[Survival predictors in patients with ectopic acth syndrome].

AIM: To determine significant factors affecting the survival of patients with ectopic ACTH syndrome (EAS). MATERIALS AND METHODS: A multi-center, observational study with a retrospective analysis of patients with EAS. The end point of the study was the fatal outcome of patients from various causes. In order to identify predictors of survival or mortality, univariate and multifactorial Cox regression analyses were carried out. ROC-analysis was used to determine the prognostic threshold values of individual predictors. The survival analysis was carried out using the Kaplan-Mayer method. Statistical data processing was carried out by using IBM SPSS Statistics 23. RESULTS: The age of patients at the time of diagnosis ranged from 12 to 76 years (Me 40 years [28;54]). The age of the studied population was 55 years [38; 64] for women and 42 years [32; 54] for men. The median period of observation was 50 months [13;91], with a maximum follow-up of 382 months. 92 patients (60,9%) had bronchopulmonary NET, 17 (11,3%) - thymic carcinoid, 8 - pancreatic NET, 5 -pheochromocytoma, 1- cecum NET, 1- appendix carcinoid tumor, 1 - medullary thyroid cancer and 26 (17,2%) patients had an occult NET. The primary tumor was removed in 101 patients (66,9%). Bilateral adrenalectomy was performed in 42 (27,8%) cases. Metastases were revealed in 23,2% (n=35) of patients. Relapse of the disease was observed in 24,4%, long-term remission was preserved in 64 patients (74,4%). Death occurred in 42 patients (28%). The average age of survivors was 47,0±15,2 versus 53,5±15,6 years for the deceased (p=0,022). The average survival time from diagnosis for the deceased was 32 months, Me 16,5 months [7;54]. Multivariate analysis revealed that the following factors have a direct impact on survival: age of diagnosis ≥51 years (OR 4,493; 95% CI 2,056-9,818, p<0,001), bronchopulmonary neuroendocrine tumor (NET) (OR 0,281; 95% CI 0,119-0,665, p=0,004), the presence of distant metastases (OR 2,489; 95% CI 1,141-5,427, p=0,022), late-night salivary cortisol (LNSC) ≥122,2 nmol/L (OR 2,493; 95% CI 1,014-6,128, p=0,047). CONCLUSION: The prognosis of patients with EAS is influenced by the age of diagnosis, NET localization, distant metastases and level of LNSC. The most common cause of ectopic ACTH syndrome was bronchopulmonary NET which was associated with the best survival rate.

[Clinical and laboratory characteristics and results of treatment of patients with ACTH-producing neuroendocrine tumors of various localization].

AIM: To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome EAS (ACTH adrenocorticotropic hormone ). MATERIALS AND METHODS: A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. RESULTS: The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 thymic carcinoid, 7 pancreatic NET, 5 pheochromocytoma, 1 cecum NET, 1 appendix carcinoid tumor, 1 medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) had relapse of the disease and 26 (20%) died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). CONCLUSION: In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

[Surgical treatment of ACTH-ectopic syndrome]. / Khirurgicheskoe lechenie AKTG-éktopicheskogo sindroma.

ACTH-ectopic syndrome is a severe, multiple-symptom disease characterized by secretion of adrenocorticotropic hormone (ACTH) by ectopic tumor, increased release of adrenal cortical hormones and clinical picture of hypercorticism. Diagnosis and treatment of ACTH-ectopic syndrome is still difficult problem despite the achievements of modern medicine. There are several unresolved issues including optimal diagnostic algorithm, indications for various surgical procedures and their optimal dates. This review is devoted to these questions.

[Evaluation of the biological behavior of ACTH-secreting pituitary tumors using various methods].

