Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial

Background Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. Methods This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 μg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4–12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and

Analysis of 15N incorporation into D-alanine: a new method for tracing nitrogen uptake by bacteria

The quantitative contribution of bacteria to total microbial uptake of nitrogenous substrates is an aspect of the aquatic nitrogen cycle that is still largely unclear, mainly because existing methods are generally inadequate. We investigated the feasibility of measuring 15N incorporation into bacterial D-amino acids by gas chromatography- combustion-isotope ratio mass spectrometry (GC-c-IRMS) and the potential of this method as a new tool for quantification of 15N uptake by bacteria. The presented method allowed analysis of 15N incorporation into various hydrolysable amino acids (HAAs), including the bacterial biomarker D-alanine (D-Ala), at trace levels. The potential of the method was tested in a 15N labeling experiment in which sediment slurries were incubated with 15NH4+ and a 15N-labeled amino acid mixture. 15N incorporation into D-Ala was used to calculate total bacterial 15N uptake while comparison of 15N incorporation into D-Ala versus L-Ala provided a direct measure for the relative contributions of bacteria versus algae to the total microbial 15N uptake. Subsequently, it was also possible to calculate 15N uptake by algae. Results for the test experiment showed that bacteria accounted for 38% of total 15NH4+ uptake and dominated uptake of the 15N-amino acid mixture (90%). Analysis of 15N incorporation into other (non-biomarker) HAAs yielded useful additional information on the transformation of these HAAs during organic matter degradation. In conclusion, GC-c-IRMS analysis of D-Ala combined with 15N labeling is a unique approach in aquatic sciences that provides a powerful new method for quantification of nitrogen flows through bacteria in natural microbial communities.