Thymidine phosphorylase induction by ionizing radiation antagonizes 5-fluorouracil resistance in human ductal pancreatic adenocarcinoma.

Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) frequently contributes to failure of systemic therapy. While the radiosensitizing properties of 5-fluorouracil (FU) are well known, it is unknown whether ionizing radiation (IR) sensitizes towards FU cytotoxicity. Here, we hypothesize that upregulation of thymidine phosphorylase (TP) by IR reverses FU chemoresistance in PDAC cells. The FU resistant variant of the human PDAC cell line AsPC-1 (FU-R) was used to determine the sensitizing effects of IR. Proliferation rates of FU sensitive parental (FU-S) and FU-R cells were determined by WST-1 assays after low (0.05 Gy) and intermediate dose (2.0 Gy) IR followed by FU treatment. TP protein expression in PDAC cells before and after IR was assessed by Western blot. To analyze the specificity of the FU sensitizing effect, TP was ablated by siRNA. FU-R cells showed a 2.7-fold increase of the half maximal inhibitory concentration, compared to FU-S parental cells. Further, FU-R cells showed a concomitant IR resistance towards both doses applied. When challenging both cell lines with FU after IR, FU-R cells had lower proliferation rates than FU-S cells, suggesting a reversal of chemoresistance by IR. This FU sensitizing effect was abolished when TP was blocked by anti-TP siRNA before IR. An increase of TP protein expression was seen after both IR doses. Our results suggest a TP dependent reversal of FU-chemoresistance in PDAC cells that is triggered by IR. Thus, induction of TP expression by low dose IR may be a therapeutic approach to potentially overcome FU chemoresistance in PDAC.

Early treatment of complex located pediatric low-grade gliomas using iodine-125 brachytherapy alone or in combination with microsurgery.

To analyze efficacy, functional outcome, and treatment toxicity of low-dose rate I-125 brachytherapy (SBT) alone or in combination with best safe resection (in case of larger tumor volumes) as first-line treatment for pediatric low-grade gliomas (PLGGs) not suitable for complete resection. Consecutively treated (2000-2014) complex located circumscribed WHO grade I/II PLGGs were included. For small tumors (≤4 cm in diameter) SBT alone was performed; for larger tumors best safe resection and subsequent SBT was chosen. Temporary Iodine-125 seeds were used (median reference dose: 54 Gy). Treatment response was estimated with the modified MacDonald criteria. Analysis of functional outcome included ophthalmological, endocrinological and neurological evaluation. Survival was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from proportional hazards models. Toxicity was categorized according to the Common Terminology Criteria for Adverse Events. Fifty-eight patients were included treated either with SBT alone (n = 39) or with SBT plus microsurgery (n = 19). Five-year progression-free survival was 87%. Two patients had died due to tumor progression. Among survivors, improvement/stabilization/deterioration of functional deficits was seen in 20/14/5 patients, respectively. Complete/partial response had beneficial impact on functional scores (P = 0.02). The 5-year estimated risk to receive adjuvant radiotherapy/chemotherapy was 5.2%. The overall early (delayed) toxicity rate was 8.6% (10.3%), respectively. No permanent morbidity occurred. In complex located PLGGs, early SBT alone or combined with best safe resection preserves/improves functional scores and results in tumor control rates usually achieved with complete resection. Long-term analysis is necessary for confirmation of these results.

Hippocampal EUD in primarily irradiated glioblastoma patients.

BACKGROUND: Radiation delivery for malignant brain tumors is gradually becoming more precise. Particularly the possibilities of sparing adjacent normal structures such as the hippocampus are increasing. To determine its radiation exposure more exactly, the equivalent uniform dose (EUD) of the hippocampus was compared with further treatment parameters. This way sparing options could be found. METHODS: From the database of the University hospital of Munich 61 glioblastoma patients were selected who received primary radiotherapy in 2011. General data about the etiology, treatment course, survival of the patients and dose parameters were retrieved. RESULTS: In a linear regression analysis the side of the tumor (left hippocampus: p < 0.001/right hippocampus: p = 0.009) and its temporal location (left hippocampus: p = 0.015/right hippocampus: p = 0.033) were identified as factors with a significant influence on the EUD of the respective hippocampus. Besides this, the size of the planning target volume (PTV) and the EUD of the hippocampus correlated significantly (p = 0.027; Pearson correlation = 0.291). The median PTV size of the tumor in the right hemisphere was 386.1 ml (range 131.2-910.7 ml), and in the left hemisphere 291.3 ml (range 146.0-588.9 ml) (Kruskal-Wallis test: p = 0.048). A dose quartile analysis showed that 31 patients had a high dose exposure of the hippocampus on one side while having a moderate dose exposure in the other side. CONCLUSIONS: The radiation exposure of the respective hippocampus is dependent on the side where the tumor is located as well as on whether it is temporally located. The exposure of the contralateral hippocampus is further dependent on multiple additional factors - nevertheless a reasonable protection seems to be possible in about half of all cases.

Analysis of equivalent uniform dose (EUD) and conventional radiation treatment parameters after primary and re-irradiation of malignant glioma.

BACKGROUND: Re-irradiation is a reasonable second treatment option for patients with recurrent malignant glioma (MG) after previous radio(chemo)therapy. However, only limited data is available allowing for a precise selection of patients suitable for re-treatment in regard to safety and efficacy. METHODS: Using the department database, 58 patients with two courses of percutaneous radiation were identified. Besides classical dose-volume histogram (DVH) parameters equivalent uniform dose (EUD) values were calculated for the tumor and organs at risk (OARs), retrospectively analyzed and correlated to survival outcome parameters. Cumulative EUD values were also calculated in all cases where previous OAR DVHs were available. RESULTS: Median follow-up was 265 days and no relevant toxicity was observed after re-irradiation in our patient cohort during follow-up. Time interval between first and second irradiation was regularly above 6 months. As a conservative estimation of the cumulative EUD to the OARs, the EUDs of first and second irradiation were added. Median cumulative EUD to the optic chiasm was 48.8 Gy (range, 2.5-76.5 Gy), 57.4 Gy (range, 2.7-75.3 Gy) to the brainstem, 20.9/22.1 Gy (range, 0.0-68.3 Gy) to the right/left optic nerve and 73.8 Gy (range, 64.9-77.3 Gy) to the brain. No correlation between treated volume and survival was seen. CONCLUSIONS: This study provides retrospective estimates on cumulative doses at the OARs. EUD values are derived and may serve as reference for further studies, including planning studies where specific constraints are needed.