This literature review is aimed at studying markers obtained by various research methods to assess the biological behavior of ACTH-secreting pituitary tumors. This paper presents the clinical, laboratory, instrumental. histological, and immunohistochemical aspects of ACTH-secreting pituitary tumors. Histological method allows assessing the structures of a tumor and differential diagnosis of other pathological process in the sella turcica. Immunohistochemical method enables determining the expression of multiple markers (fibroblast growth factors, matrix metalloproteinases, apoptotic factors, pituitary tumor transforming gene, and vascular markers), which reflect various processes of oncogenesis of studied tumors, and according to the authors, are promising with regard to predicting biological behavior using corticotropin. Epigenetic investigations including the study of micro-RNA expression, proteomics, and transcriptomics are the new methods in this area, which are expected to provide additional details regarding the prediction using corticotropin. Thus, the cumulative assessment using laboratory and instrumental methods, the study of immunoexpression of malignant potential markers in the tissue using corticotropin and micro-RNA allow predicting the future biological behavior of ACTH-secreting pituitary tumors.

[Histological and immunohistochemical characteristics of ACTH-secreting tumors].

The histological and immunohistochemical characteristics of pituitary (corticotropinomas) and nonpituitary adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors (NET) were comparatively analyzed. The study included 46 corticotropinomas and 37 ectopic ACTH-secreting tumors. Removed NET tissue was investigated using routine histological and immunohistochemical techniques. A study of the morphofunctional characteristics of removed NETs yielded the following data: their ability to express ACTH, growth hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin in both in pituitary and nonpituitary NET tumors. Angiogenic markers (CD31 and VEGF) were found in equal frequency. The histological structure of all corticotropinomas suggested their benign origin while nonpituitary NETs had different morphological structures, malignancy and invasiveness grades, and metastatic properties. The highest cell proliferation potential (Ki-67) was discovered in NET in ectopic ACTH syndrome as compared to corticotropinomas.

Comparative Analysis of Clinical, Hormonal and Morphological Studies in Patients with Neuroendocrine ACTH-Producing Tumours.

This paper highlights the problem of neuroendocrine tumours (NETs) with clinical symptoms of hypercorticism caused by hypersecretion of adrenocorticotropic hormone (ACTH) by tumour cells. In most cases (85%), the tumours were localized in the pituitary gland (Cushing's disease); 15% of the patients had an extrapituitary tumour that manifest as an ectopic ACTH secretion (EAS). Comparative analysis of clinical, hormonal, histological, and immunohistochemical characteristics of pituitary and extrapituitary ACTH-secreting NET was performed. It included 46 patients with CD and 38 ones exhibiting ectopic ACTH secretion (EAS). Results of the study suggest differences between CD and EAS in terms of the severity of clinical manifestations and duration of the disease. Hormonal studies showed that EAS unlike CD was associated with high plasma ACTH and cortisol levels, late-evening salivary cortisol and daily urinary free cortisol, the absence of a 60% or greater reduction of cortisol in the HDDST test, and the presence of a low (less than 2) ACTH gradient in response to desmopressin administration with catheterization of cavernous sinuses. The study of morphofunctional characteristics of the removed NET demonstrated the ability of both pituitary and extrapituitary NETs to express ACTH as well as GH, PRL, LH, and FSH. The angiogenic markers (CD31 and VEGF) were detected with equal frequency regardless of the NET localization. The histological structure of all corticotropinomas suggested their benign origin, but extrapituitary NETs were represented by different morphological types with varying malignancy, invasiveness, and metastatic properties. A higher cell proliferation potential (Ki-67) was documented for NET in patients presenting with an ectopic ACTH secretion compared to those having corticotropinomas.

[Prognostic value of of the expression Ki-67, CD31, and VEGF in somatotropinomas].

Pituitary adenomas are benign, but 30-50% of patients do not achieve remission after treatment. The purpose of the study was to analyze the prognostic value of immunoexpression of the proliferation marker Ki-67 and the angiogenetic factors CD31 and VEGF in somatotropinomas. Ki-67, CD31, and VEGF were immunohistochemically studied in the samples of 52 somatotropin-removed samples; medical records were used to analyze the outcome of treatment in the early and late postoperative periods. Ki-67 immunoexpression proved to be significantly higher in the patients who had not achieve remission both in the early (p = 0.042) and late (p = 0.012) postoperative period than in those who had achieved remission and in patients who were resistant to postoperative treatment with somatostatin analogues (p = 0.040) than in those who were sensitive to therapy. The immunoexpression of CD31 and VEGF was not associated with the outcome of treatment. Thus, high Ki-67 levels may be regarded as a poor postoperative prognostic factor in acromegaly.

