Colorectal cancer in 18- to 49-year-olds: rising rates, presentation, and outcome in a large integrated health system.

BACKGROUND AND AIMS: Colorectal cancer (CRC) rates are increasing in young people, and new guidelines recommend screening should begin at age 45 years. We aimed to evaluate CRC detection rates in a large integrated healthcare system to assess treatment outcomes in younger CRC patients and to determine factors that could aid in identifying these individuals. METHODS: We analyzed confirmed cases of CRC using a cancer database spanning from 1985 to 2017 from a large integrated healthcare system composed of 15 hospitals, 150 outpatient clinics, and 20 outpatient oncology clinics. Three cohorts were evaluated (18-44 years, 45-49 years, and ≥50 years). RESULTS: Significant increases in CRC detection were seen in the cohort aged 18 to 44 (annual percentage change, 2.70%) and the cohort aged 45 to 49 (annual percentage change, 4.15%). A higher proportion of African American, Hispanic, and obese subjects were seen in the younger cohorts. A family history of CRC was found in 49% of patients aged 18 to 44 and 38% of patients aged 45 to 50. Patients younger than age 50 were more likely to have metastases at diagnosis (6.8%) versus the cohort over 50 (4.15%; P < .05). Survival was better in younger cohorts, and they were more likely to receive multimodality treatment (surgery with chemotherapy or radiation). Survival probability was similar in different ethnic groups. CONCLUSIONS: CRC is increasing at similar rates in young people aged 18 to 44 and 45 to 49, and they are more likely to present with advanced disease needing multimodality treatment. A family history identifies some patients <50 years. Young patients presenting with changes in bowel habit, rectal bleeding, anemia, and weight loss should undergo colonoscopy. Rectal and anal symptoms should prompt careful physical and endoscopic evaluation.

R-type bacteriocins of Xenorhabdus bovienii determine the outcome of interspecies competition in a natural host environment.

Xenorhabdus species are bacterial symbionts of Steinernema nematodes and pathogens of susceptible insects. Different species of Steinernema nematodes carrying specific species of Xenorhabdus can invade the same insect, thereby setting up competition for nutrients within the insect environment. While Xenorhabdus species produce both diverse antibiotic compounds and prophage-derived R-type bacteriocins (xenorhabdicins), the functions of these molecules during competition in a host are not well understood. Xenorhabdus bovienii (Xb-Sj), the symbiont of Steinernema jollieti, possesses a remnant P2-like phage tail cluster, xbp1, that encodes genes for xenorhabdicin production. We show that inactivation of either tail sheath (xbpS1) or tail fibre (xbpH1) genes eliminated xenorhabdicin production. Preparations of Xb-Sj xenorhabdicin displayed a narrow spectrum of activity towards other Xenorhabdus and Photorhabdus species. One species, Xenorhabdus szentirmaii (Xsz-Sr), was highly sensitive to Xb-Sj xenorhabdicin but did not produce xenorhabdicin that was active against Xb-Sj. Instead, Xsz-Sr produced high-level antibiotic activity against Xb-Sj when grown in complex medium and lower levels when grown in defined medium (Grace's medium). Conversely, Xb-Sj did not produce detectable levels of antibiotic activity against Xsz-Sr. To study the relative contributions of Xb-Sj xenorhabdicin and Xsz-Sr antibiotics in interspecies competition in which the respective Xenorhabdus species produce antagonistic activities against each other, we co-inoculated cultures with both Xenorhabdus species. In both types of media Xsz-Sr outcompeted Xb-Sj, suggesting that antibiotics produced by Xsz-Sr determined the outcome of the competition. In contrast, Xb-Sj outcompeted Xsz-Sr in competitions performed by co-injection in the insect Manduca sexta, while in competition with the xenorhabdicin-deficient strain (Xb-Sj:S1), Xsz-Sr was dominant. Thus, xenorhabdicin was required for Xb-Sj to outcompete Xsz-Sr in a natural host environment. These results highlight the importance of studying the role of antagonistic compounds under natural biological conditions.

Multitarget stool DNA testing for the prevention of colon cancer: outcomes in a large integrated healthcare system.

