Abstract. Transarterial chemoembolization (TACE) is an established therapeutic approach for the treatment of hepatocellular carcinoma (HCC). Although patients who undergo TACE may have prolonged survival, there are indications that the malignancy of residual HCC tissue can increase subsequent to the procedure. Although hypoxia, which occurs during TACE due to ischemia, is known to contribute to angiogenesis, little is known with regard to the undesirable effects of chemotherapeutic agents on residual HCC cells. Doxorubicin is one of the most commonly used drugs in TACE. The aim of the present study was to analyze alterations in Hep3B and HepG2 human HCC cell lines surviving doxorubicin treatment in vitro. Initially, the toxic concentration range was determined, and doxorubicin was subsequently applied in concentrations that killed >80% of the HCC cells. During the first days subsequent to treatment, surviving cells had higher expression levels of the epithelial-mesenchymal transition marker SNAIL, and exhibited increased migratory activity compared with control cells. At 3 weeks after the first doxorubicin treatment, surviving HCC cells tolerated significantly higher doxorubicin concentrations compared with control cells. As a potential explanation for this doxorubicin resistance, significantly increased mRNA expression levels of ATP-binding cassette ABCB1 (multidrug resistance protein 1) and ABCC1 (multidrug resistance-associated protein 1) were observed by reverse transcription-quantitative polymerase chain reaction. In summary, these findings indicate that, following TACE treatment, hypoxia as well as doxorubicin may induce a more malignant phenotype in surviving HCC cells and decrease susceptibility to further chemotherapeutic treatment.

BackgroundMetastasized soft-tissue sarcomas still pose a significant therapeutic challenge given the limited efficacy of currently available multimodal treatment strategies. Recent progress in molecular characterization of sarcoma subtypes has enabled successful personalized therapy approaches in a minority of selected patients with targetable mutations. However, in the majority of patients with refractory soft tissue sarcomas, long-term survival remains poor.MethodsWe report on three adult patients with various soft tissue sarcomas subjected to Gemcitabine maintenance therapy. Tumor entities included leiomyosarcoma of the pancreas (patient 1), undifferentiated pleomorphic sarcoma of the right femur (patient 2), and peri-aortic leiomyosarcoma (patient 3). Metastatic sites encompassed liver, lung, and bones. All patients received Gemcitabine maintenance therapy until disease progression following prior salvage chemotherapy with Docetaxel and Gemcitabine. Patients were treated outside of clinical trials. Response assessment was based on radiological imaging.ResultsIn response to salvage chemotherapy with Docetaxel and Gemcitabine, one patient exhibited a partial remission, and two patients showed stable disease. Patient 1 exhibited stable disease for 6 months during Gemcitabine maintenance therapy before suffering rapid progression of hepatic metastases. Patient 2 underwent 21 months of Gemcitabine maintenance therapy, which was discontinued after progressive pulmonary metastases were detected. Patient 3 is still being treated with Gemcitabine maintenance therapy. Remarkably, owing to significant chemotherapy-associated hematotoxicity, the dose of Gemcitabine dose was reduced by two-thirds. Nevertheless, stable disease with constant pulmonary metastases has been maintained in this patient for 14 months.ConclusionsGemcitabine maintenance therapy following prior Docetaxel and Gemcitabine chemotherapy is manageable and reveals potential benefits for patients with aggressive metastasized soft tissue sarcomas. Prospective trials evaluating Gemcitabine maintenance therapy are encouraged.

No abstract