our article, the Updated Sydney System (USS) was used as gold standard and all samples were evaluated and classified using that system (including the severity of each one of the variables measured with USS). It is true that GastroPanel diagnosis is based on the Gastrosoft software, and we used Gastrosoft, version 0.4b; however, we asked Biohit Oyj for the algorithm underlying the software programming (Fig. 1 of our article) for independent analysis. The output (diagnostic classification) of Gastrosoft for each patient was the value used in the GastroPanel section of our article (comparing Gastrosoft diagnosis to USS histological diagnosis). As the results were extremely poor (interassay agreement κ 0.089; slight/insignificant concordance) they were not included in the article; for example, 85% of patients diagnosed as corpus atrophy by Gastrosoft had normal mucosa by USS.

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Adrian G. McNicholla, Julio Valleb and Javier P. Gisberta, aUniversity Hospital of ‘La Princesa’ and Health Research Institute Princesa, Center for Network Biomedical Research on Hepatic and Digestive Diseases, Madrid and b Virgen de La Salud Hospital, Toledo, Spain Correspondence to Adrian G. McNicholl, PhD, MSc, University Hospital of ‘La Princesa’ and Health Research Institute Princesa, Center for Network Biomedical Research on Hepatic and Digestive Diseases, 28006, Madrid, Spain Tel: +0034 913093911; fax: +0034 914022299; e-mail: [email protected] Received 5 November 2014 Accepted 6 November 2014

We thank Korpela et al. [1] for their comments regarding our study on the accuracy of GastroPanel for the diagnosis of atrophic gastritis [2]. We respect the interest of Biohit to defend its product that, we agree, is based on the best available noninvasive test for atrophy [pepsinogens (PGs)]. However, even the Maastricht IV Consensus states the low sensitivity of these tests, and the need of local validation before implementing their recommendation [3]. We agree with the correspondents that our study contradicts some previous experiences; however, as mentioned and exemplified in our response letter to Professor Di Mario, the debate on the real usefulness of PG and gastrin serologic marker panels is still ongoing, and conflicting results have been published [4]. Deltaclon (Helsinky, Finland) was, at the time of the study, the official distributer of Biohit in Spain, and Biohit Oyj (Helsinky, Finland) had full knowledge of this protocol and collaborated with the development of this project. Biohit Oyj provided the enzyme-linked immunosorbent assay kits, and the Gastrosoft (Helsinky, Finland), as well as giving information regarding the internal calculations of the algorithm. After contacting the Deltaclon staff in charge of the study samples, it has been confirmed that the use of chemiluminescent assay is a manuscript erratum, and that, as specified in the study protocol, the biomarkers were measured using the GastroPanel-Biohit Oyj validated enzyme-linked immunosorbent assay method (correction for this erratum has been sent to the European Journal of Gastroenterology & Hepatology editors). Although several series have proposed a PGI threshold for the diagnosis of atrophy at 25 μg/l, these values have been shown to be population specific and different

Korpela et al. [1] in their letter mention that GastroPanel should always be used taking moderate or marked/severe atrophy as endpoints. However, GastroPanel, through its website and publicity, claims to be able to, among other things, identify normal mucosa and to diagnose gastric atrophy, it does not specify that is only valid for high-risk (moderate and marked) atrophy [6]. Our aim was not to evaluate, per se, the claims/conclusions published in other studies on serological biomarkers, but to evaluate the clinical utility of GastroPanel itself, and therefore the endpoint has to be the claims of the product on its brochure and website (as that is the information generally available to practitioners). Besides, in our study only one of the patients had mild corpus atrophy, and excluding it from the analysis or grouping it with the normal mucosa patients did not improve the results. Therefore, our results also invalidate the use of GastroPanel in our population for the diagnosis of moderate and severe atrophy. It is true that the number of atrophies found in our studied population is a limitation of our study, making our confidence intervals wider. Nevertheless, our results do not fall as outliers if compared with the studies evaluated by Dinis-Ribero et al. [7] in his meta-analysis (sensitivities ranging from 16 to 90%). Finally, we disagree with Biohit’s final remarks regarding the invalidity of our study to draw conclusions on the screening capacity of the product. It is GastroPanel’s publicity that claims its use not only for screening purposes but also in clinical practice for the diagnosis of

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Response to: misleading results in the diagnosis of atrophic gastritis.

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