The NETest liquid biopsy is diagnostic for gastric neuroendocrine tumors: observations on the blood-based identification of microscopic and macroscopic residual diseaseOK.

BACKGROUND: NETest, a novel multi-gene liquid biopsy has utility in neuroendocrine tumor (NET) diagnosis and identification of residual disease. We independently assessed utility of the NETest to diagnose gastric neuroendocrine neoplasms (GNENs) and identify micro- and macroscopic residual disease. METHODS: Cohorts comprised histologically confirmed GNENs at biopsy, n = 46; GNETs Type 1: 42 (32 NET G1, 10 NET G2), a GNET Type 3: 1 well-differentiated NET G3, neuroendocrine carcinomas (NECs) (n = 3), and controls (n = 63). Disease status at sampling was assessed by gastroscopy, histology (resection margin [R] positivity of polypectomy or biopsy), EUS, CT or MRI, and/or 68Ga-DOTA-TATE PET/CT. Groups included image- (gastroscopy, EUS, and anatomical and/or functional imaging) positive or image negative disease. NETest assay by PCR (spotted plates, normal cut-off: 20). DATA: mean ± SD. RESULTS: Disease extent: Image-negative (n = 30) (21 R0, 9 R1); Image-positive, n = 16. DIAGNOSIS: NETest was increased in GNETs (23 ± 11) vs. controls (7 ± 4, p < 0.0001). In histology-positive, the NETest accuracy was 100% (25/25). Microscopic disease: In image-negative but R1, NETest was elevated in 100% (9/9; 28 ± 9). Levels were elevated vs. controls (7 ± 4, p < 0.0001), or R0 (16 ± 11, p = 0.02). Eight of 21 R0, exhibited positive NETest. Macroscopic disease: Gastric lesions were multiple: 38%, single: 62%, submucosal: 13%, or ulcerated: 13%. Lesions size was ≤5 mm (50%), > 5-9.9 mm (17%), 10-19.9 mm (17%), ≥20 mm (17%) [≥10 mm: 34%). The NETest accuracy was 100% (16/16). Levels (28 ± 7) were higher than controls (7 ± 4, p < 0.0001) or R0 (16 ± 11, p = 0.002) but not to R1 (28 ± 9, p = 0.5). CONCLUSIONS: NETest is diagnostic for gastric NETs. Elevated levels identify both microscopic and macroscopic residual disease. In histology/image-negative disease, elevated NETest may reflect early evidence of increased neuroendocrine gene expression of hypergastrinemia-induced neoplastic transformation of enterochromaffin-like (ECL) cells to tumor status. A sensitive liquid biopsy has utility in the management and surveillance of gastric NET disease.

Serum concentrations of HGF and IL-8 in patients with active Graves' orbitopathy before and after methylprednisolone therapy.

INTRODUCTION: Graves' disease is the most common cause of hyperthyroidism, and orbitopathy is the most frequent extrathyroidal manifestation of Graves' disease. The aims of this study were as follows: (1) to evaluate the serum concentration of HGF and IL-8 in the blood of newly diagnosed Graves' disease patients with the first episode of active GO and healthy controls; (2) to estimate the influence of the thyroid function (euthyreosis vs. hyperthyreosis) on HGF and IL-8 blood levels in patients with active GO; (3) to evaluate the influence of intravenous (i.v.) methylprednisolone (MP) pulse therapy and additional oral MP treatment on HGF and IL-8 blood levels in patients with active GO. PATIENTS AND METHODS: Thirty-nine Graves' disease patients with the first episode of clinically active GO (Group A) were enrolled in the study. To estimate the influence of the thyroid function on serum concentrations of the studied proangiogenic factors, Group A was divided into Group A I (n = 18) in euthyroid and Group A II (n = 21) in hyperthyroid stage of Graves' disease in moderate-to-severe stage of GO. The control group consisted of 20 healthy volunteers age- and sex-matched to the GO group. Concentrations of the studied proangiogenic factors in serum samples were measured by an enzyme-linked immunosorbent assay before (Group A) and after (Group A1) intensive pulse i.v.MP treatment and 1 month after the end of additional oral MP treatment (Group A2). RESULTS: We found a significant increase in serum concentrations of studied factors in the GO group before immunosuppressive therapy when compared with the control group and decrease after i.v.MP treatment. One month after the end of additional oral MP treatment (Group A2), serum concentrations of HGF and IL-8 still decreased and no significant difference was observed in HGF and IL-8 concentrations when compared with the control group. We did not find the difference in serum concentration of the studied proangiogenic factors between patients in euthyroid and hyperthyroid stage of Graves' disease before MP therapy. CONCLUSIONS: Serum HGF and IL-8 concentrations are elevated in Graves' disease patients with active Graves' orbitopathy as compared to the healthy control group. Successful management of active Graves' orbitopathy with glucocorticoids is associated with a decrease in HGF and IL-8 serum concentrations.

