@article{CanuPuglisiBerchiallaetal.2021, author = {Canu, Letizia and Puglisi, Soraya and Berchialla, Paola and De Filpo, Giuseppina and Brignardello, Francesca and Schiavi, Francesca and Ferrara, Alfonso Massimiliano and Zovato, Stefania and Luconi, Michaela and Pia, Anna and Appetecchia, Marialuisa and Arvat, Emanuela and Letizia, Claudio and Maccario, Mauro and Parasiliti-Caprino, Mirko and Altieri, Barbara and Faggiano, Antongiulio and Modica, Roberta and Morelli, Valentina and Arosio, Maura and Verga, Uberta and Pellegrino, Micaela and Petramala, Luigi and Concistr{\`e}, Antonio and Razzore, Paola and Ercolino, Tonino and Rapizzi, Elena and Maggi, Mario and Stigliano, Antonio and Burrello, Jacopo and Terzolo, Massimo and Opocher, Giuseppe and Mannelli, Massimo and Reimondo, Giuseppe}, title = {A multicenter epidemiological study on second malignancy in non-syndromic pheochromocytoma/paraganglioma patients in Italy}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {22}, issn = {2072-6694}, doi = {10.3390/cancers13225831}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250148}, year = {2021}, abstract = {No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8\%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95\% CI 5.46-15.71) in males and 13.21 (95\% CI 7.52-21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95\% CI 1.15-5.44, p = 0.021 for 50-59 vs. <50-year category; HR 3.46, 95\% CI 1.67-7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95\% CI 0.10-0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.}, language = {en} } @article{KimpelBedroseMegerleetal.2021, author = {Kimpel, Otilia and Bedrose, Sara and Megerle, Felix and Berruti, Alfredo and Terzolo, Massimo and Kroiss, Matthias and Mai, Knut and Dekkers, Olaf M. and Habra, Mouhammed Amir and Fassnacht, Martin}, title = {Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study}, series = {British Journal of Cancer}, volume = {125}, journal = {British Journal of Cancer}, number = {9}, issn = {1532-1827}, doi = {10.1038/s41416-021-01513-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-273000}, pages = {1233-1238}, year = {2021}, abstract = {Background After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. Methods In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias. Results Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30\%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95\% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007). Conclusions Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.}, language = {en} } @article{BasilePuglisiAltierietal.2021, author = {Basile, Vittoria and Puglisi, Soraya and Altieri, Barbara and Canu, Letizia and Lib{\`e}, Rossella and Ceccato, Filippo and Beuschlein, Felix and Quinkler, Marcus and Calabrese, Anna and Perotti, Paola and Berchialla, Paola and Dischinger, Ulrich and Megerle, Felix and Baudin, Eric and Bourdeau, Isabelle and Lacroix, Andr{\´e} and Loli, Paola and Berruti, Alfredo and Kastelan, Darko and Haak, Harm R. and Fassnacht, Martin and Terzolo, Massimo}, title = {What is the optimal duration of adjuvant mitotane therapy in adrenocortical carcinoma? An unanswered question}, series = {Journal of Personalized Medicine}, volume = {11}, journal = {Journal of Personalized Medicine}, number = {4}, issn = {2075-4426}, doi = {10.3390/jpm11040269}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236507}, year = {2021}, abstract = {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.}, language = {en} } @article{AltieriSbieraHerterichetal.2020, author = {Altieri, Barbara and Sbiera, Silviu and Herterich, Sabine and De Francia, Silvia and Della Casa, Silvia and Calabrese, Anna and Pontecorvi, Alfredo and Quinkler, Marcus and Kienitz, Tina and Mannelli, Massimo and Canu, Letizia and Angelousi, Anna and Chortis, Vasileios and Kroiss, Matthias and Terzolo, Massimo and Fassnacht, Martin and Ronchi, Cristina L.}, title = {Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers12020359}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200565}, pages = {359}, year = {2020}, abstract = {Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2\% vs 51.7\%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55\% of patients with CYP2B6*6 vs. 28.2\% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6\%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.