[Estrogen receptors in the diagnosis and treatment of hormone-dependent tumors].

The paper presents the current data available on the etiology of tumor diseases, among other things, shows the role of hormones, namely: estrogens and their receptors, in the mechanism responsible for the occurrence of these diseases. Each tumor was shown to have its receptor status and to be unresponsive to this or that therapy differently. The efficiency of treatment and its prognosis may be determined if the receptor composition of an involved organ is estimated correctly. The authors summarize the data available in the literature, as well as the results of their own investigations explaining the selective effect of estradiol receptor agonists and antagonists in various tissues. The mRNA varieties that potentially encoding for the synthesis of different subtypes of estrogen receptors (ER) - ER-α and ERß, which are also coded by various genes located in different chromosomes. Pituitary adenomas as hormone-dependent masses are described in detail. The authors data on the concentration of nuclear estrogen receptors in different types of adenomas are given.

[The first experience with selective blood collection from the inferior petrosal sinuses in Russia (case reports)].

This paper reports two clinical cases of ACTH-dependent hypercorticism. Difficulties encountered in differential diagnosis of this condition were due to poor informative value of routine diagnostic methods. The use of selective blood collection from the inferior petrosal sinuses (for the first time in Russia) greatly facilitated the choice of the adequate treatment strategy. A detailed description of clinical features of ACTH-dependent hypercorticism in two young women is presented along with the results of laboratory and instrumental studies. Technical aspects of selective blood collection from the inferior petrosal sinuses in conjunction with the desmopressin stimulation protocol are considered. Indications for the use of this diagnostic method under real clinical conditions are proposed. Results of the study are discussed with reference to the treatment strategy chosen for the management of ACTH-dependent hypercorticism and the outcome of surgical intervention.

[Significance of the method of selective blood collection from the inferior petrosal sinuses for differential diagnosis of ACTH-dependent hypercorticism].

This review paper was designed to discuss the accumulated worldwide experience with selective collection of blood from the inferior petrose sinuses for the purpose of differential diagnostics of ACTH-dependent hypercorticism. The history of the development of the method is described, principal indications and contraindications to its clinical application are considered with reference to the informative value of this diagnostic tool. Possible causes of false positive and false negative results as well as complications ever reported as associated with the diagnostic procedure are discussed. Much attention is given to the comparative analysis of advantages and disadvantages of alternative techniques for blood collection and to the use of pharmaceutical agents that may increase efficiency of the method under consideration.

[Efficacy and safety of bivalos therapy for postmenopausal osteoporosis. Results of Russian multicenter trial].

AIM: To study effects of one-year therapy with bivalos on mineral bone density (MBD) of the spine in patients with postmenopausal osteoporosis (PMO), effects of bivalos (strontium ranelate) on MBD of the neck of the femur and femur, the levels of bone metabolism markers, quality of life, tolerance of long-term therapy. MATERIAL AND METHODS: The study was made of 60 females aged 54-75 years with PMO. MBD was measured with x-ray absorptiometry in the vertebra and proximal femur. Bone markers in blood serum were detected by enzyme immunoassay. RESULTS: After a year of taking bivalos MBD in lumbar vertebra increased by 4.68 +/- 4.94%, in the neck of the femur--by 2.0 +/- 4.29%, in the proximal femur--by 3.10 +/- 3.34%. A significant 19.5% rise in bone alkaline phosphatase and a 16.5% fall in the level of CT were noted showing a stimulating effect of bivalos on bone formation and an inhibiting effect--on bone tissue resorption. Bivalos treatment raised quality of life of the patients: better motility, regress of depression, improved self-appraisal, decreased number of patients with pain in the spine, attenuated pain. The drug was well tolerated, unwanted effects arose in 15% patients, discontinuation of the drug because of toxicity occurred in 5%. Serious side effects were not observed. CONCLUSION: Strontium ranelate is effective in PMO and is well tolerated.