Differential action of two prolactin isoforms on ischemia and re-perfusion-induced arrhythmias in rats in vivo.

BACKGROUND: The different influences of one of the PRL isoforms (PRL I) on the cardiovascular system have been described in the past. AIM: Our goal was to establish an appropriate iv dose of 2 PRL isoforms (PRL I and PRL II) in intact rats. After establishing this dose, PRL I (0.01 mg/kg) or PRL II (0.001 mg/kg) was administered in bolus 10 min before left anterior descending coronary artery occlusion (7 min) followed by re-perfusion (15 min). We then aimed to study and compare the effects of these isoforms on ischemia- and re-perfusion-induced arrhythmias in the ischemia and re-perfusion-induced arrhythmias model in rats. MATERIALS AND METHODS: Mortality index, ventricular fibrillation and tachycardia (VF, VT) incidence and duration, systolic, diastolic, and mean arterial blood pressure, heart rate and myocardial index of oxygen consumption [pressure rate product (PRP)] were measured and calculated. RESULTS: Both PRL isoforms reduced animal mortality (from 50 to 18.75 and 25%, respectively). PRL II significantly reduced VF incidence (to 25%) as well as VT duration (18.21 ± 3.09) and these effects were markedly different from PRL I and from the control group (p<0.05). Both PRL reduced PRP in the recovery phase (p<0.05). CONCLUSIONS: We proved that supraphysiological doses of PRL isoforms administered in bolus could protect against sudden cardiac death as well as severe arrhythmias episodes during re-perfusion. Because of PRL's positive influence on the cardiovascular system and as an endogenous, well-tolerated substance, it might be of potential clinical use.

Serum concentrations of adiponectin and resistin in hyperthyroid Graves' disease patients.

UNLABELLED: This study was undertaken to determine whether serum adiponectin and resistin levels are influenced by hyperthyroidism and autoimmune factors and to find out whether their levels are dependent on the presence of ophthalmopathy. We measured serum concentrations of adiponectin and resistin in 76 patients (63 women, 13 men) with Graves' disease (GD) and compared them with levels of the control group which consisted of 30 healthy subjects. Patients were separated into two groups according to the presence or the absence of thyroid-associated ophthalmopathy (TAO). TAO (-) group consisted of 26 subjects without eye signs of GD and TAO (+) group included 50 subjects with ophthalmopathy. The latter group was further divided into 2 subgroups: with active TAO [26 patients, clinical activity score (CAS)> or =4] and with inactive TAO (24 patients, CAS<4). Groups did not differ in age, sex, body mass index (kg/m2) and smoking habits. Compared with euthyroid subjects, hyperthyroid GD patients had elevated mean serum adiponectin concentrations (19.96+/-4.97 microg/ml vs 15.01+/-3.99 microg/ml, p<0.001). However we did not observe any disparity between the TAO (-) and TAO (+) groups (20.60+/-5.06 microg/ml vs 19.63+/-4.94 microg/ml, p=ns). Comparing patients with a CAS> or =4 and patients with a CAS<4, we found similar mean serum concentrations of adiponectin (20.04+/-5.01 microg/ml vs 18.74+/-4.83 microg/ml, p=ns). Serum levels of resistin did not differ between the hyperthyroid patients and control subjects (13.11+/-4.26 ng/ml vs 12.82+/-4.75 ng/ml, p=ns). Serum resistin levels did not differ between TAO (+) and TAO (-) groups nor in patients with active and inactive TAO. Serum adiponectin correlated significantly with free T4 (FT4), free T3 (FT3), and TSH-R antibodies (TRAb) in GD patients (r=0.40, 0.41, and 0.37, respectively; p<0.001 for each). Serum resistin levels were not correlated with thyroid hormones and thyroid antibodies. The variables that in simple linear regression analyses were found to be correlated with serum adiponectin were then used in multiple regression analysis. In a model including adiponectin as dependent variable and FT4, FT3 and TRAb levels as independent variables, FT3 and TRAb remained as parameters independently related to adiponectin level (R2=0.35, p<0.001). CONCLUSIONS: Elevated serum adiponectin levels in GD patients are related to the degree of hyperthyroidism and autoimmune process. The presence and activity of ophthalmopathy is not a modifier of serum adiponectin and resistin.

