Medizinische Klinik und Poliklinik I - Allgemeine Innere Medizin
https://hdl.handle.net/20.500.11811/809
Allgemeine Innere Medizin mit den Schwerpunkten Gastroenterologie und Hepatologie, Nephrologie, Infektiologie, Endokrinologie und Diabetologie2024-03-28T16:24:59ZSecond-line and third-line therapy with nanoliposomal irinotecan (nal-IRI) in pancreatic cancer
https://hdl.handle.net/20.500.11811/10815
Second-line and third-line therapy with nanoliposomal irinotecan (nal-IRI) in pancreatic cancer
Möhring, Christian; Frontado Graffe, Freddy José; Bartels, Alexandra; Sadeghlar, Farsaneh; Zhou, Taotao; Mahn, Robert; Marinova, Milka; Feldmann, Georg; Brossart, Peter; Glowka, Tim; Kalff, Jörg; Strassburg, Christian; Gonzalez-Carmona, Maria
Background: Prognosis of patients with pancreatic cancer is still extremely poor. First-line palliative therapies with FOLFIRINOX or gemcitabine/nab-paclitaxel have been established in the last decade. In the second-line, 5-FU/LV in combination with nanoliposomal irinotecan (nal-IRI) after gemcitabine has been shown to be effective. However, the use of nal-IRI as third-line therapy after FOLFIRINOX and gemcitabine-based chemotherapies is still controversial. In this study, we report about the use of 5-FU/LV + nal-IRI in a daily practice and analyze whether nal-IRI is an option as third-line therapy after FOLFIRINOX and gemcitabine/nab-paclitaxel.
Methods: This is a single center retrospective analysis of patients with irresectable pancreatic cancer who were treated with 5-FU/LV and nal-IRI from 2017 to 2021 as second- or third-line palliative treatment. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed, and multivariate analysis was used to identify independent prognostic factors.
Results: Twenty-nine patients receiving 5-FU/LV and nal-IRI were included in the analysis. The majority of patients (n=19) received 5-FU/nal-IRI as third-line therapy after pre-exposition to FOLFIRINOX and gemcitabine/nab-paclitaxel. Median OS and PFS were 9.33 months (95% CI: 3.37, 15.30) and 2.90 months (95% CI: 1.64, 4.16), respectively. Furthermore, patients receiving nal-IRI + 5-FU/LV as third-line treatment also showed some benefits, with no OS difference compared to second-line patients (9.33 vs. 10.27 months; HR: 1.85; 95% CI: 0.64, 5.41; P=0.253). Adverse effects were similar to reported trials.
Conclusions: In our study, the use of 5-FU/nal-IRI in unselected patients with advanced pancreatic cancer showed similar OS, PFS and tolerance as randomized prospective phase II/III trials. Interestingly, the use of 5-FU/nal-IRI seemed to be beneficial in third-line therapy, despite a pre-exposure to non-liposomal irinotecan.
2023-02-15T00:00:00ZUDP-glucuronosyltransferase polymorphisms affect diethylnitrosamine-induced carcinogenesis in humanized transgenic mice
https://hdl.handle.net/20.500.11811/10616
UDP-glucuronosyltransferase polymorphisms affect diethylnitrosamine-induced carcinogenesis in humanized transgenic mice
Landerer, Steffen; Kalthoff, Sandra; Paulusch, Stefan; Strassburg, Christian P.
UDP-glucuronosyltransferase (UGT) 1A enzymes detoxify a broad array of exogenous compounds including environmental toxins and carcinogens. Case-control studies identified genetic variations in UGT1A genes leading to reduced glucuronidation activity, which were associated with hepatocellular carcinoma (HCC) formation and progression. The aim of the study was therefore to examine the direct effect of common UGT1A polymorphisms (SNPs) on HCC development and outcome in a diethylnitrosamine (DEN)-induced mouse model. Therefore, a single intraperitoneal DEN injection (20 mg/kg) was administered to 15-day-old htgUGT1A-WT and htgUGT1A-SNP mice (containing a human haplotype of 10 common UGT1A SNPs) either receiving water or coffee cotreatment for the following 39 weeks. After this time, tumor incidence, size (>1 mm), histology, liver-body ratio, serum aminotransferase activities, and UGT1A regulation and activity levels were determined. In DEN-treated htgUGT1A-SNP mice, a markedly higher number of tumors with a bigger cumulative diameter were detected. The relative liver weight and aminotransferase activity levels were also significantly higher in mice carrying UGT1A SNPs. After coffee + DEN cotreatment, susceptibility for tumor development and growth considerably decreased in both mouse lines, but was still higher in htgUGT1A-SNP mice. In conclusion, our study provides experimental evidence for the protective role of UGT1A enzymes in neoplastic transformation. These data confirm case-control studies implicating impaired UGT1A-mediated carcinogen detoxification as a risk factor for individual cancer disposition. Coffee treatment, which is able to activate UGT1A expression and activity, reduced HCC development and provides an explanation for the protective properties of coffee on liver diseases including liver cancer.
2020-08-28T00:00:00Z