800 results on '"Kaltsas G."'
Search Results
2. 95 MODIFIED HISTOPATHOLOGICAL GRADING OPTIMIZES PREDICTION OF SURVIVAL OUTCOMES IN SMALL INTESTINAL NEUROENDOCRINE TUMOURS
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Daskalakis, K, primary, Tsoli, M, additional, Wallin, G, additional, Kogut, A, additional, Srirajaskanthan, R, additional, Giovos, G, additional, Weickert, M O, additional, Kos-Kudla, B, additional, and Kaltsas, G, additional
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- 2024
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3. Managing Ipilimumab-Induced Hypophysitis: Challenges and Current Therapeutic Strategies
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Tsoli M, Kaltsas G, Angelousi A, Alexandraki K, Randeva H, and Kassi E
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immune checkpoint inhibitors ,hypopituitarism ,immune-related adverse effects ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Marina Tsoli,1 Gregory Kaltsas,1 Anna Angelousi,2 Krystallenia Alexandraki,1 Harpal Randeva,3 Eva Kassi1 1First Department of Propaedeutic and Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 2First Department of Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 3Warwick Medical School, University of Warwick, Coventry CV4 7AL, UKCorrespondence: Marina TsoliFirst Department of Propaedeutic and Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Agiou Thoma 17, Athens 11527, GreeceTel +30 6972692962Fax +30 2132061794Email martso.mt@gmail.comAbstract: Over the past years, progress has been made in cancer immunotherapy following the development of immune checkpoint inhibitors (ICI) that have been proved effective in the management of many malignancies. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4), has been approved for the treatment of advanced melanoma but has been associated with the development of several endocrine immune-related adverse events (irAEs). Hypophysitis is the most common endocrine irAE related to ipilimumab with a reported incidence ranging from 1.8% to 17%. The mechanism underlying ipilimumab-induced hypophysitis implicates immune, inflammatory and genetic factors, but there are still some points that are not well understood and remain to be elucidated. The diagnosis is based mainly on clinical, biochemical and imaging data. The majority of patients display multiple hormone deficiencies that may recover or persist for a prolonged period of time with corticotroph deficiency usually being permanent. Immune-related hypopituitarism is treated with replacement of deficient hormones while in severe forms of hypophysitis treatment with high-dose glucocorticoids may be required. Proper evaluation and registration of patients in clinical trials and further investigation are needed to precisely clarify the pathophysiology of the ICI-related hypophysitis, define predictive factors and ameliorate the management and outcome of the disease.Keywords: immune checkpoint inhibitors, hypopituitarism, immune-related adverse effects
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- 2020
4. A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood
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Öberg, K., Califano, A., Strosberg, J.R., Ma, S., Pape, U., Bodei, L., Kaltsas, G., Toumpanakis, C., Goldenring, J.R., Frilling, A., and Paulson, S.
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- 2020
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5. A Novel Thermal Position Sensor Integrated On A Plastic Substrate
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Petropoulos, A., Kaltsas, G., Goustouridis, D., and Nassiopoulou, A. G.
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Physics - General Physics - Abstract
A thermal position sensor was fabricated and evaluated. The device consists of an array of temperature sensing elements, fabricated entirely on a plastic substrate. A novel fabrication technology was implemented which allows direct integration with read out electronics and communication to the macro-world without the use of wire bonding. The fabricated sensing elements are temperature sensitive Pt resistors with an average TCR of 0.0024/C. The device realizes the detection of the position and the motion of a heating source by monitoring the resistance variation of the thermistor array. The application field of such a cost-effective position sensor is considered quite extensive., Comment: Submitted on behalf of TIMA Editions (http://irevues.inist.fr/tima-editions)
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- 2008
6. Hepatic intra-arterial therapies in metastatic neuroendocrine tumors: lessons from clinical practice
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Grozinsky-Glasberg, S., Kaltsas, G., Kaltsatou, M., Lev-Cohain, N., Klimov, A., Vergadis, V., Uri, I., Bloom, A. I., and Gross, D. J.
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- 2018
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7. Hypoglycaemia requiring medical assistance in patients with diabetes: A prospective multicentre survey in tertiary hospitals
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Liatis, S., Mylona, M., Kalopita, S., Papazafiropoulou, A., Karamagkiolis, S., Melidonis, A., Xilomenos, A., Ioannidis, I., Kaltsas, G., Lanaras, L., Papas, S., Basagiannis, C., and Kokkinos, A.
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- 2015
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8. Corrigendum to ‘Coronavirus disease 2019 in patients with neuroendocrine neoplasms: Preliminary results of the INTENSIVE study’ [European Journal of Cancer 154 (2021) 246-252] (European Journal of Cancer (2021) 154(246-252) (S0959804921004044), (10.1016/j.ejca.2021.06.029))
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Fazio, N. Gervaso, L. Halfdanarson, T.R. La Salvia, A. Hofland, J. Hernando, J. Sonbol, M.B. Garcia-Carbonero, R. Capdevila, J. de Herder, W.W. Koumarianou, A. Kaltsas, G. Rossi, M. Grozinsky-Glasberg, S. Oleinikov, K. Boselli, S. Tamayo, D. Bagnardi, V. Laffi, A. Rubino, M. Spada, F.
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The authors regret that the world map presented in Figure 1 was incomplete. Please see the correct image for Fig 1 below. This has also been updated in the online article. [Figure presented] The authors would like to apologise for any inconvenience caused. © 2021 Elsevier Ltd
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- 2022
9. Management and Long-Term Follow-Up of Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1: Single Center Experience
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Yavropoulou, M.P. Vlachou, S. Tsoli, M. Fostira, F. Kaltsas, G. Kassi, E.
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endocrine system diseases - Abstract
Background: Primary hyperparathyroidism (PHPT) in the most common and earliest manifestation of multiple endocrine neoplasia type-1 (MEN1). Epidemiological data have been reported in MEN1 patients but data on long-term follow-up focusing on PHPT are scarce. Methods: In this retrospective cohort study, we included patients diagnosed with MEN1-related PHPT that were under regular follow-up in our institution. Results: Data on 68 patients (39 males), with a mean age at MEN1-diagnosis of 39 ± 13.06 years, were analyzed. Pancreatic neuroendocrine tumors were encountered in 82% (71% nonsecreting) followed by pituitary adenomas in 66% (49% nonsecreting). Mean age at PHPT diagnosis was 35.2 ± 4.0 years. Parathyroidectomy was performed in 57 patients (82.3%), of whom 56% achieved long-term remission, while 12.2% and 31.5% had persistent and recurrent disease, respectively (median follow-up of 4 years; range 1–21 years). Cinacalcet restored serum calcium levels in 33.8%, both as first and as a second line treatment. Permanent hypoparathyroidism occurred in 19.2%. MEN1 pathogenic variants were identified in 77.2% of the tested individuals, but no genotype-phenotype associations were reported. Conclusions: MEN1-related PHPT involves a multiglandular disease and its management remains a therapeutic challenge, as recurrent disease can develop even after 20 years of follow-up. Prolonged follow-up of these patients at referral centers is critical for their optimal management. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2022
10. A Real-world Multicenter Prospective Study of Everolimus in Pancreatic Neuroendocrine Tumors: The ‘PROTOR’ Study
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Kaltsas, G. Andreadis, C. Kosmidis, P. Mavroudis, D. Pazaitou-Panayiotou, K. Vaslamatzis, M. Athanasiadis, I.
