Assessment of real-world usage of lanreotide AUTOGEL 120 in Polish acromegalic patients - results from the prospective 12-month phase of Lanro-Study.

AIM OF THE STUDY: To assess resource utilization and costs of treatment with lanreotide AUTOGEL 120 mg (ATG120) administered as part of routine acromegaly care in Poland. MATERIAL AND METHODS: A multicentre, non-interventional, observational study on resource utilization in Polish acromegalic patients treated with ATG120 at 4 weeks or extended (> 4 weeks) dosing interval. The study recruited adult acromegalic patients treated medically for ≥ 1 year including at least 3 injections of ATG120. Data on dosing interval, aspects of administration, and resource utilization were collected prospectively during 12 months. Costs were calculated in PLN from the public health-care payer perspective for the year 2013. RESULTS: 139 patients were included in the analysis. Changes in dosing regimen were reported in 14 (9.4%) patients. Combined treatment was used in 11 (8%) patients. Seventy patients (50%) received ATG120 at an extended dosing interval; the mean number of days between injections was 35.56 (SD 8.4). ATG120 was predominantly administered in an out-patient setting (77%), by health-care professionals (94%). Mean time needed for preparation and administration was 4.33 and 1.58 min, respectively, mean product wastage - 0.13 mg. Patients were predominantly treated in an out-patient setting with 7.06 physician visits/patient/year. The most common control examinations were magnetic resonance imaging of brain and brain stem (1.36/patient/year), ultrasound of the neck (1.35/patient/year), GH (1.69/patient/year), glycaemia (1.12/patient/year), IGF-1 (0.84/patient/year), pituitary-thyroid axis hormone levels assessment (TSH-0.58/patient/year, T4-0.78/patient/year). There were 0.43 hospitalizations/patient/year. For direct medical costs estimated at PLN 50 692/patient/year the main item was the costs of ATG120 (PLN 4103.87/patient/month; 97%). The mean medical cost, excluding pharmacotherapy, was PLN 1445/patient/year (out-patient care - 49%, hospitalization - 23%, diagnostics/laboratory tests - 28%). CONCLUSIONS: These results represent the current use of ATG120 in the population of Polish acromegalic patients in a realistic clinical setting. Findings that 50% of patients could be treated with dose intervals of longer than 28 days support the potential of ATG120 to reduce the treatment burden.

Angiotensins inhibit cell growth in GH3 lactosomatotroph pituitary tumor cell culture: a possible involvement of the p44/42 and p38 MAPK pathways.

The local renin-angiotensin system is present in the pituitary. We investigated the effects of angiotensins on GH3 lactosomatotroph cells proliferation in vitro and the involvement of p44/42 and p38 MAPK inhibitors in the growth-regulatory effects of angiotensins. Materials and Methods. Cell viability using the Mosmann method and proliferation by the measurement of BrdU incorporation during DNA synthesis were estimated. Results. Ang II and ang IV decreased the viability and proliferation of GH3 cells. Inhibitor of p44/42 MAPK attenuated the effects of ang II on cell viability and proliferation but did not affect the ang 5-8-dependent actions. Inhibitor of p38 MAPK prevented the decrease in the number of GH3 cells in ang-II- and ang-IV-treated groups. Conclusions. The growth-inhibitory effect of ang II is possibly mediated by the p44/42 MAPK. The p38 MAPK appears to mediate the inhibitory effects of both ang II and ang 5-8 upon cell survival.

The involvement of angiotensin type 1 and type 2 receptors in estrogen-induced cell proliferation and vascular endothelial growth factor expression in the rat anterior pituitary.