[Sex hormone receptors in pituitary prolactinomas].

An attempt was made to interpret the mechanism responsible for the occurrence of pituitary tumors - prolactinoma in persons of different sex. The presence or absence of androgenic receptors in the tumors was studied. Analysis of the concentration of nuclear receptors, estrogen ones in particular, showed their higher concentration in prolactin-positive pituitary adenomas than in inactive pituitary adenomas. Androgen receptors were detected in the gonadotropic and lactotropic cells of the Intact pituitary. Analysis of the concentration of nuclear testosterone receptors in different morphological types of pituitary adenomas revealed no differences in the luteinizing hormone/follicle-stimulating hormone-positive and prolactin-positive tumors.

[Postoperative prognosis in acromegaly: a role of immunohistochemical markers].

The aim of the investigation was to examine the markers of tumor progression in pituitary adenomas in acromegalic patients and to study their relationship to the poor postoperative predictive factors. Case histories were analyzed in 39 arcomegalic patients undergone transphenoidal adenomectomy as the method of choice at the Endocrinology Research Center, Russian Academy of Medical Sciences. The immunohistochemical technique was used to explore Ki-67, CD31, and galectin-3 in the cells of removed adenomas. Young age, high postoperative growth hormone (GH) levels, a large adenoma, and signs of its paracellular dissemination were poor postoperative predictors. Ki-67 was present In 9 (23%) of the 39 patients, CD31 in 16 (31%), galectin-3 in 11 (28%), and prolactin in 9 (23%). The preoperative GH levels were significantly higher in patients with positive immunostaining for the potential malignancy marker galectin3 and the angiogenetic marker CD31. The cell proliferation marker Ki-67 was present only in adenomas positive for prolactin. Positive immunostaining for Ki-67 and prolactin correlated with large adenoma sizes and intracavernous extension.

[Vitrum osteomag in prevention of osteoporosis in postmenopausal women: results of the comparative open multicenter trial]. / Vitrum osteomag v profilaktike osteoporoza u zhenshchin v postmenopauze: rezul'taty sravnitel'nogo otkrytogo mnogotsentrovogo issledovaniia.

AIM: To investigate efficacy, tolerance and safety of the drug vitrum osteomag one tablet of which contains 600 mg calcium (1500 mg calcium carbonate), 200 IU of cholecalcepherol, 40 mg of magnesium, zinc (7.5 mg), copper (1 mg), manganese (1.8 mg) and boron (250 mcg) in women with osteopenia for prevention of osteoporosis. MATERIAL AND METHODS: A multicenter comparative open trial of vitrum osteomag influence on mineral bone density (MBD), change of pain syndrome in bones, index of calcium-phosphorous metabolism covered 334 postmenopausal women with osteopenia. MBD was measured in low-back spine and proximal part of the hip with DEXA method. All the patients were divided into 3 groups: 125 women taking 2 tablets of vitrum osteomag daily for 12 months (group 1); 111 women taking 1500 mg calcium carbonate (group 2); 96 women--control group (only observation). RESULTS: Vitrum osteomag relieved pain in the back and joints, had a positive effect on bone density (+1.5%) and proximal parts of the hip (0.6-0.93%) exceeding the effect of calcium carbonate only which preserves the initial MBD in low back spine but does not prevent bone loss in the hip. MBD dynamics in patients given vitrum osteomag differs essentially from one in the control group (from -1.9 to -2.91%) which demonstrates a reliable preventive anti-osteoporotic effect of this medication. The drug increases the level of general and ionized calcium in blood but does not cause hypercalcemia lowering the level of parathormone in blood. The rate of side effects in group 1 was 14.4% and did not differ much from that in group 2 (16.2%). CONCLUSION: The results of the study allow to recommend vitrum osteomag for prophylaxis of a rapid loss of bone tissue mineral density.