Homocysteine, vitamin B12, and folic acid in age-related macular degeneration.

PURPOSE: Hyperhomocysteinemia is considered an independent risk factor for atherosclerosis and thrombosis. The purpose of this study was to evaluate plasma homocysteine, red blood cell folate, plasma folate, and plasma vitamin B12 concentration in patients with exudative age-related macular degeneration (ARMD). METHODS: The participants of this study included 30 patients aged 60 to 71 years (mean age 66.2+/-3.6) with exudative ARMD. Plasma homocysteine levels were determined by high performance liquid chromatography (HPLC). Red blood cell folate, plasma folate, and plasma vitamin B12 concentration were determined using a standard kit (Dualcount Solid Phase No Boill radioassay kit for B12/folic acid, DPC Diagnostic, USA) by radioassay method. RESULTS: The plasma concentration of Hcy (14.88+/-6.23 micromol/L) in ARMD patients was significantly increased (p<0.0001) compared with the control group (8.72+/-3.34 micromol/L). We found not a significant decrease of the plasma vitamin B12 concentration in the ARMD group (476.88+/-220.91 pg/mL) compared with the control group (527.08+/-208.97 pg/mL). Red blood cell folate (158.44+/-56.30 ng/mL) and plasma folate (6.5+/-3.4 ng/mL) in ARMD patients were also not significantly decreased when compared with the control group (183.86+/-59.33 ng/mL and 7.93+/-5.05 ng/mL). CONCLUSIONS: Hyperhomocysteinemia might be one of the risk factors for the exudative form of ARMD.

Quantitative ultrasound of the heel and serum and urinary cortisol values in assessment of long-term corticotherapy side effects in female bronchial asthma patients.

Female asthma patients (26) with and without corticotherapy were studied. The control group included 19 healthy women. Skeletal status was assessed by ultrasound measurement of the heel (Achilles, Lunar, Madison, WI, USA) and serum and urinary corisol expressed adrenal function. Ultrasound and hormonal values were significantly lower in patients treated with glucocorticosteroids (GC) than in controls. In patients without GC, cortisol parameters were normal and ultrasound measurements were moderately diminished. 57% of women with and 33% of women without GC-therapy had an ultrasound T-score less than -2.5. Decrease of ultrasound values estimated by linear regression in relationship to time of asthma duration was highest in women with GC therapy. Several significant coefficients of correlation between ultrasound and adrenal function parameters were noted only in patients treated with GC. These data suggest that bone and endocrinological side effects due to steroid therapy in asthma patients show similar trends. Results obtained in present study require further longitudinal investigations.

Assessment of the relationship between circadian variations of salivary melatonin levels and type I collagen metabolism in postmenopausal obese women.