The aim of our study was to examine the involvement of renin-angiotensin system (RAS) in estrogen-induced lactotropes proliferation and vascular endothelial growth factor (VEGF) expression in rat pituitary. The study was performed on Fisher 344 rats underwent 8-day treatment with diethylstilboestrol (DES). The proliferation index (PCNA) and VEGF expression in pituitary sections were estimated using immunohistochemical methods. Treatment with DES increased the number of PCNA-positive cells, VEGF-positive cells, and VEGF-positive blood vessels in pituitary. Stimulatory effect of estrogen on cell proliferation and VEGF expression in blood vessels was attenuated by losartan, PD123319, and captopril. VEGF immunoreactivity in pituitary cells of DES-treated rats was decreased by AT1 antagonist and not changed by AT2 blocker and ACE inhibitor. Our findings suggest the involvement of RAS in DES-induced cell proliferation and VEGF expression in pituitary. Both the AT1 and AT2 receptors appear to mediate the estrogen-dependent mitogenic and proangiogenic effects in rat pituitary.

Elevated peripheral blood plasma concentrations of tie-2 and angiopoietin 2 in patients with neuroendocrine tumors.

BACKGROUND: Gastro-entero-pancreatic/neuroendocrine (NET) tumors are highly vascularized neoplasms. However, our knowledge concerning circulating levels of the angiogenic factors in NET patients still remains insufficient. METHODS: The aim of this study was to measure plasma concentrations of VEGF, angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), soluble Tie-2, endostatin, osteopontin (OPN) and chromogranin A (CgA) in 36 NET patients and 16 controls. RESULTS: Only the plasma concentrations of Tie-2 and CgA were higher in NET patients as compared to controls. These levels were within the reference range in controls; however one control demonstrated slightly elevated Tie-2 and 4 elevated CgA. Similarly, in the subgroup of patients with carcinoid syndrome, only Tie-2 and CgA concentrations were higher than those in patients with non-functioning NETs. In turn, in the subgroup of metastatic patients, only Ang-2 levels were higher than in those with localized disease. A positive correlation was found between Ang-2 and Tie-2 levels in metastatic patients and between Ang-1 and Tie-2 in localized NETs. CONCLUSIONS: The plasma concentration of Tie-2 is proposed as an additional marker for NET patients and seems to be similarly effective as the currently used CgA level. Moreover, higher plasma levels of Ang-2 together with the positive correlation between Ang-2 and Tie-2 levels in metastatic subjects, implies that cases with a Tie-2 level above the upper limits, together with higher level of Ang-2 seem to be highly predictive of metastases.

[The assessment of the mental state of patients during simultaneous treatment with psychotropic drugs, antipsychotics included, and bromocriptine]. / Ocena stanu psychicznego pacjentek w trakcie jednoczesnego stosowania leków psychotropowych, w tym leków przeciwpsychotycznych, oraz bromokryptyny.

AIM: The aim of this study was to assess the mental state of patients treated with psychotropic drugs (LPT) and bromocriptine (BRC) at the same time. METHODS: 25 female patients in the stable mental state treated with antipsychotics (LPP) (13 patients were also treated with other LPT) with an average age of 25.56 years were included in the study. All patients presented clinical symptoms of HPRL: menstrual disturbances or galactorrhea and their serum PRL was increased or the test with metoclopramide was incorrect. BRC (1.25-8.75 mg per day) was ordered to eliminate HPRL and observation was conducted over a period of 3 months. Two weeks, a month, 2 months and 3 months after the BRC treatment had been started, an evaluation of the mental state of the patients was conducted. The patients' mental state was evaluated with the Clinical Global Impression Scale (CGI), the Hamilton Depression Rating Scale (HDRS) and the Positive and Negative Syndrome Scale (PANSS). RESULTS: After 3 months of the study in the whole group there was no significant change in the mental state evaluated with the CGI and the HDRS. There was a worsening in PANSS (p < 0.05) which was mainly due to the worsening (p < 0.01) in the subscale of general psychiatric symptomatology of PANSS (PANSS-G). There was no significant change in the subscales of positive and negative symptoms of PANSS (PANSS-P and PANSS-N respectively). CONCLUSIONS: The results show that during the 3 months of the BRC treatment there was no worsening in positive, negative and affective symptoms. The study suggests that adding BRC may be a safe option of management of psychotropic-induced HPRL in some psychiatrically stable patients, although further studies are necessary.

