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B Wängberg, A Khorram-Manesh, S Jansson, B Nilsson, O Nilsson, C E Jakobsson, S Lindstedt, A Odén, and H Ahlman

Adrenocortical carcinoma (ACC) is a rare tumour disease with sinister prognosis also after attempts to radical surgery; better prognosis is seen for low-stage tumours. Adjuvant treatment with the adrenolytic drug mitotane has been attempted, but not proven to prevent from recurrence. The drug may offer survival advantage in case of recurrence. The aim of this single-centre study (1979–2007) of 43 consecutive patients was to evaluate the long-term survival after active surgical treatment combined with monitored mitotane (to reduce side effects of the drug). The series is unique, since all patients were offered a period of mitotane as adjuvant or palliative treatment; six patients refused mitotane. Despite a high proportion of high-stage tumours (67%), the complete resection rate was high (77%). The disease-specific 5-year survival was high (64.1%); very high for patients with low-stage tumours without evident relation to mitotane levels. Patients with high-stage tumours had a clear survival advantage with mitotane levels above a threshold of 14 mg/l in serum. The hazard ratio for patients with high mitotane levels versus all patients indicates a significant effect of the drug. The results indicate that adjuvant mitotane may be the standard of care for patients with high-stage ACC after complete resection.

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Thomas G Papathomas, Lindsey Oudijk, Ellen C Zwarthoff, Edward Post, Floor A Duijkers, Max M van Noesel, Leo J Hofland, Patrick J Pollard, Eamonn R Maher, David F Restuccia, Richard A Feelders, Gaston J H Franssen, Henri J Timmers, Stefan Sleijfer, Wouter W de Herder, Ronald R de Krijger, Winand N M Dinjens, and Esther Korpershoek

Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.

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D E Schteingart, G M Doherty, P G Gauger, T J Giordano, G D Hammer, M Korobkin, and F P Worden

Adrenocortical carcinomas are rare, highly malignant tumors that account for only 0.2% of deaths due to cancer. Given the limited number of patients seen in most medical centers with this diagnosis, series usually reported are small and clinical trials not randomized or blinded. In an attempt to answer important questions concerning the management of patients with adrenal cancer, a consensus conference was organized and held at the University of Michigan in Ann Arbor, MI, 11–13 September 2003, with the participation of an international group of physicians who had reported on the largest series of patients with this disease and who had recognized basic and clinical research expertise in adrenal cortical cancer. Totally 43 questions were addressed by the presenters and recommendations discussed in plenary and breakout sessions. Evidence for the recommendations of this conference was at the 2–4+ level and based on available literature and participants’ experience.

In addition to setting up guidelines in specific areas of the diagnosis and treatment of adrenal cancer, the conference recommended and initiated the planning of an international prospective trial for treatment of patients with adrenal cancer in stages III and IV. In terms of new therapies, first trials of dendritic cell therapy in human subjects with adrenal cancer have been started, but it is too early to comment on efficacy. Different strategies of immunotherapy, including DNA vaccination are currently being tried in animal models. There are no clinical gene therapy trials for human adrenal cortical cancer. The adrenals are a preferred target for adenovirus and the results of gene therapy in preclinical studies are promising. In addition, there is evidence that histone deacetylase inhibitors can further enhance the rate of adenoviral infectivity in human adrenal cancer cells. Testing of retroviral vectors, non-viral vectors, small interfering RNA technology, and combined approaches could be performed in various laboratories. Anti-angiogenic substances have only been applied in preclinical studies. The use of these and other agents in the treatment of adrenal cancer should be hypothesis-driven and based on a thorough analysis of tumor biology.