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Background/Aim: Pancreatic neuroendocrine tumors (panNETs) are rare neoplasms with challenging disease management. We aimed to evaluate the progression-free survival (PFS) and overall response rate (ORR) in chemotherapy-naïve patients with unresectable or metastatic Grade (G) 1-2 panNETs treated with everolimus in the routine care in Greece. Patients and Methods: This was a multicenter, prospective, observational study. Eligible patients were recently (≤4 weeks) initiated on treatment with everolimus and were followed for up to 48 months. Results: Nineteen eligible patients (mean age 55.1 years) were enrolled. All patients had metastatic disease and 84.2% had G2 panNET. Everolimus was initiated in combination with somatostatin analogues in 84.2% of the patients. The mean everolimus treatment duration was 21.5 months. The median Kaplan-Meier-estimated PFS was 20.4 months (95% confidence interval=14.1-41.5). The ORR was 27.8%. The rate of everolimus-related adverse events was 84.2% (Grade ≥3: 31.6%). Conclusion: Everolimus displayed clinical benefit and a predictable safety profile in pancreatic neuroendocrine tumors. © 2022 International Institute of Anticancer Research. All rights reserved.
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- 2022
11. Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)
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Flessa, C.-M. Kyrou, I. Nasiri-Ansari, N. Kaltsas, G. Kassi, E. Randeva, H.S.
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nutritional and metabolic diseases ,digestive system ,digestive system diseases - Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress-related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process. © 2022 Wiley Periodicals LLC.
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- 2022
12. A pumping actuator implemented on a PCB substrate by employing water electrolysis
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Pagonis, D.N., Petropoulos, A., and Kaltsas, G.
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- 2012
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13. Adrenal Tumors, Molecular Pathogenesis☆
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Tsoli, M., primary, Kaltsas, G., additional, and Chrousos, G.P., additional
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- 2016
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14. Gas-mass-flow transfer-rate simulation and experimental evaluation in microchannels
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Patsis, G. P., Ninos, K., Mathioulakis, D., and Kaltsas, G.
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- 2013
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15. Modelling and evaluation of a thermal microfluidic sensor fabricated on plastic substrate
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Patsis, G.P., Petropoulos, A., and Kaltsas, G.
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- 2010
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16. A novel system for displacement sensing, integrated on a plastic substrate
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Petropoulos, A., Kaltsas, G., and Goustouridis, D.
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- 2009
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17. Consensus on molecular imaging and theranostics in neuroendocrine neoplasms
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Ambrosini, V. Kunikowska, J. Baudin, E. Bodei, L. Bouvier, C. Capdevila, J. Cremonesi, M. de Herder, W.W. Dromain, C. Falconi, M. Fani, M. Fanti, S. Hicks, R.J. Kabasakal, L. Kaltsas, G. Lewington, V. Minozzi, S. Cinquini, M. Öberg, K. Oyen, W.J.G. O'Toole, D. Pavel, M. Ruszniewski, P. Scarpa, A. Strosberg, J. Sundin, A. Taïeb, D. Virgolini, I. Wild, D. Herrmann, K. Yao, J.
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Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing 68gallium-labelled somatostatin analogue ([68Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing 18fluorine-fluoro-2-deoxyglucose ([18F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[68Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [68Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [18F]FDG and [68Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies. © 2021 Elsevier Ltd
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- 2021
18. Currently available treatment options for neuroendocrine liver metastases
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Machairas, N. Daskalakis, K. Felekouras, E. Alexandraki, K.I. Kaltsas, G. Sotiropoulos, G.C.
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Neuroendocrine neoplasms (NEN) are frequently characterized by a high propensity for metastasis to the liver, which appears to be a dominant site of distant-stage disease, affecting quality of life and overall survival. Liver surgery with the intention to cure is the treatment of choice for resectable neuroendocrine liver metastases (NELM), aiming to potentially prolong survival and ameliorate hormonal symptoms refractory to medical control. Surgical resection is indicated for patients with NELM from well-differentiated NEN, while its feasibility and complexity are largely dictated by the degree of liver involvement. As a result of advances in surgical techniques over the past decades, complex 1- and 2-stage, or repeat liver resections are performed safely and effectively by experienced surgeons. Furthermore, liver transplantation for the treatment of NELM should be anchored in a multimodal and multidisciplinary therapeutic strategy and restricted only to highly selected individual cases. A broad spectrum of interventional radiology treatments for NELM have recently been available, with expanding indications that are more applicable, as they are less limited by patient- and tumor-related parameters, being therefore important adjuncts or alternatives to surgery. Overall, liver-targeted treatment modalities may precede the administration of systemic molecular targeted agents and chemotherapy for patients with liver-dominant metastatic disease; these appear to be a crucial component of multimodal management of patients with NEN. In the present review, we discuss surgical and non-surgical liver-targeted treatment approaches for NELM, each complementing the other, with a view to assisting physicians in optimizing multimodal NEN patient care. © 2021 Hellenic Society of Gastroenterology.
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- 2021
19. Endoplasmic Reticulum Stress and Autophagy in the Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD): Current Evidence and Perspectives
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Flessa, C.-M. Kyrou, I. Nasiri-Ansari, N. Kaltsas, G. Papavassiliou, A.G. Kassi, E. Randeva, H.S.
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nutritional and metabolic diseases ,digestive system diseases - Abstract
Purpose of Review: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease with rising prevalence worldwide. Herein, we provide a comprehensive overview of the current knowledge supporting the role of ER stress and autophagy processes in NAFLD pathogenesis and progression. We also highlight the interrelation between these two pathways and the impact of ER stress and autophagy modulators on NAFLD treatment. Recent Findings: The pathophysiological mechanisms involved in NAFLD progression are currently under investigation. The endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR) seem to contribute to its pathogenesis mainly due to high ER content in the liver which exerts significant metabolic functions and can be dysregulated. Furthermore, disruption of autophagy processes has also been identified in NAFLD. The crucial role of these two pathways in NAFLD is underlined by the fact that they have recently emerged as promising targets of therapeutic interventions. Summary: There is a greater need for finding the natural/chemical compounds and drugs which can modulate the ER stress pathway and autophagy for the treatment of NAFLD. Clarifying the inter-relation between these two pathways and their interaction with inflammatory and apoptotic mechanisms will allow the development of additional therapeutic options which can better target and reprogram the underlying pathophysiological pathways, aiming to attenuate NAFLD progression. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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- 2021
20. The role of immunohistochemical markers for the diagnosis and prognosis of adrenocortical neoplasms
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Angelousi, A. Kyriakopoulos, G. Athanasouli, F. Dimitriadi, A. Kassi, E. Aggeli, C. Zografos, G. Kaltsas, G.