BACKGROUND AND AIMS: Multitarget stool DNA (MT-sDNA) testing is used in primary care as a screening test for colon cancer. Test effectiveness and patient compliance were examined in clinical practice. METHODS: We assessed outcomes of MT-sDNA testing in a cohort study conducted in a large integrated healthcare system comprising 15 hospitals and 150 outpatient clinics using advanced electronic data capture (Clarity2 [Epic, Verona, Wisc, USA] and REDCap [Encinitas, Calif, USA]) followed by manual chart review to confirm MT-sDNA test results and to monitor the outcomes of subsequent colonoscopy. RESULTS: A total of 6835 MT-sDNA tests were performed over 1 year between 2017 and 2018. Of 1242 patients (18%) who tested positive, 1109 (89%) were referred for colonoscopy, and 905 of them (73%) underwent colonoscopy. Eleven patients (<1%) with a positive test had colorectal cancer, 215 (17%) had advanced adenomas, 110 (9%) had serrated adenomas, and 546 (60%) patients had an adenoma. Of the 6835 patients tested, adenoma or cancer was found in 557 patients (8%). An advanced adenoma or cancer was found in 226 of 1242 patients with a positive test (18%). Nonadherence with colonoscopy after a positive test was high (21%), and the cost to detect 1 advanced adenoma or cancer was $38,849. CONCLUSIONS: The frequency of adenoma detection by an MT-sDNA screening strategy is low, and many positive tests are not associated with significant findings at colonoscopy. Failure to follow a positive test with colonoscopy is a significant problem that needs to be considered when this screening strategy is adopted.

ngrA-dependent natural products are required for interspecies competition and virulence in the insect pathogenic bacterium Xenorhabdus szentirmaii.

Xenorhabdus species are symbionts of entomopathogenic nematodes and pathogens of susceptible insects. Nematodes enter insect hosts and perforate the midgut to invade the haemocoel where Xenorhabdus bacteria are released transitioning to their pathogenic stage. During nematode invasion microbes from the insect gut translocate into the haemocoel. Different species of nematodes carrying specific strains of Xenorhabdus can also invade the same insect. Xenorhabdus species thereby compete for nutrients and space with both related strains and non-related gut microbes. While Xenorhabdus species produce diverse antimicrobial compounds in complex media, their functions in insect hosts are not well understood. We show that Xenorhabdus szentirmaii produced ngrA-dependent antibiotics that were active against both gut-derived microbes and Xenorhabdus nematophila whereas antibiotics of X. nematophila were not active against X. szentirmaii. X. nematophila growth was inhibited in co-cultures with wild-type X. szentirmaii in medium that mimics insect haemolymph. An antibiotic-deficient strain of X. szentirmaii was created by inactivating the ngrA gene that encodes the enzyme that attaches the 4' phosphopantetheinyl moiety to non-ribosomal peptide synthetases involved in antibiotic biosynthesis. X. nematophila growth was not inhibited in co-cultures with the ngrA strain. The growth of X. nematophila was suppressed in Manduca sexta co-injected with wild-type X. szentirmaii and X. nematophila. In contrast, growth of X. nematophila was not suppressed in M. sexta co-injected with the ngrA strain. Two unique compounds were detected by MALDI-TOF MS analysis in haemolymph infected with the wild-type but not with the ngrA strain. Finally, killing of M. sexta was delayed in insects infected with the ngrA strain. These findings indicate that in the insect host X. szentirmaii produces ngrA-dependent products involved in both interspecies competition and virulence.

Evolution of the Stx2-encoding prophage in persistent bovine Escherichia coli O157:H7 strains.

