[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.

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.

[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.

[Early and late results of neurosurgical treatment with Itsenko-Cushing disease].

То study the efficiency of neurosurgical treatment of the Itsenko-Cushing disease (1CD), the authors analyzed the early and late results of adenomectomy in 99 patients (90 females and 9 males) with ICD. The diagnosis of ICD was verified on the basis of hormonal studies, functional tests, and the results of topic diagnosis. All the patients had an active stage of the disease and a pituitary tumor, as evidenced by magnetic resonance Imaging (MRI). Out of the 99 patients, 75% had a microadenoma of the pituitary and 25% had its macroadenoma. No correlation was found between the sizes of a tumor, the duration of the disease, and the severity of hy-percorticism. The Indication for surgery was a well-defined localized pituitary tumor as verified by MRI. The patients tolerated a neurosurgery well and complications as incoming diabetes insipidus were observed only in 12%, which is in agreement with the data available in the literature. Algorithms were developed for postoperative management of these patients. The findings have indicated that the development of the hormonal and clinical signs of hypocorticism serves as a good predictive marker of a radically performed operation. Six months after surgery, 82% of the patients were at remission. At an average 8.6-year follow-up, remission continued to be in 69(85.2%) of 81 patients. After surgery, patients with ICD should be, however, followed up since 14% developed a recurrence in the late postoperative period.

[Drug treatment for acromegaly: results of long-term use of Sandostatin LAR].

То evaluate the effectiveness and safety of drug treatment for acromegaly, the authors conducted an open-labeled prospective study of the impact of treatment with long-acting octreotide Sandostatm LAR) on the content of growth hormone (GH) and IRF-1 and on the size of a pituitary tumor. The study covered 40 patients (28 females and 12 males) aged 21 to 65 years (median 45 years) who had active acromegaly; 4 (10%) patients were diagnosed as having pituitary microadenoma; 36 (90%) had pituitary macroadenoma. Twenty-four patients received no therapy; 16 patients had tumors after their ineffective removal. All the patients took Sandostatin LAR, 20 mg intramuscularly, once every 28 days. The mean duration of treatment was 8.25 months (range: 3 to 12 months). Clinical and hormonal parameters were estimated 3, 6, and 12 months of treatment. A treatment-induced decrease in GH and/or insulin-like growth factor 1 (ILGF-1) by at least 30% of their baseline values considered effective. The state of a tumor was evaluated by brain magnetic resonance imaging in 26 patients. Three month following Sandostatin LAR treatment, the median concentration of GH significantly decreased from 33.5 to 5.55 ng/ ml (p < 0.001) and later on it remained nearly at this level (5.1 ng/ml and 5.35 ng/ml after 6 and 12 months, respectively). The concentrations of ILGF -1 similarly changed: its median was 779 ng/ml at baseline, 390 (p < 0.001), 390, and 330 ng/ml after 3, 6, and 12 months, respectively. Following 12 months of treatment, there were reductions in GH levels in 52.2% of the patients (including a < 2.5-ng/ml reduction in 33.3% of the patients) in the concentration of ILGF-1 by more than 50% of the baseline values in 49.9% (including a complete ILGF-1 concentration normalization in 33.3%). Twelve months after treatment, there was a reduction in the size of a tumor in 38.4% of the patients (by an average of41.25±7.22% of the baseline volume) and its growth stabilization in 59.1%. The findings suggest that treatment with Sandostatin LAR in a dose of 20 mg Is an effective and safe treatment, leads to a significant reduction in the values of GH and IL GF-1 just 3 months after treatment, and controls hormonal secretion and tumor growth in most patients with acromegaly.

[Effect of desmopressin on the production of corticosteroids in patients with different forms of hypercorticism].

То investigate the direct effect of desmopressin (DP), a vasopressin agonist, on the adrenal cortex, the authors studied a response of the pituitary and all three adrenal cortical areas in patients with different forms ofhypercorticism (active stage): ACTH-dependent Itsenko-Cushing syndrome, ectopic ACTH-dependent syndrome, corticosteroma. The levels of ACTH, cortisol, dehydroepiandros-terone sulfate, and aldosterone were used to assess a response to DP 15, 30, 60, 90, and 120 minutes after administration. There were several types of a response of corticosteroids to DP: 1) an increase in the level of ACTH and, subsequently, in the concentration of either all test steroids, one of the steroids, or two steroids in different combinations; 2) an elevation of the concentration of steroids in different combinations irrespective the response of ACTH to DP. Thus, there are patients with hypercorticism whose adrenals respond to DP by the higher synthesis and secretion of glucocorticoids (cortisol), mineralcorticoids (aldosterone), and adrenal androgens (dehydroepiandrosterone sulfate). The findings suggest that there are "ectopic" receptors to vasopressin in the adrenal cortex of patients.

[The results of neurosurgical treatment in Itsenko-Cushing's disease]. / Rezul'taty neirokhirurgicheskogo lecheniia bolezni Itsenko--Kushinga.