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stomatognathic diseases - Abstract
Adrenal cortical carcinoma (ACC) is a rare cancer with poor prognosis that needs to be dis-tinguished from adrenocortical adenomas (ACAs). Although, the recently developed transcriptome analysis seems to be a reliable tool for the differential diagnosis of adrenocortical neoplasms, it is not widely available in clinical practice. We aim to evaluate histological and immunohistochemical markers for the distinction of ACCs from ACAs along with assessing their prognostic role. Clinical data were retrospectively analyzed from 37 patients; 24 archived, formalin-fixed, and paraffin-embedded ACC samples underwent histochemical analysis of reticulin and immunohistochemical analysis of p27, p53, Ki-67 markers and were compared with 13 ACA samples. Weiss and Helsinki scores were also considered. Kaplan−Meier and univariate Cox regression methods were implemented to identify prognostic effects. Altered reticulin pattern, Ki-67% labelling index and overexpression of p53 protein were found to be useful histopathological markers for distinguishing ACAs from ACCs. Among the studied markers, only pathological p53 nuclear protein expression was found to reach statistically significant association with poor survival and development of metastases, although in a small series of patients. In conclusion, altered reticulin pattern and p53/Ki-67 expression are useful markers for distinguishing ACCs from ACAs. Immunohistopathology alone cannot discrim-inate ACCs with different prognosis and it should be combined with morphological criteria and transcriptome analysis. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2021
21. Transcriptomics, epigenetics, and metabolomics of primary aldosteronism
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Spyroglou, A. Piaditis, G.P. Kaltsas, G. Alexandraki, K.I.
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Introduction: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone‐producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in this field, in particular in the clarification of the genetic and molecular mechanisms responsible for the pathogenesis of aldosterone‐producing adenomas (APAs). Methods: Systematic searches of the PubMed and Cochrane databases were performed for all human studies applying transcriptomic, epigenetic or metabolomic analyses to PA subjects. Studies involving serial analysis of gene expression and microarray, epigenetic studies with methylome analyses and micro‐RNA expression profiles, and metabolomic studies focused on improving understanding of the regulation of autonomous aldosterone production in PA were all included. Results: In this review we summarize the main findings in this area and analyze the interplay between primary aldosteronism and several signaling pathways with differential regulation of the RNA and protein expression of several factors involved in, among others, steroidogenesis, calcium signaling, and nuclear, membrane and G‐coupled protein receptors. Distinct transcriptomic and metabolomic patterns are also presented herein, depending on the mutational status of APAs. In particular, two partially opposite transcriptional and steroidogenic profiles appear to distinguish APAs carrying a KCNJ5 mutation from all other APAs, which carry different mutations. Conclusions: These findings can substantially contribute to the development of personalized treatment in patients with PA. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2021
22. Neuroendocrine manifestations of Langerhans cell histiocytosis
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Yavropoulou, M.P. Tsoli, M. Kaltsas, G.
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Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia that can affect any organ or system in the human body. It is usually diagnosed during childhood but can also affect adults. Recent studies have demonstrated involvement of the hypothalamo–pituitary axis (HPA) in a significant proportion of patients with deficiencies in both anterior and posterior pituitary function that in the majority of cases are permanent and require specific hormone replacement regimes. Central diabetes insipidus is considered the most frequent abnormality of HPA involvement in LCH and can be encountered either as isolated deficiency or along with other pituitary deficiencies. Complete hormonal evaluation of pituitary hormones and long-term follow-up of LCH patients are strongly recommended, especially when pituitary involvement is established. © 2021 Elsevier B.V.
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- 2021
23. Surufatinib — a novel oral agent for neuroendocrine tumours
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Koumarianou, A. Kaltsas, G.
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- 2021
24. A critical appraisal of contemporary and novel biomarkers in pheochromocytomas and adrenocortical tumors
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Tsoli, M. Daskalakis, K. Kassi, E. Kaltsas, G. Tsolakis, A.V.
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Pheochromocytomas/Paragangliomas (PPGLs) and adrenocortical tumors are rare neo-plasms with significant heterogeneity in their biologic and clinical behavior. Current diagnostic and predictive biomarkers include hormone secretion, as well as histopathological and genetic features. PPGL diagnosis is based on biochemical measurement of catecholamines/metanephrines, while histopathological scoring systems have been proposed to predict the risk of malignancy. Adreno-cortical tumors are mostly benign, but some can be malignant. Currently, the stage of disease at diagnosis and tumor grade, appear to be the most powerful prognostic factors. However, recent genomic and proteomic studies have identified new genetic and circulating biomarkers, including genes, immunohistochemical markers and micro-RNAs that display high specificity and sensitivity as diagnostic or prognostic tools. In addition, new molecular classifications have been proposed that divide adrenal tumors in distinct subgroups with different clinical outcomes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2021
25. Clinical utility of18f-fdg pet in neuroendocrine tumors prior to peptide receptor radionuclide therapy: A systematic review and meta-analysis
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Alevroudis, E. Spei, M.-E. Chatziioannou, S.N. Tsoli, M. Wallin, G. Kaltsas, G. Daskalakis, K.
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The role of18F-FDG PET in patients with variable grades of neuroendocrine tumors (NETs) prior to peptide receptor radionuclide therapy (PRRT) has not been adequately elucidated. We aimed to evaluate the impact of18F-FDG PET status on disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in neuroendocrine tumor (NET) patients receiving PRRT. We searched the MEDLINE, Embase, Cochrane Library, and Web of Science databases up to July 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5091 articles were screened. In 12 studies, 1492 unique patients with NETs of different origins were included. The DCR for patients with negative18F-FDG PET status prior to PRRT initiation was 91.9%, compared to 74.2% in patients with positive18F-FDG PET status (random effects odds ratio (OR): 4.85; 95% CI: 2.27–10.36). Adjusted analysis of pooled hazard ratios (HRs) confirmed longer PFS and OS in NET patients receiving PRRT with negative18F-FDG PET (random effects HR:2.45; 95%CIs: 1.48–4.04 and HR:2.25; 95% CIs:1.55–3.28, respectively). In conclusion,18F-FDG PET imaging prior to PRRT administration appears to be a useful tool in NET patients to predict tumor response and survival outcomes and a negative FDG uptake of the tumor is associated with prolonged PFS and OS. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2021
26. Empagliflozin attenuates non-alcoholic fatty liver disease (NAFLD) in high fat diet fed ApoE(-/-) mice by activating autophagy and reducing ER stress and apoptosis
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Nasiri-Ansari, N. Nikolopoulou, C. Papoutsi, K. Kyrou, I. Mantzoros, C.S. Kyriakopoulos, G. Chatzigeorgiou, A. Kalotychou, V. Randeva, M.S. Chatha, K. Kontzoglou, K. Kaltsas, G. Papavassiliou, A.G. Randeva, H.S. Kassi, E.
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Aims/hypothesis: SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. Methods: Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Xbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. Results: Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. Conclusion: These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2021
27. Impact of the COVID-19 pandemic on neuroendocrine tumour services in England
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Weickert, M.O. Robbins, T. Kyrou, I. Hopper, A. Pearson, E. Barber, T.M. Kaltsas, G. Randeva, H.S.
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Purpose: During the COVID-19 pandemic, there have been particular concerns regarding the related impact on specialist tumour services. Neuroendocrine tumour (NET) services are delivered in a highly specialised setting, typically delivered in a small number of centres that fulfil specific criteria as defined by the European Neuroendocrine Tumour Society (ENETS). We aimed to address the COVID-19-related impact on specialist NET tumour services in England and other countries. Methods: Electronic survey addressing patient access and delivery of care distributed to all ENETS Centres of Excellence (CoE) in England and matching number of ENETS CoE elsewhere. Semi-quantitative and qualitative analyses of survey responses were performed. Results: Survey response of ENETS CoE in England was 55% (6/11). Responses from six non-UK ENETS CoE elsewhere were received and analysed in a similar manner. Relevant disruption of various NET services was noted across all responding Centres, which included delayed patient appointments and investigations, reduced availability of treatment modalities including delayed surgical treatment and a major negative impact on research activities. The comparison between English and non-UK ENETS CoE suggested that the former had significantly greater concerns related to future research funding (p = 0.014), whilst having less disruption to multidisciplinary meetings (p = 0.01). A trend was also noted towards virtual patient appointments in ENETS CoE in England vs. elsewhere (p = 0.092). Conclusions: Restoration of highly specialised NET services following COVID-19 and planning for future service delivery and research funding must take account of the severe challenges encountered during the pandemic. © 2021, The Author(s).
