ACTA ENDOCRINOLOGICA (BUC)

Denosumab,a monoclonal IgG2 antibody directed against RANK-L,is used as a neoadjuvant therapy for inoperable or metastatic giant cell tumor of bone. Many side effects like as hypocalcemia during treatment and rarely severe hypercalcemia especially in children after discontinuation of denosumab occurred. The unpredictable onset and recurrent episodes of severe hypercalcemia increase the duration of hospitalization and the risk of complications. Persistent hypercalcemia and difficulties in management have prompted the search for different more effective therapeutic options. Objectives. To share our experience with the use of oral bisphosphonate in acute and long-term therapy of severe hypercalcemia following high-dose denosumab therapy and to review the literature on this subject Case. We report the management of a case of severe hypercalcemia that developed 4 months after the completion of 18-month denosumab treatment in a 9-year-old girl who was followed up with a giant cell bone tumor for 6 years. Based on an evaluation aiming to determine etiology, hypercalcemia was considered as "rebound-linked" upon denosumab discontinuation. Severe hypercalcemia attacks recurring with an interval of 2 weeks were treated with IV bisphosphonate, but when mild hypercalcemia developed again, treatment with 70 mg per week of oral bisphosphonate was planned. After the second dose of alendronate, the calcium level always remained below 10.5 mg/dl. In the 14-month follow-up, no hypercalcemia attack was observed again. Results. Rebound hypercalcemia can occur as an unpredictable recurrent episode at any time after denosumab cessation. Thus, the patient should be closely monitored especially in childhood due to rapid bone cycle. In longterm follow-up, oral biphosphonates can be used effectively to reduce hospitalization time and the management of especially life-threatening recurrent attacks.

Hypoglycemia from a non-insulin-secreting extrapancreatic tumor is a paraneoplastic syndrome characterized by the tumor production of a substance with an insulin-like effect (insulin-like growth factor 1 or 2 - IGF 1 or 2). Diagnosis is confirmed by the determination of IGF-1 and IGF-2 and finding an elevated IGF - 2/IGF- 1 ratio. The availability of these tests is limited in many laboratories, so prompt recognition and therapies are late. We present the case of a 70-year-old patient diagnosed with right lower lobe bronchopulmonary neoplasm who presented to the emergency department with an altered general condition and hypoglycemic coma. The evaluation revealed low levels of insulin and C-peptide along with an elevated IGF-2/IGF-1 ratio of more than 10, suggesting a diagnosis of lung sarcoma with production of IGF-2. Because the tumor could not be resected in this case, chemotherapy and radiotherapy were performed, along with glucocorticoid therapy to prevent recurrent hypoglycemia. In the case of a patient with lung sarcoma and recurrent hypoglycemia (especially severe hypoglycemia or coma), extrapancreatic non-hyperinsulinemic hypoglycemia should be determinate tumor IGF-2 secretion.

Based on epidemiological, clinic, biochemical and hormonal data (both personal and\r\ninternational), our personal view is that natural history of autoimmune type 1 diabetes could\r\ninclude the following stages: 1) The presence of a complex genetic predisposition towards ?\r\ncell autoimmunity (possibly “latent” until death); 2) The “initiation” of autoimmunity in\r\nsubjects carrying a defect in the post-translational processing of pre-proinsulin/ proinsulin/\r\ninsulin, manifested precociously as increased proinsulin-to-insulin ratio; 3) Stimulation by the\r\nincreased proinsulin of the plasmacytoid dendritic cell clones capable to capture the natural\r\nantigens (proinsulin/insulin, Glutamic Acid Decarboxylase, etc.) from the pancreatic beta\r\ncells; 4) Activation of the process generating reactive T cell clones (Teffs) in the detriment of\r\nprotective immuno-regulatory T cell clones (Tregs), triggering the anti-beta cell attack,\r\nexpressed as autoimmune insulitis and/or the presence of circulating anti beta cell antibodies;\r\n5) The onset of the beta cell apoptosis process mediated by pro-inflammatory cytokines (IFN\r\n?, TNF ?, IL6) or by the direct contact between Teffs and the beta cells; 6) Identification of\r\nthe first secretory beta cell defects (the loss of the first phase insulin response followed by the\r\nprogressive decrease of the area under the insulin curve and the progressive increase of the\r\narea under the blood glucose curve) while fasting glycemia is still normal; 7) The progressive\r\nloss of the beta cell mass. All these processes take place during the pre-hyperglycemic stage\r\nof diabetes, with a higher or lower speed depending on the genetic background. The overt\r\nclinical stage of diabetes, marked by the presence of hyperglycemia, occurs rather late, when\r\nmore than 90% of the beta cell function/mass is irreversibly lost.