The Polish version of the Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) - four-stage translation and validation.

INTRODUCTION: The Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) was developed simultaneously in five languages (English, Swedish, German, Italian and Spanish) to measure quality of life (QoL) in adult patients with Growth Hormone (GH) deficiency. The aim of the project was to produce a validated Polish version of the QoL-AGHDA that was conceptually equivalent to the UK-English version. MATERIAL AND METHODS: Translation and validation procedure consisted of 4 stages. Stage 1: A bilingual translation panel [7 participants, fluent in both English and Polish (Polish as their first language) with university education] translated the questionnaire. Stage 2: A lay translation panel (6 participants of an average to lower than average educational level, speaking only the target language) reviewed the wording of the draft version produced by bilingual panel to improve clarity and immediacy. Stage 3: The translated questionnaire was then field-tested with 15 adults with GH deficiency. Stage 4: Finally, the amended version underwent psychometric evaluation to check its reliability and validity (it was administered to 85 GH-deficient adults on two occasions, two weeks apart). RESULTS: The Polish QoL-AGHDA version was successfully adapted and it is characterized by a high degree of reliability and validity. The test-retest reliability coefficient for the Polish QoL-AGHDA was 0.92. The Cronbach's Alpha coefficient for the Polish QoL-AGHDA was 0.91 (N = 70) at Time 1 and 0.94 (N = 79) at Time 2. Correlation between QoL-AGHDA and Nottingham Health Profile items confirmed high convergent and divergent validity. CONCLUSIONS: The Polish QoL-AGHDA is a reliable and valid measure of QoL suitable for use in clinical studies and routine clinical practice.

Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat.

The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. Pituitary tumors were induced in male F344 rats by s.c. implantation of Silastic tubes containing diethylstilbestrol (DES). The effects of chronic treatment with BB-94 (30 mg/kg b.w.) on pituitary weight, cell proliferation, apoptosis and vascular density were evaluated. We have stated that chronic treatment with batimastat caused a significant reduction in the pituitary weight. Batimastat has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. A marked increase in the apoptotic index within the pituitary was observed in the study group. Moreover, the density of microvessels identified by CD31 was reduced in the group treated with BB-94. The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma. The ability of BB-94 to suppress established pituitary tumor growth suggests a possible application of MMPIs in the treatment of pituitary adenomas.

Inhibitory effect of thalidomide on the growth, secretory function and angiogenesis of estrogen-induced prolactinoma in Fischer 344 rats.

The process of angiogenesis has been found to be essential for the development of estrogen-induced pituitary prolactinoma in Fischer 344 rats. Thalidomide [(alpha-(N-phthalimido)-glutarimide] is known to be a potent immunomodulatory drug with antiangiogenic properties, but its effect on lactotroph cell secretory function and pituitary prolactinoma formation has not been described yet. The purpose of this study was to examine the effects of thalidomide on secretion of prolactin (PRL) and vascular endothelial growth factor (VEGF), cell proliferation, apoptosis and angiogenesis within the anterior pituitary gland in long-term diethylstilboestrol (DES)-treated male F344 rats in vivo and in vitro. It was found that DES sharply increased serum PRL and VEGF levels. On the other hand, simultaneous treatment of F344 rats with thalidomide for the last 15 days of the experiment attenuated the stimulatory effect of DES on PRL and VEGF secretion. It also diminished prolactin cell proliferation evaluated as the number of proliferating cell nuclear antigen (PCNA)-positive stained cell nuclei and increased the number of apoptotic bodies determined by the terminal deoxynucleotidyl-mediated dUTP nick-end labeling (TUNEL) method in sections of the DES-induced pituitary prolactinoma. The density of pituitary microvessels evaluated by microscopic counting of CD-31-positive blood vessels was also diminished by the tested drug. In addition, thalidomide (10(-4) to 10(-6) M) inhibited cell proliferation, prolactin and VEGF secretion from rat pituitary prolactinoma cells cultured in vitro. In conclusion, our results provide strong evidence for the antiprolactin and antitumor activity of thalidomide in experimentally DES-induced pituitary adenoma.