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- 2021
28. Cardiovascular toxicities secondary to biotherapy and molecular targeted therapies in neuroendocrine neoplasms: A systematic review and meta-analysis of randomized placebo-controlled trials
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Aktypis, C. Spei, M.-E. Yavropoulou, M. Wallin, G. Koumarianou, A. Kaltsas, G. Kassi, E. Daskalakis, K.
- Abstract
A broad spectrum of novel targeted therapies with prime antitumor activity and/or ample control of hormonal symptoms together with an overall acceptable safety profile have emerged for patients with metastatic neuroendocrine neoplasms (NENs). In this systematic review and quantitative meta-analysis, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases were searched to assess and compare the safety profile of NEN treatments with special focus on the cardiovascular adverse effects of biotherapy and molecular targeted therapies (MTTs). Quality/risk of bias were assessed using GRADE criteria. Placebocontrolled randomized clinical trials (RCTs) in patients with metastatic NENs, including medullary thyroid cancer (MTC) were included. A total of 3695 articles and 122 clinical trials registered in clinicaltrials.gov were screened. We included sixteen relevant RCTs comprising 3408 unique patients assigned to different treatments compared with placebo. All the included studies had a low risk of bias. We identified four drug therapies for NENs with eligible placebo-controlled RCTs: somatostatin analogs (SSAs), tryptophan hydroxylase (TPH) inhibitors, mTOR inhibitors and tyrosine kinase inhibitors (TKI). Grade 3 and 4 adverse effects (AE) were more often encountered in patients treated with mTOR inhibitors and TKI (odds ratio [OR]: 2.42, 95% CI: 1.87–3.12 and OR: 3.41, 95% CI: 1.46–7.96, respectively) as compared to SSAs (OR:0.77, 95% CI: 0.47–1.27) and TPH inhibitors (OR:0.77, 95% CI: 0.35–1.69). MTOR inhibitors had the highest risk for serious cardiac AE (OR:3.28, 95% CI: 1.66–6.48) followed by TKIs (OR:1.51, 95% CI: 0.59–3.83). Serious vascular AE were more often encountered in NEN patients treated with mTOR inhibitors (OR: 1.72, 95% CI: 0.64–4.64) and TKIs (OR:1.64, 95% CI: 0.35–7.78). Finally, patients on TKIs were at higher risk for new-onset or exacerbation of pre-existing hypertension (OR:3.31, 95% CI: 1.87–5.86). In conclusion, SSAs and TPH inhibitors appear to be safer as compared to mTOR inhibitors and TKIs with regards to their overall toxicity profile, and cardiovascular toxicities in particular. Special consideration should be given to a patient-tailored approach with anticipated toxicities of targeted NEN treatments together with assessment of cardiovascular comorbidities, assisting clinicians in treatment selection and early recognition/management of cardiovascular toxicities. This approach could improve patient compliance and preserve cardiovascular health and overall quality of life. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2021
29. Mechanisms of central hypogonadism
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Barber, T.M. Kyrou, I. Kaltsas, G. Grossman, A.B. Randeva, H.S. Weickert, M.O.
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endocrine system - Abstract
Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (com-bined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti‐related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin re-sistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic‐androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduc-tion or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vul-nerable, and their clinical management requires both sensitivity and empathy. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2021
30. Identification of an optimal prolactin threshold to determine prolactinoma size using receiver operating characteristic analysis
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Leca, B.M. Mytilinaiou, M. Tsoli, M. Epure, A. Aylwin, S.J.B. Kaltsas, G. Randeva, H.S. Dimitriadis, G.K.
- Abstract
Prolactinomas represent the most common type of secretory pituitary neoplasms, with a therapeutic management that varies considerably based on tumour size and degree of hyperprolactinemia. The aim of the current study was to evaluate the relationship between serum prolactin (PRL) concentrations and prolactinoma size, and to determine a cut-off PRL value that could differentiate micro- from macro-prolactinomas. A retrospective cohort study of 114 patients diagnosed with prolactinomas between 2007 and 2017 was conducted. All patients underwent gadolinium enhanced pituitary MRI and receiver operating characteristic (ROC) analyses were performed. 51.8% of patients in this study were men, with a mean age at the time of diagnosis of 42.32 ± 15.04 years. 48.2% of the total cohort were found to have microadenomas. Baseline serum PRL concentrations were strongly correlated to tumour dimension (r = 0.750, p = 0.001). When performing the ROC curve analysis, the area under the curve was 0.976, indicating an excellent accuracy of the diagnostic method. For a value of 204 μg/L (4338 mU/L), sensitivity and specificity were calculated at 0.932 and 0.891, respectively. When a cut off value of 204 μg/L (4338 mU/L) was used, specificity was 93.2%, and sensitivity 89.1%, acceptable to reliably differentiate between micro- and macro- adenomas. © 2021, The Author(s).
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- 2021
31. Langerhans Cell Disease (LCH)☆
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Makras, P., primary, Kaltsas, G., additional, and Grossman, A.B., additional
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- 2014
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32. Modelling and evaluation of a thermal microfluidic sensor fabricated on plastic substrate
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Patsis, G. P., Petropoulos, A., and Kaltsas, G.
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- 2012
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33. Clinical value of right hemicolectomy for appendiceal carcinoids using pathologic criteria
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Alexandraki, K. I., Griniatsos, J., Bramis, K. I., Ballian, N., Dimitriou, N., Giannakakis, T., Tsigris, C., Felekouras, E., and Kaltsas, G. A.
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- 2011
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34. Study of an integrated thermal sensor in different operational modes, under laminar, transitional and turbulent flow regimes
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Stamatopoulos, Ch., Petropoulos, A., Mathioulakis, D.S., and Kaltsas, G.
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- 2008
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35. The value of 11C-5-hydroxy-tryptophan positron emission tomography in neuroendocrine tumor diagnosis and management: experience from one center
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Nikolaou, A., Thomas, Dimitrios, Kampanellou, C., Alexandraki, K., Andersson, L. G., Sundin, A., and Kaltsas, G.
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- 2010
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36. Hypophysitis superimposed on a non-functioning pituitary adenoma: Diagnostic clinical, endocrine, and radiologic features
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Ballian, N., Chrisoulidou, A., Nomikos, P., Samara, C., Kontogeorgos, G., and Kaltsas, G. A.