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Constanze Hantel, Sara Jung, Thomas Mussack, Martin Reincke, and Felix Beuschlein

Owing to high relapse rates and early metastatic spread, prognosis in adrenocortical carcinoma (ACC) patients remains poor, highlighting the importance of developing new treatment alternatives for them. Recently, polychemotherapy regimens including etoposide, doxorubicin, and cisplatin together with mitotane (EDP-M) have been defined as the standard treatment for late-stage disease patients. Nevertheless, the administration of conventional cytostatic drugs is associated with severe and dose-limiting side effects. In an attempt to optimize existing clinical treatment regimens, in this study, we investigated the therapeutic efficacy of EDP-M in comparison with that of a paclitaxel-modified scheme (paclitaxel, doxorubicin, cisplatin plus mitotane (PDP-M)) in preclinical in vitro and in vivo models. In addition, based on an extraordinary uptake phenomenon of liposomes in ACC cells, we further evaluated liposomal variants of these protocols (etoposide, liposomal doxorubicin, liposomal cisplatin plus mitotane (LEDP-M) and nab-paclitaxel, liposomal doxorubicin, liposomal cisplatin plus mitotane (LPDP-M)). In vitro, PDP-M was more potent in the induction of apoptosis and inhibition of cell viability as well as cell proliferation than EDP-M. Following the administration of a single therapeutic cycle, we further demonstrated that LEDP-M and LPDP-M exerted significant antitumoral effects in vivo, which were not as evident upon EDP-M and PDP-M treatments. These results were confirmed in a long-term experiment, in which the highest and sustained antitumoral effects were observed for LEDP-M. In summary, liposomal cytostatic substances could represent a promising option that deserves testing in appropriate clinical protocols for the treatment of ACC patients.

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A Falchetti and M L Brandi

Multiple Endocrine Neoplasias type 1 (MEN 1) and type 2 (MEN 2) represent complex inherited (autosomal dominant traits) syndromes characterized by occurrence of distinct proliferative disorders of endocrine tissues, varying from hyperplasia to adenoma and carcinoma.

MEN 1 syndrome is characterized by parathyroid gland, anterior pituitary and endocrine pancreas tumors. Other endocrine and non endocrine tumors, such as carcinoids, lipomas, pinealomas, adrenocortical and thyroid follicular tumors, have been also described in MEN 1 patients occurring at higher frequency than in general population (Brandi ML et al. 1987). Recently also a spinal ependymoma has been found in a patient with MEN 1 syndrome (Kato H et al 1997)

MEN 2 syndromes recognize three main clinical entities, MEN 2A, characterized by medullary thyroid carcinoma (MTC), primary hyperparathyroidism (PHPT) and pheochromocytoma (PHEO); MEN 2B that exhibits MTC, usually developing sooner than the MEN 2A- associated one, pheochromocytoma, multiple neuromas of gastroenteric mucosa, myelinated corneal nerves (Gorlin RJ et al. 1968) and a typical marphanoid habitus; and familial medullary thyroid carcinoma only (FMTC) featuring by families with at least four members with MTC and no objective evidence of pheochromocytoma and parathyroid disease on screening of affected and at-risk members, as stated by the International RET Mutation Consortium (Larsson C et al. 1994).

Acknowledgements

This work was supported by grants of the Associazione Italiana per la Ricerca sul Cancro (to MLB), from CNR/PF ACRO (INV. 95.00316 PF 39) and by MURST 60% (to MLB).

Free access

Dorota Dworakowska and Ashley B Grossman

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterised by the development of multiple hamartomas in numerous organs. It is caused by mutations of two tumour suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, which encode for hamartin and tuberin respectively. The interaction between these two proteins, the tuberin–hamartin complex, has been shown to be critical to multiple intracellular signalling pathways, especially those controlling cell growth and proliferation. TSC may affect skin, central nervous system, kidneys, heart, eyes, blood vessels, lung, bone and gastrointestinal tract. Small series and case reports have documented that in tuberous sclerosis patients many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid and other neuroendocrine tissue. There have been scattered reports of the involvement of such tissue in the pathological process of TSC, but no systematic review as to whether this is a true association. We have therefore systematically assessed all available published literature in this area. We conclude that there may be an association with pituitary and parathyroid tumours, and two recent descriptions of Cushing's disease are especially intriguing. However, the evidence seems more firm in the case of islet cell tumours, particularly insulinomas. As these latter may cause changes in mental state that may be confused with the cerebral manifestations of TSC per se, it is particularly important for physicians working with these patients to be aware of the putative and indeed likely association.