Fifty three consecutive patients with Cushing's disease were operated on in the Neurosurgical Institute from 1987 to 1995. In all cases the diagnosis was based on clinical and laboratory data, as well as radiographic images. Ten patients with false-negative CT scans had MRI confirming the presence of microadenomas less than 5 mm in size. The majority of patients (n = 51) were operated via transsphenoidal approach, transcranial route was utilized in 2 cases. Among the pathological findings, corticotropinomas were revealed in 49 cases, 4 patients were considered to have hyperplasia of the anterior pituitary without well demarcated adenoma. All patients were divided into 2 groups based on the history of previous treatment. Group 1 included 37 primary patients who had not been treated before admission. Group 2 included 16 patients treated surgically (e.g. neurosurgical operations, bilateral/unilateral adrenalectomy), or with irradiation therapy, including proton beam irradiation prior to admission. We came to conclusion that the following principles were essential in the management of Cushing's disease. 1. Properly interpreted clinical signs and symptoms along with biochemical data and radiographic imaging (including MRI) are extremely helpful in the preoperative evaluation of such patients. Our approach helped us reveal corticotropinomas with 98% accuracy. 2. Microsurgical removal was proved to be effective in up to 83% of patients, which was demonstrated by clinical and biochemical remission. 3. It should be emphasized that the results of treatment were significantly better in the first group versus the second one. In group 1, remission was reached in 91.1% of patients as compared to 62.5% in Group 2. 4. In primary patients, the trauma associated with surgical procedure is less and tumors demonstrate a less aggressive biological behavior.

[Diagnosis and surgical treatment of microcorticotropinomas]. / Diagnostika i khirurgicheskoe lechenie mikrokortikotropinom.

Microsurgical selective removal of hypophyseal adenomas is more and more frequently used in the treatment of Itsenko-Cushing's disease of late. This permits complete cure of approximately 90% of the patients. Ten patients with this disease, induced by corticotropinoma, were observed. The hormonal methods, as well as computer-aided tomography and NMR tomography, were used to diagnose the condition. A high resolving power of these methods for the diagnosis of this disease is noteworthy. The authors describe the method for microadenoma detection during the operation and present the data of hormonal studies after selective adenomectomy. They emphasize that in cases when clinical data are supported by the hormonal and x-ray findings that confirm the presence of a microcorticotropinoma in Itsenko-Cushing's disease transsphenoidal adenomectomy must be the method of choice for the treatment of such patients.

[Changes in immunochemical properties of serum ferritin after its post-translation modification with glucose in patients with diabetes mellitus]. / Izmeneni immunokhimicheskikh svoistv ferritina syvorotki v rezul'tate posttransliatsionnoi modifikatsii gliukozoi u bol'nykh sakharnym diabetom.

The paper is concerned with experimental and clinical problems. Posttranslation modification of ferritin with glucose has been shown to cause change of its immunochemical properties. Changes in iron metabolism and in the level of glycosylated hemoglobin A1c were noted in patients with different forms of diabetes mellitus.

[Dynamics of the content of immunoreactive insulin and sugar in the blood during tests with glucose, tolbutamide and leucine in patients with Cushing's syndrome]. / Dinamika soderzhaniia immunoreaktivnogo insulina i sakhara v krovi vo vremia prob s gliukozoi, tolbutamidom i leitsinom u bol'nykh s bolezn'iu Itsenko-Kushinga.

This work was aimed at the study of reserve capacities of the insular apparatus of the pancreas during the glucose tolerance test, and the test with tolbutamide and leucine in patients with Itsenko-Cushing's disease. The mentioned patients showed an increase in the immunoreactive insulin (IRI) level on the fasting stomach and a fall of the regulatory capacities of the insular apparatus of the pancreas; this was expressed in a later and high increase in the IRI level during the tests.

[The concentration of 17-OHKS and glucose in the blood during the insulin test in patients with hypothalamo-hypophyseal diseases]. / Soderzhanie 17-OKS i gliukozy v krovi vo vremia insulinovogo testa u bol'nykh a gipotalamo-gipofizarnymi zabolevaniiami

A study was made of the hypothalamo-hypophysio-adrenal gland interrelations during the insulin test in patients with Itsenko-Cushing disease, dyspituitrism of the puberto-juvenile period and diencephalic syndrome. The majority of the patients with Itsenko-Cushing disease displayed a reduction of insulin sensitivity, this being expressed in a delayed fall of the glucose level during the insulin test and the absence of any increase in the blood 17-OCS. An increased reaction of the hypothalamo-hypophysio-adrenal system to insulin hypoglycemia was observed in the patients with dyspituitrim of the puberto-juvenile period. A normal reaction to the insulin test was seen in all the patients with the diencephalic syndrome. The data obtained could be used in differential diagnosis between these diseases and Itsenko-Cushing disease.