Positron emission tomography (18FDG-PET) in the detection of medullary thyroid carcinoma metastases.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is usually more advanced at presentation than differentiated thyroid cancers and often has distant metastases. The primary treatment of MTC is total thyroidectomy and regional lymph node dissection. The efficacy of these procedures has been limited by the aggressiveness of the disease and metastatic spread at the time of surgery. Persistently elevated levels of calcitonin (CT) and carcinoembryonic antigen (CEA) or their increase postoperatively are indicative for residual or recurrent disease. Conventional imaging methods such as ultrasonography, computed tomography, magnetic resonance imaging and MIBI scintigraphy usually fail to find the source of calcitonin. Better imaging properties have been shown by DMSA scintigraphy, somatostatin receptor scintigraphy or by positron emission tomography (PET). The aim of the study was to evaluate the diagnostic accuracy of PET for the localisation of occult MTC in patients after surgery with increased concentrations of CT, in whom conventional imaging procedures have not been successful. MATERIAL AND METHODS: The PET investigation using (18)F-fluoro- 2-deoxy-D-glucose combined with computed tomography ((18)FDG-PET/CT) was performed at the Department of Nuclear Medicine (Oncology Centre in Bydgoszcz) between January and October 2004. In five patients with postoperative calcitonin ranging from 164 to > 2000 ng/l (normal < 10 ng/l) no tumour lesions were found using other imaging methods. RESULTS: In four of five cases, responsible lesions with a higher metabolism of FDG, indicating MTC tissue (remnants or metastases), were localised. In one patient no focus of FDG accumulation was found despite high CT concentration. PET detected tumour manifestations in the neck and the mediastinum in two patients, in the lung and the left adrenal gland in one case and in the neck and the liver in another patient. As a result of surgery for the removal of a residual tumour or metastases the accuracy of diagnosis was confirmed by histopathology in all four cases and a decrease in CT and CEA levels was observed in 3/4 cases. The metabolic imaging findings by PET/CT ensured that the surgery on these patients was successful. CONCLUSIONS: For the detection of occult residual or metastatic MTC lesions, (18)FDG-PET is a valuable procedure in imaging diagnostics.

Patient satisfaction and preferences of lanreotide Autogel treatment in acromegaly.

INTRODUCTION: Despite the known importance of somatostatin analogues (SSAs) in the treatment of acromegaly, patient satisfaction leading to preferences for specific SSAs have received little attention so far. MATERIAL AND METHODS: This open, prospective, observational, multicentre patient-reported outcome study included adult patients with acromegaly, who switched from another SSA to lanreotide Autogel (new and previous devices) at least two months prior to enrolment. The observation period was around 12 months. The primary outcome assessed was overall treatment satisfaction, measured using the five-point Likert scale. The secondary outcomes were: 1) treatment effectiveness, in terms of symptom control; 2) technical problems related to treatment administration, measured by the Visual Analog Scale (VAS); and 3) ease and safety of lanreotide Autogel delivery (new device vs. previous device). RESULTS: Of the 102 patients who completed the study, 97 (95.1%) were "completely or rather satisfied" with lanreotide Autogel therapy, four (3.9%) were "neither satisfied nor dissatisfied", and one (1%) was "rather dissatisfied". Symptom control was reported as "excellent" or "good" by 88-89% of patients throughout the study. Patients reported fewer technical problems related to administration of lanreotide Autogel (final mean VAS: 5.3) compared to previous SSAs (mean VAS: 37.6). Of the 31 patients treated with lanreotide Autogel using the previous device followed by the new device, 64.5% reported the new device as improved. CONCLUSIONS: Lanreotide Autogel therapy resulted in greater patient satisfaction with overall acromegaly management, when compared to previous SSAs. The new lanreotide Autogel device was found to be easier to use than the previous one. (Endokrynol Pol 2016; 67 (6): 572-579).

