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Due to heterogeneity in presentation and outcome, patients with metastatic disease cannot be considered a single group. The timing, location and combinations of recurrences determine the feasibility of treatment of the individual patient in an era in which the options for local and systemic treatment have expanded. Studies investigating this complexity are hampered by the lack of both large cohorts and adequate methods.In a well-defined cohort of rectal cancer patients from a randomized clinical trial, with long standardized follow-up, we applied spatial projection models derived from population ecology to overcome the complexity problem. We describe the recurrence patterns in detail and performed stochastic simulation experiments resulting in 1.5 million evaluable patients. The risk of subsequent recurrences was dependent on the presentation of the first recurrent event and decreased with increasing recurrence-free interval. The risk of local recurrence for the median patient (65.8 years, pT3 adenocarcinoma) was threefold increased after the development of rare metastases. The risk of development of rare metastases was increased after the development of other extrahepatic metastases.Our cross-disciplinary approach delivers insights allowing for the development of personalized strategies for (local) treatment of recurrent disease, as well as for surveillance strategies that may potentially impact large patient cohorts. In this proofof-principle study we demonstrate the feasibility of spatial projection models for cancer research.

Carbapenem-hydrolyzing enzymes belonging to the OXA-48-like group are encoded by blaOXA-48-like alleles and are abundant among Enterobacterales in the Netherlands. Therefore, the objective was to investigate the characteristics, gene content, and diversity of the blaOXA-48-like carrying plasmids and chromosomes of Escherichia coli and Klebsiella pneumoniae collected in the Dutch national surveillance from 2014-2019 in comparison with genome sequences retrieved from 29 countries. By combining short-read and long-read sequencing, 47 and 132 complete blaOXA-48-like plasmids were reconstructed for E. coli and K. pneumoniae, respectively. Distinct plasmid groups designated as pOXA-48, pOXA-181, and pOXA-232 were identified in the Netherlands and varied in size, % G+C, presence of antibiotic resistance genes, replicons and gene content. The pOXA-48 plasmids were variable, while pOXA-181 and pOXA-232 plasmids were conserved. A group of non-related pOXA-48 plasmids contained different resistance genes, non-IncL type replicons or carried no replicons. K. pneumoniae isolates carrying blaOXA-48 or blaOXA-232 were mostly resistant, while E. coli blaOXA-48, blaOXA-181 and chromosomal blaOXA-48 or blaOXA-244 isolates were mostly sensitive for meropenem. Analysis of chromosomally localized blaOXA-48-like alleles revealed that these were flanked by a direct repeat (DR) upstream of IS1R, which were found at multiple locations in the chromosome of distinct genetic backgrounds. In conclusion, the overall blaOXA-48-like plasmid population in the Netherlands is conserved and similar to that reported for other countries, although a highly diverse blaOXA-48-like plasmid subgroup was present. Chromosomally encoded blaOXA-48-like alleles are from distinct genetic backgrounds and occurs at variable positions containing the DR, thereby indicating multiple independent transpositions.ImportanceOXA-48-type of carbapenem hydrolyzing enzymes encoded by blaOXA-48-like genes from transmissible plasmids or chromosomes of Escherichia coli and Klebsiella pneumoniae have spread world-wide and are of concern. Dissecting the blaOXA-48-like genome architecture at the molecular level by combining short-read and long-read sequencing will lead to understanding trends in the plasmid reservoir of E. coli and K. pneumoniae in the Netherlands and may enhance future international pathogen surveillance.

Background: Shigella spp. and entero-invasive Escherichia coli (EIEC) can cause mild diarrhea to dysentery. In the Netherlands, although shigellosis is a notifiable disease, there is no laboratory surveillance for Shigella spp. and EIEC in place. Consequently, the population structure for circulating Shigella spp. and EIEC isolates is not known. This study describes the phenotypic and serological characteristics, the phenotypic and genetic antimicrobial resistance profiles, the virulence gene profiles, the classic multi-locus sequence types (MSLT) and core genome MLST (cgMLST) types, and the epidemiology of Shigella spp. and EIEC isolates collected during a cross-sectional study in the Netherlands in 2016 and 2017. Results: S. sonnei, S. flexneri and EIEC were predominantly detected in the Netherlands. A substantial part of the characterized isolates was resistant to antimicrobials advised for treatment, i.e., 73% was phenotypically resistant to co-trimoxazol and 19% to ciprofloxacin. Antimicrobial resistance was particularly observed in isolates from male patients who had sex with men or from patients that had travelled to Asia. Furthermore, isolates related to international clusters were also circulating in the Netherlands. Travel-related isolates formed clusters with isolates from patients without travel history, indicating their emergence into the Dutch population. Conclusions: In conclusion, laboratory surveillance using whole genome sequencing for genetic characterization of isolates complements the current epidemiological surveillance, as the latter is not sufficient to detect all (inter)national clusters, emphasizing the importance of multifactorial public health approaches.