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- 2007
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37. Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors
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Marques, P, Caimari, F, Hernández-Ramírez, LC, Collier, D, Iacovazzo, D, Ronaldson, A, Magid, K, Lim, CT, Stals, K, Ellard, S, Grossman, AB, Korbonits, M, Abraham, P, Aflorei, E, Agha, A, Ahlquist, J, Akker, SA, Alexandraki, K, Alföldi, S, Anselmo, J, Arlt, W, Atkinson, B, Aulinas-Masó, A, Aylwin, SJ, Baborie, A, Backeljauw, PF, Badiu, C, Baldeweg, S, Ball, S, Bano, G, Barkan, A, Barton, J, Barwell, J, Bates, P, Bernal-González, C, Besser, M, Bevan, JS, Bickerton, A, Blair, J, Bolanowski, M, Bouloux, P, Bradley, L, Bradley, K, Brain, C, Brooke, A, Brown, R, Buchfelder, M, Burren, C, Cakir, M, Canham, N, Capraro, J, Carroll, P, Carter, P, Carty, D, Cavlan, D, Chahal, HS, Cheetham, T, Chentli, F, Choong, C, Christ-Crain, M, Chung, T-T, Clayton, P, Clayton, RN, Cohen, M, Courtney, H, Cove, D, Crowne, E, Cuthbertson, D, Dal, J, Dalantaeva, N, Damjanovic, S, Daousi, C, Darzy, K, Dattani, M, Davies, M, Davies, J, Davis, J, de Castro, M, de Marinis, L, Deal, C, Dénes, J, Dimitri, P, Dorward, N, Dow, G, Drake, W, Druce, M, Drummond, J, Dutta, P, Dzeranova, L, Edén-Engström, B, Eeles, R, Elfving, M, Ellis, K, Elston, M, Emmerson, L, Ezzat, S, Fersht, N, Fica, S, Fischli, S, Fleseriu, M, Forsythe, E, Foulkes, W, Freda, P, Friedman, T, Gadelha, M, Gainsborough, M, Gallacher, S, Gallego, P, Gan, H-W, Georgescu, C, Gevers, E, Gilkes, C, Glynn, N, Goldman, JE, Goldstone, AP, Góth, M, Green, A, Greenhalgh, L, Grieve, J, Griz, L, Guitelman, M, Gürlek, A, Gurnell, M, Hamblin, PS, Hana, V, Harding, P, Hay, E, Hilton, DA, Ho, W, Hong, G, Horváth, K, Howell, S, Howlett, TA, Höybye, C, Hunter, S, Idampitiya, C, Igaz, P, Imran, A, Inder, WJ, Iwata, T, Izatt, L, Jagadeesh, S, Johnston, C, Jose, B, Kaltsas, G, Kaplan, F, Karavitaki, N, Kastelan, D, Katz, M, Kearney, T, Kershaw, M, Khoo, B, Kiraly-Borri, C, Knispelis, R, Kovács, GL, Kumar, A, Kumar, AV, Kun, IZ, Kyriaku, A, Lambrescu, I, Lampe, AK, Laws, ER, Lebek-Szatanska, A, Lechan, RM, Leese, G, Levy, A, Levy, MJ, Lewandowski, K, Lin, E, Lo, J, Lyons, C, Maartens, N, Maghnie, M, Makaya, T, Marcus, H, Niedziela, M, Martin, N, Matsuno, A, McGowan, B, McQuaid, SE, Medic-Stojanoska, M, Mendoza, N, Mercado-Atri, M, Mettananda, S, Mezősi, E, Miljic, D, Miller, KK, Modenesi, S, Molitch, ME, Monson, J, Morris, DG, Morrison, PJ, Mosterman, B, Munir, A, Murray, RD, Musat, M, Musolino, N, Nachtigall, L, Nagi, D, Nair, R, Nelson, R, Newell-Price, J, Nikookam, K, Ogilivie, A, Orme, SM, O´Weickert, M, Pal, A, Pascanu, I, Patócs, A, Patterson, C, Pearce, SH, Giraldi, FP, Penney, L, Perez-Rivas, LG, Pfeifer, M, Pirie, F, Poplawski, N, Popovic, V, Powell, M, Pullan, P, Quinton, R, Radian, S, Randeva, H, Reddy, N, Rees, A, Renals, V, de Oliveira, AR, Richardson, T, Rodd, C, Ross, RJM, Roncaroli, F, Ryan, F, Salvatori, R, Schöfl, C, Shears, D, Shotliff, K, Skelly, R, Snape, K, Soares, BS, Somasundaram, N, Spada, A, Sperber, J, Spoudeas, H, Stelmachowska-Banas, M, Stewart, S, Storr, HL, Strasburger, C, Street, ME, Suter-Widmer, I, Suthers, G, Swords, F, Syro, LV, Swantje, B, Sze, C, Taylor, J, Thakker, RV, Tham, E, Thompson, C, Thorner, MO, Tóth, M, Trainer, PJ, Tsagarakis, S, Twine, G, Tzanela, M, Vadasz, J, Vaidya, B, Vaks, V, Vance, ML, Verkauskiene, R, Von Esch, H, Wass, JA, Waterhouse, M, Webb, S, Weber, A, Wernig, F, Widell, H, Yamada, S, Yap, P, Yarman, S, Yeoh, P, Yoshimoto, K, Yuen, K, and Zammitt, NN
- Abstract
Context\ud \ud Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).\ud \ud \ud \ud Objective\ud \ud To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.\ud \ud \ud \ud Design\ud \ud 12-year prospective, observational study.\ud \ud \ud \ud Participants & Setting\ud \ud We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.\ud \ud \ud \ud Interventions & Outcome\ud \ud AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).\ud \ud \ud \ud Results\ud \ud Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).\ud \ud \ud \ud Conclusions\ud \ud Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.