Aim. To investigate the cause of infertility in an azoospermic man and to describe the phenotype of a new 46,XX male case. Case report. We present the case of an infertile man, 33 years old, with a history of several years of infertility, diagnosed with the 46,XX male syndrome, SRY positive. The patient was diagnosed by clinical, hormonal, ultrasound and genetic criteria. Our patient was born at 39 weeks of pregnancy, from unrelated parents. The mother’s age was 22 years old and father’s age was 23 years old at the time of the conception. Both of his parents were exposed to chemical noxae before his conception. The case we report is a SRY positive 46,XX male with complete masculinization, confirmed by FISH and molecular analyses, caused by an X/Y chromosome inter-change during paternal meiosis. Conclusions. In our case, the SRY translocation, could probably be related to the paternal exposure to external factors like chemical noxae, but more data are necessary. Cytogenetic and molecular analyses are necessary for an accurate diagnosis, as well as endocrine testing and pelvis ultrasound.

Melanoma has a significant mortality and its growing incidence is associated with important social and health care costs. Thus, investigation of the complex mechanisms contributing to emergence and development of melanoma are of real interest both in scientific research and clinical practice. Estrogens play an important role in the emergence and development of certain types of cancer, such as breast cancer, endometrial cancer and ovarian cancer, but their role in development of cutaneous melanoma is still a matter of debate. Various data suggest that increased levels of endogenous estrogens during pregnancy or exposure to exogenous estrogens by use of oral contraceptives (OCs) and hormone replacement therapy (HRT) may have a potential role in melanoma development and progression. Moreover, there were revealed several intracellular pathways which can support the connection between estrogens, estrogen receptors (ER) and melanoma. While ER-β plays an antiproliferative role, ER-α promotes cell growth and cellular atypia. Thus, inhibition of ER-β activity in the skin can increase the risk for development of cutaneous melanoma and spread of metastatic cells. However, despite recent advances in this area, the exact role and clinical implications of estrogens and estrogen receptors in melanoma are still not entirely understood and require further investigations

Epidemic of obesity is ongoing and did not slow down. Causes of obesity are numerous and very complex. Among them, the concept of bidirectional signaling within the brain-gut-microbiome axis was recently proposed as possible pathophysiological mechanism and become a hot topic in the explanations for the control of food intake. Discoveries of new anti-obesity drugs that are analogs for the receptors for some hormones derived from gastrointestinal tract contribute to the investigations in this area. The human gut microbiota plays a fundamental role in human health and disease and it is considered that it represent an endocrine organ that participate in energy homeostasis and host immunity. Role of gut microbiome has been investigated in metabolic diseases such as obesity, type 2 diabetes and non-alcoholic fatty liver disease. Gut microbiome participate in regulation of various mechanisms inside the gastrointestinal tract due to its production of different bacterial metabolites. In our manuscript we present current knowledge about microbiota in the gut; the relation between gut microbiota and brain; neuroendocrine system and gut-brain axis; immune system and gut-brain axis; endocrine system and gut-brain axis; the role of gut microbiota in obesity development and possible use of gut microbiota for the treatment of obesity.

The topic of fertility preservation has been gaining increasing importance since the beginning of this century. The reasons for this development are the advances in oncological therapy over the past few decades, with cure rates of approximately over 90%, and the fact that starting families is increasingly postponed in later periods of life in industrialized countries. Since March 2020 the whole medical and non-medical world experiences a pandemic due to Covid-19 (coronavirus disease 2019) which has never been seen before. This created a plenty of challenges for both, the patients and healthcare providers. This review article presents the fertility-protective methods currently available for women and men suffering from cancer with their clinical approach, value, advantages and disadvantages. Besides, it focuses on the changes and special considerations which have to be taken into account during pandemic times including preventive measures as well as the patient`s access to the fertility preserving options. In conclusion every premenopausal woman and every man with incomplete family planning suffering from cancer should be counselled about the existing fertility preserving techniques before commencing cancer therapy.

-

Anaplastic thyroid cancer (ATC) is a highly uncommon (less than 2% of thyroid malignancies) and aggressive type of cancer, with aggressive behavior and, therefore, exhibiting poor prognosis. ATC tumors are automatically labeled as stage IV disease regardless of standard criteria such as tumor burden or metastasis. ATC tumors require a diversified treatment approach that includes surgical resection, followed by a complete an aggressive combination of radiation and chemotherapy and/or palliative care. Despite best efforts, 1-year overall survival of patients is 20% to 40% with nearly universal mortality rate. Consequently, novel approaches (targeted therapy, immunotherapy) have been studied, alone or in combination, to improve the dire prognosis of these patients. BRAF V600E mutation is the most common genetic mutation found in ATC. We report the case of a 57-year-old man diagnosed with stage IVc (undifferentiated) ATC with hepatic and osseous metastases. The molecular analysis of the tumor revealed a V600E BRAF-mutation. The patient was treated with Dabrafenib and Trametinib, and achieved remission 5 weeks after starting the treatment. Subsequently, he had a thyroidectomy, and pembrolizumab was added to the two tyrosine kinase inhibitors. 9 months later he is still in remission. This case illustrates the importance of obtaining molecular information in anaplastic thyroid cancer and the urgent need of studies investigating the combination of tyrosine kinase inhibitors and check-point inhibitors in patients with V600E BRAF- mutations.