Antibodies to pituitary surface antigens during various pituitary disease states.

Autoantibodies to cell surface antigens of human somatotropinoma (ASAS), human prolactinoma (ASAP) and rat adenohypophysis (ASARA) were assayed in the serum of patients with pituitary diseases associated with GH deficiency (GHD), such as pituitary dwarfism and primary empty sella syndrome (ESS), and in the serum of patients with hyperprolactinaemia of different etiologies: idiopathic hyperprolactinaemia, prolactinoma and ESS. The investigation was carried out with a cellular variant of an ELISA. Among children with GHD, the highest percentage of antibody-positive patients was found in the group with idiopathic isolated GHD (89% of ASAS(+) patients and 30% of ASARA(+) patients vs 33.3% and 0% respectively in the group with idiopathic combined pituitary hormone deficiency, and 33.3% and 9% in patients with pituitary hypoplasia associated with isolated GHD or combined pituitary hormone deficiency). Among hyperprolactinaemic patients, the highest ASAP and ASARA frequency was observed in patients with idiopathic hyperprolactinaemia (67.7% and 41.9% respectively) where it was twice as high as in the group of patients with prolactinoma. The proportion of ASAS(+) and ASARA(+) did not differ significantly between the groups of patients with ess with or without GHD. Similarly, there was no significant difference between the number of ESS ASAP(+) and ASARA(+) patients with or without hyperprolactinaemia. The data obtained suggested that autoimmune disorders may be primary, and responsible, at least in part, for pituitary dysfunction in the cases of idiopathic isolated GHD and idiopathic hyperprolactinaemia. At the same time, the autoimmune disorders in the patients with prolactinoma or ESS are probably secondary to the organic pituitary lesion and their significance in the development of the pituitary dysfunction is obscure.

Role of sex hormones in development of pituitary adenoma.

Role of sex hormones in the development of pituitary adenomas was investigated by analyzing the content of nuclear estradiol and testosterone receptors in different tumors of the anterior pituitary: prolactinomas, meningiomas, growth hormone-producing adenomas, astrocytomas, neurinomas, and ependymomas. The concentration of nuclear estrogen and androgen receptors in prolactin-secreting pituitary adenomas was much higher than in growth hormone-producing adenomas and other pituitary tumors.

[Functional morphology and prognosis of hormonally-active pituitary adenomas]. / Funktsional'naia morfologiia i prognoz gormonal'no-aktivnykh adenom gipofiza.

This paper is a review of literature on the etiology, pathogenesis and morphogenesis (electron microscopy, immunocytochemistry) of pituitary adenomas (PA). Clinical manifestations of PA are considered depending on their structure. Approaches to the clinico-morphological classification of PA and factors of their prognosis are discussed.

[Role of autonomic nervous system in pathogenesis and clinical manifestation of arterial hypertension in Icenko-Cushing disease]. / Rol' vegetativnoi nervnoi sistemy v patogeneze i klinicheskikh proiavleniiakh arterial'noi gipertonii pri bolezni Itsenko-Kushinga.

AIM: To study the role of autonomic nervous system (ANS) in pathogenesis and clinical symptoms of arterial hypertension (AH) in Icenko-Cushing disease (ICD). MATERIALS AND METHODS: Clinical and paraclinical parameters (vegetative reflexes, special tables, 10 words memory and Spilberg's tests, ECG, electroencephalography, computed tomography, MR-tomography, hormonal status) were studied in 48 ICD patients before and after treatment (adenomectomy, irradiation of the hypophysis, adrenalectomy, parlodel, chlotidin chemotherapy). RESULTS: 94.5% of patients with active ICD had blood hypertension and vegetovascular asthenia. There was a trend to cerebrovascular impairment. In spite of biochemical and clinical ICD remission lipothemia persisted in many patients. CONCLUSION: Pathogenesis of blood hypertension in ICD is related to hypersecretion of ACTH and corticosteroids but further progress of the disease depends on phenotypic features of autonomic nervous system and developing defects of CNS.