BACKGROUND: Few experimental and clinical studies show that melatonin (MEL) can play a significant part to modulate circadian bone metabolism. On this basis it was suggested that MEL secretion which altered during 24-h in obese women could be of importance to regulate bony mass defect after menopause. OBJECTIVE: The aim of the study was to prove if there were any connection between changes in 24-h profile of serum MEL levels and circadian metabolism of type I collagen in postmenopausal women with visceral obesity. METHODS: The relationship of 24-h profile of salivary MEL and circadian metabolism of type I collagen (as assessed by measuring saliva concentrations of carboxyterminal propeptide of type I procollagen--PICP and cross-linked carboxyterminal telopeptide of type I collagen--ICTP) was investigated in 26 women with visceral obesity (33.5 < BMI < 42.1 kg/m(2)) and 18 healthy volunteers with correct body mass (21 < BMI < 24.5 kg/m(2); 0.73 < WHR < 0.76). The specimens were collected at subjects' home at 3 h intervals during a 24 h span. The age range of all subjects was 52-60 years. RESULTS: In all the obese women studied a tendency to suppress circadian levels of tested biochemical markers of bone metabolism was observed (especially regarding ICTP); those alterations were accompanied by substantial increment in MEL concentrations during the day. Significant and negative correlation was found between values of acrophase MEL and PICP rhythms and both amplitude and acrophase of MEL and ICTP rhythms. CONCLUSION: Our results confirm hypothesis that alterations in MEL concentrations might have a protective effect against postmenopausal loss of bone mass.

Assessment of the relationship between dynamic pattern of nighttime levels of melatonin and chosen biochemical markers of bone metabolism in a rat model of postmenopausal osteoporosis.

BACKGROUND: Lately, there have been suggestions that bone mass changes occurring in postmenopausal women may remain related to melatonin. OBJECTIVE: To assess the relationship between the dynamic pattern of nighttime levels of melatonin and chosen biochemical markers of bone metabolism in ovariectomized rats--a model of postmenopausal osteoporosis. METHODS: Mature Wistar female rats were either ovariectomozed or underwent a sham operation. Following this they were killed at 02:00AM at weekly intervals for 8 weeks after surgery. Serum levels of MEL at death related to the chosen biochemical markers of bone formation (alkaline phosphatase--ALP; carboxyterminal propeptide of type I procollagen--PICP, both in serum) and resorption (cross-linked carboxyterminal telopeptide of type I collagen--ICTP in serum; hydroxyproline--HYP and total calcium--Ca, both excreted in urine). RESULTS: In all ovariectomized rats changes of examined indices of bone tissue metabolism were found to be dynamic and statistically significant relative to the control group; however the changes were more pronounced regarding resorption markers. Following ovariectomy, the increase in ALP and PICP values was found to begin at the 4th and the 1st week, while that in ICTP, HYP and Ca at the 2nd, the 1st and the 1st week, respectively. The ALP and PICP values remained at a similar level until the end of observation, whereas ICTP, HYP and Ca gradually decreased. MEL levels were decreased during the 2nd week following surgery and slightly increased 2 weeks later. The serum MEL levels in the ovariectomized group were significantly and negatively correlated with serum ICTP and both urinary HYP and Ca levels. CONCLUSION: Our findings in rats seem to corroborate the concept of secondary changes in MEL levels co-participating in the development of bone mass changes characteristic for postmenopausal osteoporosis.

Influence of pinealectomy and long-term melatonin administration on GH-IGF-I axis function in male rats.

