Background and Aims DNA mismatch repair deficiency (MMRD) drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. LS individuals are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a Phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not been demonstrated so far. Methods A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression and mutation frequency. In silico prediction, in vivo immunogenicity testing and epitope mapping was used to identify candidates for FSP vaccination. Results We identified four shared FSP neoantigens [Nacad(FSP-1), Maz(FSP-1), Senp6(FSP-1), Xirp1(FSP-1)] that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only four FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth and prolonged survival even more effectively than FSP vaccination alone. Conclusion Our pre-clinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.

We thank Du et al. for their comments on our articles1Iwaya T. et al.Gastroenterology. 2021; 160: 463-465Abstract Full Text Full Text PDF PubMed Google Scholar,2Iwaya T. et al.MedRxiv. 2020; https://doi.org/10.1101/2020.05.01.20087106Crossref Scopus (0) Google Scholar and appreciate the opportunity to discuss circulating tumor DNA (ctDNA) analysis using individually designed digital polymerase chain reaction (dPCR) in patients with esophageal squamous cell carcinoma (ESCC).

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We read with great interest the study by Yeramaneni et al1Yeramaneni S. et al.Gastroenterology. 2021; 160: 919-921Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar in which the authors have retrospectively analyzed the effect of famotidine on 30-day mortality in hospitalized patients with Coronavirus Disease 2019 (COVID-19). In a matched cohort of 410 patients who received famotidine and 746 who did not, 30-day mortality was higher with famotidine (15.1% vs 9.8%, P = .007). A few points merit consideration. First, the authors adjusted the 2 groups for World Health Organization severity within 48 hours of admission. World Health Organization severity level 5 includes patients on mechanical ventilation or extracorporeal membrane oxygenation. Of all patients, 6.3% and 0.5% in the famotidine and nonfamotidine groups, respectively, were classified as World Health Organization severity level 5, leading to a mismatch. Even the postmatch famotidine group had a higher proportion of patients with concomitant steroids, antiviral, and tocilizumab use because of severe disease. The mortality in the famotidine group among patients on mechanical ventilation was extremely high: 63 patients required mechanical ventilation and 62 (99%) patients died. In such patients, any drug is unlikely to be of much benefit. Second, the use of steroids and tocilizumab in the cohort was associated with higher mortality. In contrast, prior studies suggest reduced mortality in patients receiving steroids and tocilizumab.2Guaraldi G. et al.Lancet Rheumatol. 2020; 2: e474-e484Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar,3The RECOVERY Collaborative GroupN Engl J Med. 2021; 384: 693-704Crossref PubMed Scopus (1629) Google Scholar

We read with interest the article by Iwaya et al,1Iwaya T. Endo F. Takahashi F. et al.Frequent tumor burden monitoring of esophageal squamous cell carcinoma with circulating tumor DNA using individually designed digital polymerase chain reaction.Gastroenterology. 2021; 160: 463-465.e4Abstract Full Text Full Text PDF PubMed Google Scholar which suggested the use of digital polymerase chain reaction (dPCR) as an economical and simple way to measure circulating tumor DNA (ctDNA) in patients with esophageal squamous cell carcinoma (ESCC). By using human cancer tissue specimens and peripheral blood, the authors indicated that frequent tumor burden monitoring with the use of ctDNA analyzed by means of dPCR can enable prediction of relapse and chemotherapeutic efficacy. However, after in-depth analyzing of the results of individual patients in the study,1Iwaya T. Endo F. Takahashi F. et al.Frequent tumor burden monitoring of esophageal squamous cell carcinoma with circulating tumor DNA using individually designed digital polymerase chain reaction.Gastroenterology. 2021; 160: 463-465.e4Abstract Full Text Full Text PDF PubMed Google Scholar we would like to raise the following issues for discussion.

Dietary therapy is emerging as a complementary strategy in some clinical guidelines to treat patients with inflammatory bowel disease (IBD),1Lichtenstein G.R. Loftus E.V. Isaacs K.L. Regueiro M.D. Gerson L.B. Sands B.E. ACG clinical guideline: management of Crohn’s disease in adults.Am J Gastroenterol. 2018; 113: 481-517Crossref PubMed Scopus (296) Google Scholar, 2Rubin D.T. Ananthakrishnan A.N. Siegel C.A. Sauer B.G. Long M.D. ACG clinical guideline: ulcerative colitis in adults.Am J Gastroenterol. 2019; 114: 384-413Crossref PubMed Scopus (227) Google Scholar, 3Lamb C.A. Kennedy N.A. Raine T. et al.British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.Gut. 2019; 68: s1-106Crossref PubMed Scopus (273) Google Scholar, 4Amiot A. Bouguen G. Bonnaud G. Bouhnik Y. Hagege H. Peyrin-Biroulet L. French National Consensus Clinical Guidelines for the Management of IBD Study Group. Clinical guidelines for the management of inflammatory bowel disease: update of a French national consensus.Dig Liver Dis. 2021; 53: 35-43Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar but there is little evidence supporting what foods or drinks can be added without affecting effectiveness, and which foods should be avoided to prevent flares or intestinal inflammation. Supporting the need for diet recommendations as modulators of IBD, exclusive enteral nutrition (EEN)1Lichtenstein G.R. Loftus E.V. Isaacs K.L. Regueiro M.D. Gerson L.B. Sands B.E. ACG clinical guideline: management of Crohn’s disease in adults.Am J Gastroenterol. 2018; 113: 481-517Crossref PubMed Scopus (296) Google Scholar,3Lamb C.A. Kennedy N.A. Raine T. et al.British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.Gut. 2019; 68: s1-106Crossref PubMed Scopus (273) Google Scholar has been used in IBD patients, but the benefits are not durable owing to poor palatability and compliance. Surprisingly, “sugar-free” nutrition trademarked beverages that use artificial sweeteners (ASs) and food additive combinations, possibly used to improve palatability, are listed in some guidelines as “permitted.”3Lamb C.A. Kennedy N.A. Raine T. et al.British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.Gut. 2019; 68: s1-106Crossref PubMed Scopus (273) Google Scholar

Since 2013, obesity has been recognized by the American Medical Association as a chronic disease as opposed to a chronic condition to alert the medical community to be more active in addressing this epidemic.1Pollack A. AMA recognizes obesity as a disease. June 18, 2013.http://www.nytimes.com/2013/06/19/business/ama-recognizes-obesity-as-a-disease.htmlDate accessed: December 12, 2018Google Scholar In 2016, approximately 39.8% of US adults met the criteria for obesity, defined as a body mass index of at least 30 kg/m,2Hales C.M. Carroll M.D. Fryar C.D. et al.Prevalence of obesity among adults and youth: United States 2015–2016. NCHS data brief no. 288. National Center for Health Statistics, Hyattsville, MD2017Google Scholar with an estimated cost of $147 billion annually.2Hales C.M. Carroll M.D. Fryar C.D. et al.Prevalence of obesity among adults and youth: United States 2015–2016. NCHS data brief no. 288. National Center for Health Statistics, Hyattsville, MD2017Google Scholar Given the relationship between obesity and the gastrointestinal (GI) tract, including gut hormones, nutrition, nonalcoholic fatty liver disease, and other obesity-related GI disorders, as well as the emerging role of endoscopy as an effective treatment modality, gastroenterologists will continue to be more involved in the management of this disease.