}, language = {en} } @article{ArltBiehlTayloretal.2011, author = {Arlt, Wiebke and Biehl, Michael and Taylor, Angela E. and Hahner, Stefanie and Lib{\´e}, Rossella and Hughes, Beverly A. and Schneider, Petra and Smith, David J. and Stiekema, Han and Krone, Nils and Porfiri, Emilio and Opocher, Giuseppe and Bertherat, Jer{\^o}me and Mantero, Franco and Allolio, Bruno and Terzolo, Massimo and Nightingale, Peter and Shackleton, Cedric H. L. and Bertagna, Xavier and Fassnacht, Martin and Stewart, Paul M.}, title = {Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors}, series = {The Journal of Clinical Endocrinology \& Metabolism}, volume = {96}, journal = {The Journal of Clinical Endocrinology \& Metabolism}, number = {12}, doi = {10.1210/jc.2011-1565}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154682}, pages = {3775 -- 3784}, year = {2011}, abstract = {Context: Adrenal tumors have a prevalence of around 2\% in the general population. Adrenocortical carcinoma (ACC) is rare but accounts for 2-11\% of incidentally discovered adrenal masses. Differentiating ACC from adrenocortical adenoma (ACA) represents a diagnostic challenge in patients with adrenal incidentalomas, with tumor size, imaging, and even histology all providing unsatisfactory predictive values. Objective: Here we developed a novel steroid metabolomic approach, mass spectrometry-based steroid profiling followed by machine learning analysis, and examined its diagnostic value for the detection of adrenal malignancy. Design: Quantification of 32 distinct adrenal derived steroids was carried out by gas chromatography/mass spectrometry in 24-h urine samples from 102 ACA patients (age range 19-84 yr) and 45 ACC patients (20-80 yr). Underlying diagnosis was ascertained by histology and metastasis in ACC and by clinical follow-up [median duration 52 (range 26-201) months] without evidence of metastasis in ACA. Steroid excretion data were subjected to generalized matrix learning vector quantization (GMLVQ) to identify the most discriminative steroids. Results: Steroid profiling revealed a pattern of predominantly immature, early-stage steroidogenesis in ACC. GMLVQ analysis identified a subset of nine steroids that performed best in differentiating ACA from ACC. Receiver-operating characteristics analysis of GMLVQ results demonstrated sensitivity = specificity = 90\% (area under the curve = 0.97) employing all 32 steroids and sensitivity = specificity = 88\% (area under the curve = 0.96) when using only the nine most differentiating markers. Conclusions: Urine steroid metabolomics is a novel, highly sensitive, and specific biomarker tool for discriminating benign from malignant adrenal tumors, with obvious promise for the diagnostic work-up of patients with adrenal incidentalomas.}, language = {en} } @article{RonchiSbieraVolanteetal.2014, author = {Ronchi, Cristina L. and Sbiera, Silviu and Volante, Marco and Steinhauer, Sonja and Scott-Wild, Vanessa and Altieri, Barbara and Kroiss, Matthias and Bala, Margarita and Papotti, Mauro and Deutschbein, Timo and Terzolo, Massimo and Fassnacht, Martin and Allolio, Bruno}, title = {CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma}, doi = {10.1371/journal.pone.0105855}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113096}, year = {2014}, abstract = {Background Adrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins. Objective To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC. Material and Methods CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples). Results CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0-1) in 72\% of non-adrenal normal tissues, but high (H-score 2-3) in 44\% of non-adrenal cancers, in 65\% of normal adrenal glands, in 62\% of ACAs and in 50\% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42\% vs 6\%, P<0.01) or adjuvant option (absence of disease recurrence in 69\% vs 45\%, P<0.01). Conclusion CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment.}, language = {en} }