Escherichia coli O157:H7 is a human pathogen that resides asymptomatically in its bovine host. The level of Shiga toxin (Stx) produced is variable in bovine-derived strains in contrast to human isolates that mostly produce high levels of Stx. To understand the genetic basis for varied Stx production, chronological collections of bovine isolates from Wisconsin dairy farms, R and X, were analyzed for multilocus prophage polymorphisms, stx(2) subtypes, and the levels of stx(2) transcript and toxin. The E. coli O157:H7 that persisted on both farms were phylogenetically distinct and yet produced little to no Stx2 due to gene deletions in Stx2c-encoding prophage (farm R) or insertional inactivation of stx(2a) by IS1203v (farm X). Loss of key regulatory and lysis genes in Stx2c-encoding prophage abolished stx(2c) transcription and induction of the prophage and stx(2a)::IS1203v in Stx2a-encoding prophage generated a truncated stx(2a) mRNA without affecting phage production. Stx2-producing strains were transiently present (farm R) and became Stx2 negative on farm X (i.e., stx(2a)::IS1203v). To our knowledge, this is the first study that details the evolution of E. coli O157:H7 and its Stx2-encoding prophage in a chronological collection of natural isolates. The data suggest the bovine and farm environments can be niches where Stx2-negative E. coli O157:H7 emerge and persist, which explains the Stx variability in bovine isolates and may be part of an evolutionary step toward becoming bovine specialists.

Effect of Naloxegol on Opioid-Induced Esophageal Motility Disorder.

Opioid effects on lower gastrointestinal motility are well documented, and increasing attention is being paid to their effect on esophageal motility. Naloxegol is a µ-opioid receptor antagonist that is used for opioid-induced constipation, but its impact on esophageal motility has not been well documented. We report a case series of 3 patients with coexisting esophageal dysmotility and constipation on chronic opioids that improved both symptoms after starting naloxegol. Based on these observational studies, we propose that formal studies be conducted to assess the effect of naloxegol on opioid-induced esophageal dysmotility.

Genetic analysis of xenocoumacin antibiotic production in the mutualistic bacterium Xenorhabdus nematophila.

Xenocoumacin 1 (Xcn1) and xenocoumacin 2 (Xcn2) are the major antimicrobial compounds produced by Xenorhabdus nematophila. To study the role of Xcn1 and Xcn2 in the life cycle of X. nematophila the 14 gene cluster (xcnA-N) required for their synthesis was identified. Overlap RT-PCR analysis identified six major xcn transcripts. Individual inactivation of the non-ribosomal peptide synthetase genes, xcnA and xcnK, and polyketide synthetase genes, xcnF, xcnH and xcnL, eliminated Xcn1 production. Xcn1 levels and expression of xcnA-L were increased in an ompR strain while Xcn2 levels and xcnMN expression were reduced. Xcn1 production was also increased in a strain lacking acetyl-phosphate that can donate phosphate groups to OmpR. Together these findings suggest that OmpR-phosphate negatively regulates xcnA-L gene expression while positively regulating xcnMN expression. HPLC-MS analysis revealed that Xcn1 was produced first and was subsequently converted to Xcn2. Inactivation of xcnM and xcnN eliminated conversion of Xcn1 to Xcn2 resulting in elevated Xcn1 production. The viability of the xcnM strain was reduced 20-fold relative to the wild-type strain supporting the idea that conversion of Xcn1 to Xcn2 provides a mechanism to avoid self-toxicity. Interestingly, inactivation of ompR enhanced cell viability during prolonged culturing.

R-type bacteriocins in related strains of Xenorhabdus bovienii: Xenorhabdicin tail fiber modularity and contribution to competitiveness.

R-type bacteriocins are contractile phage tail-like structures that are bactericidal towards related bacterial species. The C-terminal region of the phage tail fiber protein determines target-binding specificity. The mutualistic bacteria Xenorhabdus nematophila and X. bovienii produce R-type bacteriocins (xenorhabdicins) that are selectively active against different Xenorhabdus species. We analyzed the P2-type remnant prophage clusters in draft sequences of nine strains of X. bovienii The C-terminal tail fiber region in each of the respective strains was unique and consisted of mosaics of modular units. The region between the main tail fiber gene (xbpH1) and the sheath gene (xbpS1) contained a variable number of modules encoding tail fiber fragments. DNA inversion and module exchange between strains was involved in generating tail fiber diversity. Xenorhabdicin-enriched fractions from three different X. bovienii strains isolated from the same nematode species displayed distinct activities against each other. In one set of strains, the strain that produced highly active xenorhabdicin was able to eliminate a sensitive strain. In contrast, xenorhabdicin activity was not a determining factor in the competitive fitness of a second set of strains. These findings suggest that related strains of X. bovienii use xenorhabdicin and additional antagonistic molecules to compete against each other.