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The aim of this paper was to assess the cost-effectiveness of pembrolizumab in first-line for microsatellite-instability-high or mismatch-repair-deficient metastatic colorectal cancer. We have considered the pivotal phase III randomized controlled trial of pembrolizumab in first-line for microsatellite-instability-high mismatch-repair-deficient metastatic colorectal cancer. The last available update of each trial was considered as the original source. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression-free survival). The costs of drugs are at the Pharmacy of the Mater Salutis Hospital of Legnago (VR, Italy) and are expressed in euros (€). Three hundred and seven patients were considered in the pivotal phase III randomized controlled trial. Pembrolizumab obtained a cost per month progression-free survival gained ranged from 6471 € towards mFOLFOX (5-FU, oxaliplatin and leucovorin) plus cetuximab to 7886 € towards mFOLFOX. To sum up, combining pharmacological costs of drugs with the measure of efficacy represented by progression-free survival, at the actual prize pembrolizumab cannot be considered cost-effectiveness for first-line treatment for microsatellite-instability-high mismatch-repair-deficient metastatic colorectal cancer. A reduction in pharmacological costs is mandatory.

Introduction: Knowledge of the high microsatellite-instability (MSI-H)/mismatch repair deficiency (MMRd) status is of increasing interest for personalized neoadjuvant or adjuvant therapy planning. Only a few studies are available on MSI-H distribution in the Northern European Caucasian patient population. In this study, we focused on a large cohort of tumors of the upper gastrointestinal tract., Materials and Methods: Surgical material from a total of 1,965 patients was analyzed for MSI-H/MMRd status (including 1,267 carcinomas of the esophagus or stomach). All tumors were analyzed with an internationally recommended immunohistochemical panel consisting of four antibodies (MLH1, MSH2, PMS2, and MSH6). The results were molecularly objectified., Results: Adenocarcinomas with MSI-H/MMRd were detected with the following distribution: esophagus (1.4%), stomach (8.3%), small intestine (18.2%), large intestine (8.5%), intrahepatic bile ducts (1.9%), and pancreas (0%). In case of gastric tumors with MSI-H/MMRd, neoadjuvant therapy did not influence the prognosis of patients (p = 0.94). Within all tumor entities with MSI-H/MMRd, patients with a UICC stage 4 were also represented. In this advanced stage, 11.7% of patients with MSS tumors were diagnosed compared to 0.5% of patients with MSI-H tumors relative to the entire tumor collective., Discussion: In this study, the proportion of MSI-H/MMRd tumors in the stomach is smaller than would have been expected in knowledge of the data published by TCGA or AGRC. Negative prognostic effects regarding MSI-H status and neoadjuvant therapy as described by the MAGIC study group were not seen in our cohort. The extent to which the MSI-H/MMRd status should be known for neoadjuvant therapy planning must be clarified in prospective studies in the future. At present, there is no convincing data to dispense the neoadjuvant therapy for gastric carcinoma. Due to the very convincing, positive data regarding the response rates of MSI-H tumors to treatment with PD1/PD-L1 inhibitors, every metastatic carcinoma of the gastrointestinal tract should be tested for its MSI-H status., Competing Interests: Author JR was employed by company Nordhessen and Targos Molecular Pathology GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Quaas, Rehkaemper, Rueschoff, Pamuk, Zander, Hillmer, Siemanowski, Wittig, Buettner, Plum, Popp, Gebauer, Bruns, Loeser, Alakus and Schoemig-Markiefka.)

Background: Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma., Methods: We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2)., Results: In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions., Conclusion: Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

Aim: To analyze the cellular immune response towards microsatellite-instability (MSI)-induced frameshift-peptides (FSPs) in patients suffering from inflammatory bowel disease (IBD) with and without thiopurine-based immunosuppressive treatment., Methods: Frequencies of peripheral blood T cell responses of IBD patients (n = 75) against FSPs derived from 14 microsatellite-containing candidate genes were quantified by interferon-γ enzyme-linked immunospot. T cells derived from 20 healthy individuals served as controls., Results: Significant T cell reactivities against MSI-induced FSPs were observed in 59 of 75 IBD patients (78.7%). This was significantly more as we could observe in 20 healthy controls (P = 0.001). Overall, the reactivity was significantly influenced by thiopurine treatment (P = 0.032) and duration of disease (P = 0.002) but not by duration or cumulative amount of thiopurine therapy (P = 0.476). Unexpected, 15 of 24 (62.5%) IBD patients without prior thiopurine treatment also showed increased FSP-specific immune responses (P = 0.001)., Conclusion: These findings propose FSPs as potential novel class of inflammation-associated antigens and this in turn may have implications for screening, diagnosis as well as clinical management of patients suffering from IBD and other inflammatory conditions.