BACKGROUND: A relationship between circadian GH-IGF-I axis activity and pineal gland function in rats is not sufficiently elucidated, particularly in the aspect of melatonin (MEL) participation with relation to a possible mechanism of these dependencies. OBJECTIVE: Influence of pinealectomy and long-term MEL administration on circadian GH-IGF-I axis function in male rats was evaluated. An attempt was also made to determine whether the effect of exogenous MEL is dependent on the pineal gland presence. METHODS: Studies were performed in 192 sexually mature male Wistar rats, which were subjected to pinealectomy or sham operation. In half of the animals from each group MEL (Sigma, USA) in dose of 50 microg/ 100g b.m. was administrated intraperitoneally (daily between 5 and 6 pm during a 4-week period). Blood for RIA assays of MEL, GH and IGF-I concentrations was collected every 3 hours during a day-beginning at 8 am (rats killed by decapitation). RESULTS: Significant influence of pinealectomy and exogenous MEL on a daily profile of endogenous MEL in rats was confirmed. Distinct, dependent on the time of the day anomalies in circadian oscillations of GH and IGF-I showing positive correlation with changes in endogenous MEL concentrations were also shown. GH rhythm was suppressed in a group of rats with removed pineal gland; after pinealectomy distinct decrease and after MEL use - distinct increase of GH and IGF-I concentrations during the day were observed. It had influenced mean daily concentrations and values of amplitude of circadian GH and IGF-I oscillations in all studied groups of animals. In rats with preserved pineal gland the effect of exogenous MEL action was more intensified. CONCLUSIONS: Pineal gland can influence circadian function of GH-IGF-I axis, and in mechanism of this dependence, changes in endogenous MEL concentrations seem to play an important role. Administration of MEL in rats after pinealectomy only partly prevents changes of GH-IGF-I axis function caused by gland removal, which can indicate participation of other pineal gland substances in generating disturbances. Influence of exogenous MEL on GH-IGF-I axis function during the day is dependent on the presence of pineal gland, which can be connected with indirect and/or direct influence of administrated hormone on this gland.

Changes in blood antioxidants and several lipid peroxidation products in women with age-related macular degeneration.

PURPOSE: The aim of this study was to evaluate the ferric reducing ability of plasma (FRAP), selected enzymatic and non-enzymatic components of the antioxidative system, and the intensity of peroxidative processes in the blood of patients with age-related macular degeneration (AMD). METHODS: In the peripheral blood, we evaluated FRAP; concentrations of vitamins C, A, and E; and of thiols. We assayed the activity of enzymatic components of the antioxidative system-superoxide dismutase, catalase, ceruloplasmin and the concentration of reduced glutathione as an indicator of glutathione peroxidase activity. In order to determine the intensity of lipid peroxidation, we measured the concentrations of malondialdehyde and hydroxyalkenales (MDA-HNA) and conjugated diens (CD). RESULTS: We found a significant increase in FRAP in patients with AMD compared with the control group. The average concentrations of vitamins A and C were low and vitamins E and GSH were significantly higher in AMD than in the control group. The activity of almost all the antioxidative enzymes was high. We found a significant increase in MDA-HNA but no difference in CD. CONCLUSIONS: The significantly higher concentration of lipid peroxidation products in patients with AMD indicates an important pathogenic role of oxido-reduction disturbance. The high FRAP concentration may be one of the protective mechanisms in oxidation stress. The adaptive increase of the antioxidant barrier mostly involves the enzymatic components.

[Hirsutism--difficult diagnostic and treatment problem]. / Hirsutyzm--trudny problem diagnostyczny i leczniczy.

In the study, in concise way, actual knowledge concerning hirsutism was presented. Its causes, forms, diagnostic proceeding and methods of treatment were discussed.

[Hyperprolactinemia--unappreciated clinical problem]. / Hiperprolaktynemia--niedoceniany problem kliniczny.

In the study, in concise way, actual knowledge concerning hyperprolactinemia was presented. Its causes, clinical symptoms, diagnostic proceeding, methods of treatment and prognosis were discussed.

[Function of the growth hormone axis--insulin-like growth factors--insulin-like growth factor binding proteins in patients with chronic liver diseases]. / Czynnosc osi hormon wzrostu--insulinopodobne czynniki wzrostowe--bialka wiazace insulinopodobne czynniki wzrostowe u chorych z przewleklym uszkodzeniem czynnosci watroby.

Up to date have demonstrated that more and more young people are affected by chronic liver diseased. There is a close relationship between the liver and endocrine system as far as hormone inactivation, synthesis of growth factors, proteins binding hormones and proteins binding growth factors in the liver are related. Impairment of the hepatocyte function may lead to disturbed homeostasis of the endocrine system. Current opinions on growth hormone (GH)--insulin-like growth factors (IGFs)--insulin-like growth factors binding proteins (IGFBPs) axis activity in men with chronic liver diseases are presented.