The combined effects of proglumide and fluorouracil on the growth of murine Colon 38 cancer cells in vitro.

The role of gastrins and their receptors in the pathogenesis of colon cancer has been discussed for many years but it still remains unresolved. Although fluorouracil (FU) remains to be reference chemotherapy for colon cancer, its efficacy is unsatisfactory. Recently, we have shown a synergistic effect of proglumide (a non-selective blocker of cholecystokinin-gastrin receptors) applied together with FU, on the proliferation and apoptosis of transplantable Colon 38 cancer cells in vivo. The aim of this study was to examine direct effects of proglumide (10(-5)-10(-10) M) applied either alone or together with FU (0.25, 2.5 and 25 microg/ml) on the proliferation of murine Colon 38 cancer cells in vitro. Cell proliferation was assessed by the modified colorimetric Mosmann method. Proglumide inhibited the proliferation of Colon 38 cells at the concentrations of 10(-6), 10(-8) and 10(-10) M. FU inhibited the proliferation of cancer cells in all studied concentrations, exerting the most profound antiproliferative effect at the concentrations of 2.5 and 25 microg/ml. Thus, the former concentration was chosen to study its interactions with proglumide. Proglumide applied together with FU exerted a synergistic effect on the inhibition of proliferation of Colon 38 cells at 10(-8), 10(-9), 10(-10) M concentrations. The most profound inhibitory effect was observed in the group incubated with FU and 10(-10) M of proglumide. The obtained results indicate a possibility of new therapeutic options for colon cancer, but further studies are needed to elucidate, if the synergistic effect of FU and proglumide occurs also in the colon cancer in humans.

Effect of monthly administration of GHRH (fragment 1-29) with osmotic pump on the rat anterior pituitary.

Growth Hormone-Releasing Hormone (GHRH) is the main factor, which regulates GH secretion and somatotrope proliferation. However, its chronic effect on anterior pituitary gland is still unknown. It is known that excessive GHRH secretion in patients with gastroenteropancreatic tumors secreting GHRH results in acromegaly and somatotrope hyperplasia. In mice transgenic for GHRH somatotrope tumors develop. Thus, the aim of this paper was to examine the effect of GHRH chronic administration on somatotrope secretion, their percentage and cell proliferation in anterior pituitary gland in rats. The experiment was performed on male Fischer 344 rats weighing 200+/-20 g. The animals were divided into two groups: group I-controls (13 rats) received solvent for GHRH (5% ethanol in demineralized water); group II (10 rats) received GHRH (Growth Hormone Releasing Factor, fragment 1-29 amide) at a dose of 5 microg/day. The substances were given for 1 month via osmotic pump (ALZET), which were implanted subcutaneously in the dorsal region under ketamin anesthesia. After 4 weeks all rats were decapitated and the blood was collected. In the microscopic preparations of anterior pituitary gland the morphology of pituitary (Herlant staining) and the percentage of somatotrope cells and proliferation index based on PCNA staining were assessed. It was found that the chronic treatment with GHRH caused a statistically significant increase in serum rGH concentration and in percentage of somatotropes, but did not change proliferation index and did not induce pathological changes in the morphology of the anterior pituitary gland when compared to the control group. Summing up, monthly GHRH administration did not induce somatotrope adenomas but it caused serum GH level elevation, what seems to depend partially on the increase of somatotrope number.

Effects of pentosan polysulfate sodium on the estrogen-induced pituitary prolactinoma in Fischer 344 rats.