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- 2020
38. OR25-05 Increased Overall Mortality and Cardiovascular Morbidity in Patients with Adrenal Incidentalomas and Autonomous Cortisol Secretion: Results of the ENS@T NAPACA-Outcome Study
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Paola Loli, Abdullah Serkan Yener, Sabina Zacharieva, Carla Scaroni, Alessandro Prete, Irina Bancos, Massimo Terzolo, Tomasz Kocjan, Henrik Falhammar, Guido Di Dalmazi, Miomira Ivocic, Antonio Stigliano, Zulfiya Shafigullina, Timo Deutschbein, Giuseppe Reimondo, Valentina Morelli, Claudio Letizia, Katharina Langton, John Newell-Price, Kaltsas G, Martin Fassnacht, Stylianos Tsagarakis, Darko Kastelan, Kalliopi Pazaitou-Panayiotou, and Felicia A. Hanzu
- Subjects
Cortisol secretion ,0303 health sciences ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Outcome (game theory) ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Adrenal Medicine—Clinical Applications and New Therapies ,Internal medicine ,medicine ,In patient ,Adrenal ,business ,AcademicSubjects/MED00250 ,030304 developmental biology - Abstract
Objective. Several smaller studies on adrenal incidentalomas (AI) suggested an association between autonomous cortisol secretion (ACS) and mortality (Di Dalmazi Lancet Diabetes Endocrinol 2014, Debono J Clin Endocrinol Metab 2014, Patrova Endocrine 2017). However, a recent meta-analysis (9 studies, 1356 patients) could not confirm these findings (Elhassan Ann Intern Med 2019). Aim. To investigate the effects of ACS on mortality, prevalence of cardiovascular (CV) risk factors, and (CV) morbidity, in a representative cohort of AI. Design. Retrospective observational study conducted at 27 ENS@T centers from 15 countries. Methods. Inclusion criteria: AI diagnosed 1996-2015, 1 mg dexamethasone suppression test, follow-up (FU) of ≥36 months, known survival status. Exclusion criteria: clinically relevant adrenal hormone excess (i.e. Cushing’s syndrome, pheochromocytoma, primary hyperaldosteronism), known malignancy. Patient stratification: serum cortisol after dexamethasone (>5 µg/dl, ACS; 1.9-5 µg/dl, possible ACS (PACS); ≤1.8 µg/dl, non-functioning adenoma (NFA)). Definition of CV events (CVE): hospitalization due to myocardial infarction and related interventions (PTCA, surgical bypass), stroke, deep vein thrombosis, pulmonary embolism. Results. 3640 patients (57% NFA, 36% PACS, 7% ACS) were considered eligible: 64% females; median age 61 years (range 18-91); median FU 84 months (36-277) (distribution between subgroups n.s.). 352 patients died during FU. Age- and sex adjusted overall survival was significantly reduced in patients with PACS (HR 1.55; 95%CI 1.24-1.94) and ACS (1.84; 1.29-2.61). Prevalence of CV risk factors were significantly higher in PACS and ACS than in NFA (hypertension: 72, 73, 57%, p
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- 2020
39. SAT-142 Periodic Cushing Syndrome in a Patient with an Intestinal Neuroendocrine Tumor (NET). A Novel Case Report
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Kaltsas G, Ern Typhoxylou, Dimitrios Linos, Piaditis George, Th Kounadi, George P. Chrousos, and Nektaria Papadopoulou-Marketou
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medicine.medical_specialty ,endocrine system ,business.industry ,Endocrinology, Diabetes and Metabolism ,Intestinal Neuroendocrine Tumor ,medicine.disease ,Gastroenterology ,Cushing syndrome ,Internal medicine ,medicine ,Tumor Biology ,Tumor Biology: General, Tumorigenesis, Progression, and Metastasis ,business ,AcademicSubjects/MED00250 - Abstract
Introduction A major diagnostic enigma regarding ACTH-dependent Cushing syndrome is the distinction between the source of ACTH, which may have either a pituitary or ectopic origin. We present the first described patient with cyclic Cushing syndrome caused by an intestinal neuroendocrine tumour (NET) detected by 68GA-DOTATATE PET-CT, despite functional tests that were indicative of pituitary Cushing disease. Clinical Case A 53-year old man was admitted to outpatient clinic because of muscle weakness. His phenotype and clinical findings (progressively worsening upper and lower limb weakness, emotional disturbances, easy bruising, a Buffalo hump, prediabetes and leucocytosis) led to the diagnosis of Cushing syndrome. Initial laboratory tests established the diagnosis with an abnormal diurnal cortisol and ACTH secretion (night cortisol F: 22.1μg / dl), absence of suppression with dexamethasone 1mg and increased free urinary free cortisol 24h (243.5μg /24h). Abdominal CT scanning revealed a left-sided adrenal adrenocortical adenoma 1.5 mm in max diameter. Pituitary MRI and somatostatin scintigraphy were normal. Low dexamethasone suppression test was indicative of Cushing (F: 14μg / dl) followed by a combined CRH stimulation test during bilateral inferior petrosal sinus sampling. Pituitary / peripheral ACTH ratio pre-infusion of CRH and 3 min after CRH infusion was compatible with right-sided pituitary origin of ACTH hypersecretion. Pending the results of the laboratory, the patient showed a remission of his symptoms along with a laboratory-confirmed recession of active hypercortisolaemia (LDDST test), and this led to the suspicion of periodic Cushing syndrome. The patient was followed with clinical and laboratory examinations weekly, with recurrence of symptoms 2 months later followed by a new remission 3 months later. A PETGA CT SCAN with 68GA-HA-DOTATATE was performed, which showed an increased uptake of the radioisotope in the small intestine. A surgical excision of the affected small bowel region was performed according to the guidelines for intestinal NETs. Histology confirmed the existence of a well-differentiated neuroendocrine neoplasm of the small intestine of 1.1 cm diameter, grade 1 (WHO 2010). Immunophenotype was positive for serotonin and ACTH. Postoperatively, the patient showed a complete remission of symptomatology and regression of hypercortisolaemia over a 18-month period. Follow-up abdominal MRI and 68GA-HA-DOTATATE revealed no pathological findings. Conclusion: Our patient is the first case of ectopic Cushing disease caused by intestinal NET. The differential diagnosis between pituitary and ectopic Cushing syndrome due to ACTH or CRH hypersecretion is not easy and frequently complicated by the periodicity of the disease. In patients with no visible pituitary lesions on MRI we suggest further investigation for ectopic ACTH- driven Cushing syndrome.
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- 2020
40. Neoplastic metastases to the endocrine glands
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Angelousi, A. Alexandraki, K.I. Kyriakopoulos, G. Tsoli, M. Thomas, D. Kaltsas, G. Grossman, A.
- Abstract
Endocrine organs are metastatic targets for several primary cancers, either through direct extension from nearby tumour cells or dissemination via the venous, arterial and lymphatic routes. Although any endocrine tissue can be affected, most clinically relevant metastases involve the pituitary and adrenal glands with the commonest manifestations being diabetes insipidus and adrenal insufficiency respectively. The most common primary tumours metastasing to the adrenals include melanomas, breast and lung carcinomas, which may lead to adrenal insufficiency in the presence of bilateral adrenal involvement. Breast and lung cancers are the most common primaries metastasing to the pituitary, leading to pituitary dysfunction in approximately 30% of cases. The thyroid gland can be affected by renal, colorectal, lung and breast carcinomas, and melanomas, but has rarely been associated with thyroid dysfunction. Pancreatic metastasis can lead to exo-/endocrine insufficiency with renal carcinoma being the most common primary. Most parathyroid metastases originate from breast and lung carcinomas and melanoma. Breast and colorectal cancers are the most frequent ovarian metastases; prostate cancer commonly affects the testes. In the presence of endocrine deficiencies, glucocorticoid replacement for adrenal and pituitary involvement can be life saving. As most metastases to endocrine organs develop in the context of disseminated disease, surgical resection or other local therapies should only be considered to ameliorate symptoms and reduce tumour volume. Although few consensus statements can be made regarding the management of metastases to endocrine tissues because of the heterogeneity of the variable therapies, it is important that clinicians are aware of their presence in diagnosis. © 2020 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain.
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- 2020
41. Hypophysitis (Including IgG4 and Immunotherapy)
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Angelousi, A. Alexandraki, K. Tsoli, M. Kaltsas, G. Kassi, E.
