ABSTRACT
Gastrointestinal stromal tumors (GIST) are rare tumors with a varying malignancy potential, most frequently located in the stomach and the small intestine. The median age at diagnosis is around 65 years. Standard treatment of localized disease is complete surgical resection. A GIST is generally resistant to conventional chemotherapy. Most GISTs harbor tyrosine kinase activating mutations in either the KIT or PDGFRA proto-oncogene. The standard treatment of locally advanced and metastatic GIST with such mutations is the tyrosine kinase inhibitor imatinib. In cases of progressive disease after successive treatment with imatinib, sunitinib, and regorafenib, a fourth-line therapy with ripretinib was recently approved. Approved in 2020, avapritinib is the first effective targeted therapy for advanced stage GIST harboring an imatinib-resistant PDGFRA D842V mutation.
Subject(s)
Antineoplastic Agents , Gastrointestinal Neoplasms , Gastrointestinal Stromal Tumors , Humans , Aged , Gastrointestinal Stromal Tumors/diagnosis , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/genetics , Imatinib Mesylate/therapeutic use , Antineoplastic Agents/therapeutic use , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Mutation , Gastrointestinal Neoplasms/diagnosis , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/genetics , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/therapeutic useABSTRACT
It has been known from previous studies that body fluids, such as cerebrospinal fluid, lung surfactant, and urine, have a strong impact on the bacterial killing of many anti-infective agents. However, the influence of human bile on the antimicrobial activity of antibiotics is widely unknown. Human bile was obtained and pooled from 11 patients undergoing cholecystectomy. After sterilization of the bile fluid by gamma irradiation, its effect on bacterial killing was investigated for linezolid (LZD) and tigecycline (TGC) against Enterococcus faecalis ATCC 29212. Further, ciprofloxacin (CIP), meropenem (MEM), and TGC were tested against Escherichia coli ATCC 25922. Time-kill curves were performed in pooled human bile and Mueller-Hinton broth (MHB) over 24 h. Bacterial counts (in CFU per milliliter after 24 h) of bile growth controls were approximately equal to MHB growth controls for E. coli and approximately 2-fold greater for E. faecalis, indicating a promotion of bacterial growth by bile for the latter strain. Bile reduced the antimicrobial activity of CIP, MEM, and TGC against E. coli as well as the activity of LZD and TGC against E. faecalis This effect was strongest for TGC against the two strains. Degradation of TGC in bile was identified as the most likely explanation. These findings may have important implications for the treatment of bacterial infections of the gallbladder and biliary tract and should be explored in more detail.
