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      Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients

      1 , , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , the ESE survey collaborators
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      European Journal of Endocrinology
      Bioscientifica Ltd

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          To describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC).


          Electronic survey August 2020–May 2021.


          96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8–12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7–12.1) from diagnosis. At the first surgery, the Ki67 index was ≥3% in 74/93 (80%) and ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥ 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 ≥ 10% and ACTH-secretion were associated with worse prognosis.


          APT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers.

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          Most cited references57

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          Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

          Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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            Diagnosis and Treatment of Pituitary Adenomas

            Pituitary adenomas may hypersecrete hormones or cause mass effects. Therefore, early diagnosis and treatment are important.
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              Recurrent gain-of-function USP8 mutations in Cushing's disease

              Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

                Author and article information

                Eur J Endocrinol
                Eur J Endocrinol
                European Journal of Endocrinology
                Bioscientifica Ltd (Bristol )
                26 August 2022
                01 October 2022
                : 187
                : 4
                : 593-605
                [1 ]Department of Endocrinology , Skåne University Hospital Malmö, University of Lund, Lund, Sweden
                [2 ]Faculty of Medicine Lyon-Est , University Claude Bernard Lyon 1, Lyon, France
                [3 ]Marco Losa Department of Neurosurgery , IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
                [4 ]St Vincent’s Hospital and Garvan Institute of Medical Research , Sydney, Australia
                [5 ]ENDOC Center for Endocrine Tumors , Hamburg, Germany
                [6 ]University Belgrade , Belgrade, Serbia
                [7 ]Medizinische Klinik und Poliklinik IV , LMU Klinikum, Ludwig-Maximilians-Universität München, Germany
                [8 ]Fédération d’Endocrinologie , Groupement Hospitalier Est, Hospices Civils de Lyon, University of Lyon-Est de Lyon, Bron, France
                [9 ]Department of Internal Medicine (Section Endocrinology) & Clinical Epidemiology , Leiden University Medical Centre, Leiden, The Netherlands
                Author notes
                Correspondence should be addressed to P Burman; Email: pia.burman@ 123456med.lu.se

                (The list of ESE Survey collaborators are presented in the Acknowledgements section)

                Author information
                © The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                : 15 May 2022
                : 26 August 2022
                Original Research

                Endocrinology & Diabetes
                Endocrinology & Diabetes


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