- Abstract
Hypophysitis is characterized by inflammation of the pituitary gland that can be primary (PH) or secondary (SH) to other diseases or following drug administration. It may also be classified according to anatomical and histopathological criteria, leading to variable degrees of hypopituitarism and/or compressive symptoms to nearby structures. There has recently been an increase in the number of hypophysitis cases, raising the interest on the spectrum of its pathogenesis, clinical, biochemical/endocrinological, and imaging features. However, the use of conventional biomarkers, including currently utilized pituitary autoantibodies, has relatively limited diagnostic accuracy. Lymphocytic hypophysitis (LH) is the commonest cause of PH, whereas IgG4-related hypophysitis is increasingly being recognized. Histiocytosis and granulomatous diseases are the most frequent causes of SH, although infections and lymphoma have also been reported. The increasing use of immune checkpoint inhibitors in oncology is associated with a high incidence of hypophysitis, providing further understanding of its pathogenesis. Hypophysitis can occur silently and be easily missed, potentially leading to substantial morbidity or mortality due to adrenal insufficiency, requiring a high index of clinical suspicion and timely initiation of appropriate treatment. In most cases of LH or drug-induced hypophysitis, active surveillance along with replacement of established hormonal deficiencies is needed. In the presence of compressive and/or evolving symptoms, treatment with glucocorticoids either alone or in combination with other immunosuppressive agents can be used. Surgical decompression is reserved for nonresponsive cases with threatened vital structures. Timely diagnosis and intervention are important to minimize disease-related morbidity and mortality. We aimed to review current concepts and recent developments in the pathogenesis, diagnosis, and management of hypophysitis. © 2020 S. Karger AG, Basel. All rights reserved.
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- 2020
42. Managing ipilimumab-induced hypophysitis: Challenges and current therapeutic strategies
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Tsoli, M. Kaltsas, G. Angelousi, A. Alexandraki, K. Randeva, H. Kassi, E.
- Abstract
Over the past years, progress has been made in cancer immunotherapy following the development of immune checkpoint inhibitors (ICI) that have been proved effective in the management of many malignancies. Ipilimumab, a monoclonal antibody against cyto-toxic T-lymphocyte antigen-4 (CTLA-4), has been approved for the treatment of advanced melanoma but has been associated with the development of several endocrine immune-related adverse events (irAEs). Hypophysitis is the most common endocrine irAE related to ipilimumab with a reported incidence ranging from 1.8% to 17%. The mechanism under-lying ipilimumab-induced hypophysitis implicates immune, inflammatory and genetic fac-tors, but there are still some points that are not well understood and remain to be elucidated. The diagnosis is based mainly on clinical, biochemical and imaging data. The majority of patients display multiple hormone deficiencies that may recover or persist for a prolonged period of time with corticotroph deficiency usually being permanent. Immune-related hypo-pituitarism is treated with replacement of deficient hormones while in severe forms of hypophysitis treatment with high-dose glucocorticoids may be required. Proper evaluation and registration of patients in clinical trials and further investigation are needed to precisely clarify the pathophysiology of the ICI-related hypophysitis, define predictive factors and ameliorate the management and outcome of the disease. © 2020 Tsoli et al.
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- 2020
43. Expression of clock-related genes in benign and malignant adrenal tumors
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Angelousi, A. Nasiri-Ansari, N. Karapanagioti, A. Kyriakopoulos, G. Aggeli, C. Zografos, G. Choreftaki, T. Parianos, C. Kounadi, T. Alexandraki, K. Randeva, H.S. Kaltsas, G. Papavassiliou, A.G. Kassi, E.
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endocrine system - Abstract
Although the effect of the central clock system on adrenal function has been extensively studied, the role of the peripheral clock system in adrenal tumorigenesis remains largely unexplored. In this study we investigated the expression of clock-related genes in normal adrenocortical tissue and adrenocortical tumors. Twenty-seven fresh frozen human adrenal tissues including 13 cortisol secreting adenomas (CSA), seven aldosterone producing adenomas (APA), and seven adrenocortical carcinomas (ACC) were collected. CLOCK, BMAL1, PER1, CRY1, Rev-ERB, and RORα mRNA and protein expression were determined by qPCR and immunoblotting in pathological tissues and compared with the adjacent normal adrenal tissues. A significant downregulation of PER1, CRY1, and Rev-ERB compared with their normal tissue was demonstrated in CSA. All clock-related genes were overexpressed in APA compared with their normal tissue, albeit not significantly. A significant upregulation of CRY1 and PER1 and downregulation of BMAL1, RORα, and Rev-ERB compared with normal adrenal tissue was observed in ACC. BMAL1 and PER1 were significantly downregulated in APA compared with CSA. CLOCK, CRY1, and PER1 were upregulated, whereas BMAL1, RORα, and Rev-ERB were downregulated in ACC compared with CSA. Our study demonstrated the expression of CLOCK, BMAL1, PER1, CRY1, Rev-ERB, and RORα in normal and pathological human adrenal tissues. Adrenal tumors exhibited altered expression of these genes compared with normal tissue, with specific differences between benign and malignant lesions and between benign tumors arising from glomerulosa vs fasciculata zone. Further studies should clarify whether these alterations could be implicated in adrenocortical tumorigenesis. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
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- 2020
44. The risk of lymph node metastases and their impact on survival in patients with appendiceal neuroendocrine neoplasms: a systematic review and meta-analysis of adult and paediatric patients
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Daskalakis, K. Alexandraki, K. Kassi, E. Tsoli, M. Angelousi, A. Ragkousi, A. Kaltsas, G.
- Abstract
Background: There are no clear histopathological parameters determining the risk of lymph node (LN) metastases and appropriateness of completion prophylactic right hemicolectomy (RHC) in patients with appendiceal neuroendocrine neoplasms (ANENs). Materials and methods: The PubMed, Cochrane Library, Embase, Web of Science and SCOPUS databases were searched up to November 2018. Quality/risk of bias was assessed using the Newcastle–Ottawa Scale (NOS). Results: A total of 526 articles were screened. In 11 adult and 3 paediatric studies, 602 and 77 unique patients, respectively, with ANEN and undergoing RHC, were included. The rate of LN metastases for a cutoff size >10 mm was 48.6% (vs 12.1% for lesions 20 mm as well as >10 mm and/or vascular-, lymph vessel- and perineural invasions are associated with increased risk for LN metastases in adult patients with ANEN. The prognostic value of LN positivity remains to be determined in further studies with long-term follow-up. © 2019, The Author(s).
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- 2020
45. Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms
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Daskalakis, K. Alexandraki, K.I. Kloukina, I. Kassi, E. Felekouras, E. Xingi, E. Pagakis, S.N. Tsolakis, A.V. Andreakos, E. Kaltsas, G. Kambas, K.
- Abstract
Background/aims: We assessed the levels of autophagy and mitophagy, that are linked to cancer development and drug resistance, in well differentiated pancreatic neuroendocrine neoplasms (PanNENs) and correlated them with clinico-pathological parameters. Methods: Fluorescent immunostaining for the autophagy markers LC3Β and p62/or LAMP1 was performed on 22 PanNENs and 11 controls of normal pancreatic tissues and validated through Western blotting. Autophagy quantitative scoring was generated for LC3B-positive puncta and analysed in relation to clinico-pathological parameters. TOMM20/LC3B qualitative assessment of mitophagy levels was undertaken by fluorescent immunostaining. The presence of autophagy/mitophagy was validated by transmission electron microscopy. Results: Autophagy levels (LC3B-positive puncta/cell) were discriminative for normal vs. NEN pancreatic tissue (p = 0.007). A significant association was observed between autophagy levels and tumour grade (Ki67 < 3% vs. Ki67 ≥ 3%; p = 0.021), but not functionality (p = 0.266) size (cut-off of 20 mm; p = 0.808), local invasion (p = 0.481), lymph node- (p = 0.849) and distant metastases (p = 0.699). Qualitative assessment of TOMM20/LC3B demonstrated strong mitophagy levels in PanNENs by fluorescent immunostaining as compared with normal tissue. Transmission electron microscopy revealed enhanced autophagy and mitophagy in PanNEN tissue. Response to molecular targeted therapies in metastatic cases (n = 4) did not reveal any patterns of association to autophagy levels. Conclusions: Increased autophagy levels are present in primary tumours of patients with PanNENs and are partially attributed to upregulated mitophagy. Grade was the only clinico-pathological parameter associated with autophagy scores. © 2020, The Author(s).
