@article{SalmanHaiderSchreinerKendletal.2019,
  author    = {Salman Haider, Malik and Schreiner, Jochen and Kendl, Sabine and Kroiss, Matthias and Luxenhofer, Robert},
  title     = {A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models},
  series = {Macromolecular Bioscience},
  volume    = {20},
  journal   = {Macromolecular Bioscience},
  number    = {1},
  doi       = {10.1002/mabi.201900178},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206224},
  pages     = {1900178},
  year      = {2019},
  abstract  = {Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14-20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT-loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI-H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.},
  language  = {en}
}
@article{LandwehrAltieriSchreineretal.2020,
  author    = {Landwehr, Laura-Sophie and Altieri, Barbara and Schreiner, Jochen and Sbiera, Iuliu and Weigand, Isabel and Kroiss, Matthias and Fassnacht, Martin and Sbiera, Silviu},
  title     = {Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma},
  series = {Journal for ImmunoTherapy of Cancer},
  volume    = {8},
  journal   = {Journal for ImmunoTherapy of Cancer},
  doi       = {10.1136/jitc-2019-000469},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229893},
  year      = {2020},
  abstract  = {Background Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in similar to 60\% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy. Methods We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3\(^+\)), T helper cells (CD3\(^+\)CD4\(^+\)), cytotoxic T cells (CD3\(^+\)CD8\(^+\)) and regulatory T cells (Tregs; CD3\(^+\)CD4\(^+\)FoxP3\(^+\)) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess). Results 86.3\% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0\%, 6.7 cells/HPF), cytotoxic T cells (84.3\%, 5.7 cells/HPF) and Tregs (49.3\%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95\% CI 0.25 to 0.87), which was true for CD4\(^+\)- and CD8\(^+\) subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=-0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess). Conclusion Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.},
  language  = {en}
}