[The influence of thyroid diseases and their treatment on the development of osteoporosis]. / Wplyw chorób tarczycy i ich leczenia na rozwój osteoporozy.

Thyroid diseases and their treatment may influence osseous system. This work deals the problem of hyperthyreosis, hypothyreosis and thyroid hormones therapy with osteoporosis. There is reduced bone mass in hyperthyroid patients. Process of restoring lost bone matrix is not reached with euthyroid state, but lasts longer. Changes in bone mass in hypothyreosis are not of such clinical significance as in hyperthyreosis. Other problem is an influence of thyroid hormones therapy on mineral bone density. Data from literature dealing with this problem are divergent. Control thyroxin therapy with TSH level in normal range may diminish unprofitable influence on bone. Early diagnosis of osteoporosis has also substantial importance. Non-invasive methods play an important role.

[Growth hormone and its interactions with chosen parameters of hormonal state in pre-menopausal women after mastectomy for breast cancer on adjuvant chemotherapy]. / Hormon wzrostu i jego interakcje z wybranymi parametrami stanu hormonalnego u kobiet przed menopauza po mastektomii z powodu raka sutka, poddanych uzupelniajacej chemioterapii.

It seems, that quantitative changes of growth hormone (GH) in blood and imbalance between GH and hormones can influence the breast cancer cells proliferation, and can be a favourable element in breast cancer progression. The procedure to normalize hormonal system can have a therapeutic action. The aim of the presented work is to asses the plasma GH levels in 24 pre-menopausal women after mastectomy for breast cancer on adjuvant chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil (CMF). In this study interactions between GH and insulin like growth factor-I, prolactin, estradiol, progesterone (P), melatonin, cortisol and met-enkephalin were assessed. The control group was consisted of 16 healthy women. Plasma GH concentration and interactions between GH and studied parameters in women with breast cancer did not differ from healthy women. Highly significant positive correlation between GH and P after administration CMF was shown. CMF did not influence the interactions between GH and other studied parameters.

[Glucocorticosteroids in bronchial asthma. II. Use of cortisol markers in various biological materials for evaluation of adrenocortical function]. / Glikokortykosteroidy w astmie oskrzelowej Czesc II. Zastosowanie oznaczen kortyzolu w róznych materialach biologicznych do oceny funkcji kory nadnerczy.

Glucocorticosteroids (GS) being widely used in asthma treatment are sometimes applied in high doses and for long period. This treatment is often connected with adrenocortical suppression. Adrenocortical function assessment in GS treated patients with different doses and forms of drug is of great diagnostic and prognostic importance. In the presented work the methods of adrenocortical function assessment are discussed, especially serum cortisol level and non-invasive: saliva and urine cortisol assays.

[Activities of certain endocrine glands in bronchial asthma]. / Czynnosc niektórych gruczolów wydzielania wewnetrznego w przebiegu astmy oskrzelowej.

The present reports on the effects of various levels of the endocrine system on the course of bronchial asthma are reviewed. Hypophyseal function in production of certain hormone and functioning of the hypothalamo, hypophyseal-thyroid, -adrenal, and -gonadal axis are discussed. Changes in the functions of endocrine glands may modify the course of allergic diseases.

[Glucocorticosteroids in bronchial asthma. I. Mechanism of action and use in therapy]. / Glikokortykosteroidy w astmie oskrzelowej. Czesc. I. Mechanizm dzialania i zastosowanie w leczeniu.

Inflammation plays the main role in the pathogenesis of asthma. Glucocorticosteroids (GS), as the most effective anti-inflammatory drugs are widely used in asthma treatment. So far the mechanism of action, both molecular and on the level of tissues and organs has not been entirely explained. In this work molecular mechanism of glucocorticosteroids action is discussed especially in aspect of therapy. The influence of GS on adrenocortical function is also presented.