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- 2020
46. Association of a palliative surgical approach to stage IV pancreatic neuroendocrine neoplasms with survival: A systematic review and meta-analysis
- Author
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Tsoli, M. Spei, M.-E. Wallin, G. Kaltsas, G. Daskalakis, K.
- Abstract
The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, Cochrane Library, Web of Science and SCOPUS databases up to January 2020 and used the Newcastle–Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5661 articles were screened. In 10 studies, 5551 unique patients with stage IV PanNEN and unresectable metastases were included. The five-year OS for PanNEN patients undergoing PPTR in stage IV was 56.6% vs. 23.9% in the non-surgically treated patients (random effects relative risk (RR): 1.70; 95% CI: 1.53–1.89). Adjusted analysis of pooled hazard ratios (HR) confirmed longer OS in PanNEN patients undergoing PPTR (random effects HR: 2.67; 95% CI: 2.24–3.18). Cumulative OS analysis confirmed an attenuated survival benefit over time. The complication rate of PPTR was as high as 27%. In conclusion, PPTR may exert a survival benefit in stage IV PanNEN. However, the included studies were subject to selection bias, and special consideration should be given to PPTR anchored to a multimodal treatment strategy. Further longitudinal studies are warranted, with long-term follow-up addressing the survival outcomes associated with surgery in stage IV disease. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2020
47. Authors' Response to the Letter by Lamarca et al. Entitled 'temozolomide-Capecitabine Chemotherapy for Neuroendocrine Neoplasms: The Dilemma of Treatment Duration' Regarding 'activity and Safety of Standard and Prolonged Capecitabine/Temozolomide Administration in Patients with Advanced Neuroendocrine Neoplasms'
- Author
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Chatzellis, E. Daskalakis, K. Angelousi, A. Tsoli, M. Alexandraki, K.I. Wachula, E. Meirovitz, A. Maimon, O. Grozinsky-Glasberg, S. Gross, D. Kos-Kudła, B. Koumarianou, A. Kaltsas, G.
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- 2020
48. Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study
- Author
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Partelli, S. Ramage, J.K. Massironi, S. Zerbi, A. Kim, H.B. Niccoli, P. Panzuto, F. Landoni, L. Tomazic, A. Ibrahim, T. Kaltsas, G. Bertani, E. Sauvanet, A. Segelov, E. Caplin, M. Coppa, J. Armstrong, T. Weickert, M.O. Butturini, G. Staettner, S. Boesch, F. Cives, M. Moulton, C.A. He, J. Selberherr, A. Twito, O. Castaldi, A. De Angelis, C.G. Gaujoux, S. Almeamar, H. Frilling, A. Vigia, E. Wilson, C. Muffatti, F. Srirajaskanthan, R. Invernizzi, P. Lania, A. Kwon, W. Ewald, J. Rinzivillo, M. Nessi, C. Smid, L.M. Gardini, A. Tsoli, M. Picardi, E.E. Hentic, O. Croagh, D. Toumpanakis, C. Citterio, D. Ramsey, E. Mosterman, B. Regi, P. Gasteiger, S. Rossi, R.E. Smiroldo, V. Jang, J.-Y. Falconi, M.
- Abstract
Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN 18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach. © Copyright © 2020 Partelli, Ramage, Massironi, Zerbi, Kim, Niccoli, Panzuto, Landoni, Tomazic, Ibrahim, Kaltsas, Bertani, Sauvanet, Segelov, Caplin, Coppa, Armstrong, Weickert, Butturini, Staettner, Boesch, Cives, Moulton, He, Selberherr, Twito, Castaldi, De Angelis, Gaujoux, Almeamar, Frilling, Vigia, Wilson, Muffatti, Srirajaskanthan, Invernizzi, Lania, Kwon, Ewald, Rinzivillo, Nessi, Smid, Gardini, Tsoli, Picardi, Hentic, Croagh, Toumpanakis, Citterio, Ramsey, Mosterman, Regi, Gasteiger, Rossi, Smiroldo, Jang and Falconi.
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- 2020
49. Pathogenesis and clinical management of mesenteric fibrosis in small intestinal neuroendocine neoplasms: A systematic review
- Author
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Koumarianou, A. Alexandraki, K.I. Wallin, G. Kaltsas, G. Daskalakis, K.
- Abstract
Mesenteric fibrosis (MF) constitutes an underrecognized sequela in patients with small intestinal neuroendocrine neoplasms (SI-NENs), often complicating the disease clinical course. The aim of the present systematic review, carried out by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, is to provide an update in evolving aspects of MF pathogenesis and its clinical management in SI-NENs. Complex and dynamic interactions are present in the microenvironment of tumor deposits in the mesentery. Serotonin, as well as the signaling pathways of certain growth factors play a pivotal, yet not fully elucidated role in the pathogenesis of MF. Clinically, MF often results in significant morbidity by causing either acute complications, such as intestinal obstruction and/or acute ischemia or more chronic conditions involving abdominal pain, venous stasis, malabsorption and malnutrition. Surgical resection in patients with locoregional disease only or symptomatic distant stage disease, as well as palliative minimally invasive interventions in advanced inoperable cases seem clinically meaningful, whereas currently available systemic and/or targeted treatments do not unequivocally affect the development of MF in SI-NENs. Increased awareness and improved understanding of the molecular pathogenesis of MF in SI-NENs may provide better diagnostic and predictive tools for its timely recognition and intervention and also facilitates the development of agents targeting MF. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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- 2020
50. The natural history and treatment of non-functioning pituitary adenomas (non-functioning PitNETs)
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Yavropoulou, M.P. Tsoli, M. Barkas, K. Kaltsas, G. Grossman, A.
- Abstract
Non-functioning pituitary adenomas, recently alternatively termed pituitary neuroendocrine tumours (NFpitNETs), are mostly benign neoplasms that are not associated with a hormonal hypersecretory syndrome. The clinical spectrum of NFpitNETs varies from completely asymptomatic to the development of panhypopituitarism and manifestations attributed to mass effects on nearby structures. NFpitNETs follow generally an indolent course, but in 5-10% of cases they exhibit more aggressive behaviour, characterised by rapid growth, invasiveness and early recurrence. The initial size of the adenoma, the presence of symptoms and the histological subtype are related to the natural course of NFpitNETs. Active surveillance is usually the strategy of choice in the case of an asymptomatic NFpitNET, while surgical resection is recommended in case of visual and/or neurological abnormalities or rapid tumour growth. Based on previous and emerging data, approximately 50% of patients show tumour growth, while 20% of patients with NF-macroadenomas on active surveillance may require further intervention during a follow-up period of 7 years. Adjuvant radiotherapy is usually considered for large residual tumours or recurrent and/or aggressive adenomas, but there is evidence that medical therapy, especially with cabergoline, can occasionally be beneficial, whereas newer molecular agents are under investigation. Thus, while highly effective medical therapy is awaited, a move towards a more conservative approach seems appropriate, at least until we have better molecular markers of progressiveness. © 2020 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain
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- 2020
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