Free access

Pushpa Patel, Rowan Hardy, Vaiyapuri Sumathi, Gillian Bartle, Lars-Gunnar Kindblom, Robert Grimer, Iwona Bujalska, Paul M Stewart, Elizabeth Rabbitt, Neil J L Gittoes, and Mark S Cooper

Osteosarcoma (OS) is a primary malignant tumour of bone occurring predominantly in children and young adults. Despite chemotherapy, relapse is common and mortality remains high. Non-transformed osteoblasts are highly sensitive to glucocorticoids, which reduce proliferation and induce apoptosis. Previously, we observed that OS cells, but not normal osteoblasts, express 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). This enzyme inactivates cortisol (active) to cortisone (inactive) and expression of 11β-HSD2 renders OS cells resistant to glucocorticoids. By contrast, the related enzyme 11β-HSD1 converts cortisone to cortisol and reduces OS cell proliferation in vitro. Some synthetic glucocorticoids (e.g. dehydrodexamethasone (DHD), inactive counterpart of dexamethasone (DEX)) have been reported to be activated by 11β-HSD2. We therefore investigated expression and enzymatic activity of 11β-HSD isozymes in human OS tissue, determined whether 11β-HSD expression has prognostic value in the response to therapy, and evaluated the potential use of synthetic glucocorticoids to selectively target OS cells. OS samples expressed both 11β-HSD1 and 11β-HSD2. 11β-HSD1 expression in pretreatment biopsy specimens positively correlated with primary tumour size. Expression and activity of 11β-HSD1 in post-treatment biopsies were unrelated to the degree of tumour necrosis following chemotherapy. However, high 11β-HSD2 expression in post-treatment biopsies correlated with a poor response to therapy. OS cells that expressed 11β-HSD2 inactivated endogenous glucocorticoids; but these cells were also able to generate DEX from DHD. These results suggest that OS treatment response is related to 11β-HSD2 enzyme expression. Furthermore, OS cells expressing this enzyme could be targeted by treatment with synthetic glucocorticoids that are selectively reactivated by the enzyme.

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Masanori Murakami, Takanobu Yoshimoto, Kazuhiko Nakabayashi, Yujiro Nakano, Takahiro Fukaishi, Kyoichiro Tsuchiya, Isao Minami, Ryotaro Bouchi, Kohji Okamura, Yasuhisa Fujii, Koshi Hashimoto, Ken-ichiro Hata, Kazunori Kihara, and Yoshihiro Ogawa

The pathophysiology of aldosterone-producing adenomas (APAs) has been investigated via genetic approaches and the pathogenic significance of a series of somatic mutations, including KCNJ5, has been uncovered. However, how the mutational status of an APA is associated with its molecular characteristics, including its transcriptome and methylome, has not been fully understood. This study was undertaken to explore the molecular characteristics of APAs, specifically focusing on APAs with KCNJ5 mutations as opposed to those without KCNJ5 mutations, by comparing their transcriptome and methylome status. Cortisol-producing adenomas (CPAs) were used as reference. We conducted transcriptome and methylome analyses of 29 APAs with KCNJ5 mutations, 8 APAs without KCNJ5 mutations and 5 CPAs. Genome-wide gene expression and CpG methylation profiles were obtained from RNA and DNA samples extracted from these 42 adrenal tumors. Cluster analysis of the transcriptome and methylome revealed molecular heterogeneity in APAs depending on their mutational status. DNA hypomethylation and gene expression changes in Wnt signaling and inflammatory response pathways were characteristic of APAs with KCNJ5 mutations. Comparisons between transcriptome data from our APAs and that from normal adrenal cortex obtained from the Gene Expression Omnibus suggested similarities between APAs with KCNJ5 mutations and zona glomerulosa. The present study, which is based on transcriptome and methylome analyses, indicates the molecular heterogeneity of APAs depends on their mutational status. Here, we report the unique characteristics of APAs with KCNJ5 mutations.