Faculty Bibliography

Appendicitis in pregnancy is the most common nonobstetric surgical emergency. Pregnancy causes changes in anatomy, which could lead to uncertainty regarding the diagnosis of appendicitis. This case report describes a case of appendicitis presenting with peritoneovaginal fistula in a pregnant woman in the second trimester, with interesting finding of isolated appendiceal endometriosis on pathology. The importance of complete physical examination, including speculum examination, is emphasized in the pregnant patient presenting with acute-onset abdominal pain. Imaging criteria for diagnosis of appendicitis should be adjusted to account for the gravid uterus, which may cause appendiceal abscess to appear in a variety of locations, such as posterior to the cervix, as in this case.

The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.

AIMS/OBJECTIVE:High-grade appendiceal mucinous neoplasm (HAMN) was recently proposed as a disease entity histologically analogous to low-grade appendiceal mucinous neoplasm (LAMN), but characterised by high-grade cytological atypia. The pathogenesis and clinical features of HAMN have not been fully elucidated. METHODS AND RESULTS/RESULTS:Nine cases of HAMN, eight LAMN, 10 appendiceal mucinous adenocarcinomas (MACA) and five appendiceal serrated polyps resected between 2008 and 2017 contributed by three medical centres underwent targeted next-generation sequencing of 50 cancer-related genes. The patients in each category had similar profiles with respect to gender, age, tumour stage and follow-up intervals. Both LAMN and HAMN harboured mutations of KRAS [nine of nine and eight of eight (100%), respectively] and GNAS [five of eight (63%) and five of nine (56%), respectively] in significantly higher proportions than MACA [KRAS, seven of 10 (70%, P = 0.04); GNAS: one of 10 (10%, P = 0.02)] and serrated polyps [KRAS, one of five (20%, P = 0.0007); GNAS: none of five (0%, P = 0.04)]. Four cases of HAMN, but none of LAMN, harboured mutations of TP53 [four of nine (44%)] and/or ATM [two of nine (22%)]. Three cases of HAMN (33%) showed extra-appendiceal spread with retention of the same mutational profiles in the intra- and extra-appendiceal components. The 10 cases of MACA harboured a similar prevalence of TP53 mutations (n = 5, 50%) as HAMN but, unlike LAMN and HAMN, some harboured mutations in PIK3CA, APC, FBXW7, PTEN and SMAD4. CONCLUSIONS:HAMN and LAMN share high rates of KRAS and GNAS co-mutations supporting a common histogenesis and distinguishing them from MACA. Acquisition of TP53 or ATM mutations by HAMN may drive its progression to a more advanced phenotype.