Study protocol on the role of intestinal microbiota in colorectal cancer treatment: a pathway to personalized medicine 2.0.

PURPOSE: Investigate in patients with metastatic and/or irresectable colorectal cancer treated with systemic treatment with capecitabine or TAS-102 whether: 1. Intestinal microbiota composition can act as a predictor for response. 2. Intestinal microbiota composition changes during systemic treatment and its relation to chemotoxicity. BACKGROUND: Gut microbiota and host determinants evolve in symbiotic and dependent relationships resulting in a personal ecosystem. In vitro studies showed prolonged and increased response to 5-fluorouracil, a fluoropyrimidine, in the presence of a favorable microbiota composition. Capecitabine and TAS-102 are both fluoropyrimidines used for systemic treatment in colorectal cancer patients. METHODS: An explorative prospective multicenter cohort study in the Maastricht University Medical Centre+ and Zuyderland Medical Centre will be performed in 66 patients. Before, during, and after three cycles of systemic treatment with capecitabine or TAS-102, fecal samples and questionnaires (concerning compliance and chemotoxicity) will be collected. The response will be measured by CT/MRI using RECIST-criteria. Fecal microbiota composition will be analyzed with 16S rRNA next-generation sequencing. The absolute bacterial abundance will be assessed with quantitative polymerase chain reaction. Multivariate analysis will be used for statistical analysis. CONCLUSIONS: We aim to detect a microbiota composition that predicts if patients with metastatic and/or irresectable colorectal cancer will respond to systemic treatment and/or experience zero to limited chemotoxicity. If we are able to identify a favorable microbiota composition, fecal microbiota transplantation might be the low-burden alternative to chemotherapy switch in the future.

Constant specific growth rate in fed-batch cultivation of Bordetella pertussis using adaptive control.

Monitoring and control of production processes for biopharmaceuticals have become standard requirements to support consistency and quality. In this paper, a constant specific growth rate in fed-batch cultivation of Bordetella pertussis is achieved by a newly designed specific growth rate controller. The performance of standard control methods is limited because of the time-varying characteristics due to the exponentially increasing biomass and volume. To cope with the changing dynamics, a stable model reference adaptive controller is designed which adapts the controller settings as volume and biomass increase. An important asset of the design is that dissolved oxygen is the only required online measurement. An original design without considering the dissolved oxygen dynamics resulted experimentally in oscillatory behaviour. Hence, in contrast to common believes, it is essential to include dissolved oxygen dynamics. The robustness of this novel design was tested in simulation. The validity of the design was confirmed by laboratory experiments for small-scale production of B. pertussis. The controller was able to regulate the specific growth rate at the desired set point, even during a long fed-batch cultivation time with exponentially increasing demands for substrates and oxygen.