TY - JOUR A1 - Basile, Vittoria A1 - Puglisi, Soraya A1 - Altieri, Barbara A1 - Canu, Letizia A1 - Libè, Rossella A1 - Ceccato, Filippo A1 - Beuschlein, Felix A1 - Quinkler, Marcus A1 - Calabrese, Anna A1 - Perotti, Paola A1 - Berchialla, Paola A1 - Dischinger, Ulrich A1 - Megerle, Felix A1 - Baudin, Eric A1 - Bourdeau, Isabelle A1 - Lacroix, André A1 - Loli, Paola A1 - Berruti, Alfredo A1 - Kastelan, Darko A1 - Haak, Harm R. A1 - Fassnacht, Martin A1 - Terzolo, Massimo T1 - What is the optimal duration of adjuvant mitotane therapy in adrenocortical carcinoma? An unanswered question JF - Journal of Personalized Medicine N2 - A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence. KW - mitotane KW - adjuvant treatment KW - adrenocortical cancer KW - recurrence KW - recurrence free survival KW - timing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236507 SN - 2075-4426 VL - 11 IS - 4 ER - TY - JOUR A1 - Kimpel, Otilia A1 - Schindler, Paul A1 - Schmidt-Pennington, Laura A1 - Altieri, Barbara A1 - Megerle, Felix A1 - Haak, Harm A1 - Pittaway, James A1 - Dischinger, Ulrich A1 - Quinkler, Marcus A1 - Mai, Knut A1 - Kroiss, Matthias A1 - Polat, Bülent A1 - Fassnacht, Martin T1 - Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma JF - British Journal of Cancer N2 - Background International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. Methods We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. Primary endpoint: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. Results In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50–60 Gy (n = 20) or 20–49 Gy (n = 69), stereotactic body RT of 35–50 Gy (SBRT) (n = 36), or brachytherapy of 12–25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0–148.6). In comparison to cRT\(_{20-49Gy}\), tTTP was significantly longer for cRT\(_{50-60Gy}\) (multivariate adjusted HR 0.10; 95% CI 0.03–0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12–0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22–1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. Conclusions This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC. KW - adrenal tumours KW - adrenocortical carcinoma (ACC) KW - radiotherapy (RT) Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324411 VL - 128 IS - 4 ER - TY - JOUR A1 - Siebert, Claudia A1 - Ciato, Denis A1 - Murakami, Masanori A1 - Frei-Stuber, Ludwig A1 - Perez-Rivas, Luis Gustavo A1 - Monteserin-Garcia, José Luis A1 - Nölting, Svenja A1 - Maurer, Julian A1 - Feuchtinger, Annette A1 - Walch, Axel K. A1 - Haak, Harm R. A1 - Bertherat, Jérôme A1 - Mannelli, Massimo A1 - Fassnacht, Martin A1 - Korpershoek, Esther A1 - Reincke, Martin A1 - Stalla, Günter K. A1 - Hantel, Constanze A1 - Beuschlein, Felix T1 - Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma JF - Frontiers in Endocrinology N2 - Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC. Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines. Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90β. Within a cohort of ACC patients, HSP90β expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2—and AKT—pathways by luminespib and ganetespib treatment. Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC. KW - adrenal gland KW - cortisol KW - N-terminal HSP90 inhibitors KW - C-terminal HSP90 inhibitors KW - prognostic marker Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238029 VL - 10 ER -