The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. This type of tumor is a rich source of basic fibroblast growth factor (bFGF), which possesses strong mitogenic and angiogenic properties. Pentosan polysulfate sodium (PPS) has been shown to exert antitumor activity by antagonizing the binding of bFGF to cell surface receptors. We have examined the effects of pentosan on tumor growth, hyperprolactinemia and angiogenesis in diethylstilbestrol-induced anterior pituitary adenoma in F344 rats. Chronic treatment with PPS did not cause any changes in the pituitary weight and serum prolactin concentration in comparison with untreated animals. The density of microvessels identified by CD-31 was also not affected by the tested drug. On the other hand, pentosan has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. Moreover, the TUNEL method has revealed an increased number of apoptotic bodies within the anterior pituitary after treatment with PPS. Despite the antiproliferative and proapoptotic activity of pentosan, the drug failed to inhibit tumor growth. This fact might be due to the lack of antiangiogenic activity of PPS in this experimental design.

Modulation of ghrelin axis influences the growth of colonic and prostatic cancer cells in vitro.

BACKGROUND: The risk of different cancers seems to be associated with obesity. Moreover, low ghrelin levels observed in obese people may be implicated in cancer development and progression. The aim of this study was to examine the direct effects of both forms of ghrelin (acylated and unacylated) and ghrelin receptor type 1a antagonist (D-Lys-GHRP-6) on the growth of murine colon cancer MC38 and human prostate cancer DU145 cell lines in vitro. METHODS: The cells were cultured for 72 h in the presence of rat or human acylated ghrelin (rG, hG), human unacylated ghrelin (hUAG), D-Lys-GHRP-6 (GHS-RA) applied either alone or jointly. The cell line growth was assessed by the colorimetric Mosmann method. RESULTS: hUAG (10(-6), 10(-7) and 10(-10) M) inhibited MC38 cancer cell growth and, at some concentrations (10(-8), 10(-9), 10(-10) M), enhanced the antineoplastic effect of GHS-RA(10(-4) M). In turn, GHS-RA evoked a biphasic effect on MC38 cancer growth: inhibitory at 10(-4) M and stimulatory at 10(-5) and 10(-6) M. Moreover, GHS-RA at the highest examined concentration (10(-4) M) enhanced the cytostatic effect of FU. Human acylated and unacylated ghrelin and GHS-RA inhibited DU145 cancer growth with moderate and different potencies. A dose-response effect was observed for the inhibitory action of hG together with the synergistic effect of hUAG and GHS-RA. CONCLUSION: The obtained results indicate an involvement of the ghrelin axis in the growth regulation of colon and prostate cancers and may suggest new therapeutic options for these neoplasms.

The effects of angiotensin peptides and angiotensin receptor antagonists on the cell growth and angiogenic activity of GH3 lactosomatotroph cells in vitro.

The local renin-angiotensin system (RAS) is present in the pituitary gland, and inhibitory effects of angiotensins on the lactosomatotroph (GH3) cell growth have been revealed. The aim of this study was to examine the influence of various angiotensin peptides and angiotensin AT1, AT2, and AT4 receptors antagonists on the cell proliferation, viability, and VEGF secretion in pituitary lactosomatotroph GH3 cell culture in order to identify receptors involved in antiproliferative effects of angiotensins on GH3 tumor cells. Cell viability and proliferation using Mosmann method and BrdU incorporation during DNA synthesis, and VEGF secretion using ELISA assay were estimated. The inhibitory effects of ang II, ang IV, and ang 5-8 on the cell viability and BrdU incorporation in GH3 culture were not abolished by AT1, AT2, and AT4 receptors antagonists. Ang II, as well as ang III and ang IV at lower concentrations stimulated the secretion of VEGF in GH3 cell culture. The secretion of VEGF was inhibited by ang III and ang IV at higher concentrations. AT1 and AT2 receptors antagonists prevented the proangiogenic effects of ang II. Ang II, ang IV, and ang 5-8 decrease the cell number and proliferation in GH3 cell culture independently of the AT1, AT2, and AT4 receptors. These peptides affect also secretion of VEGF in culture examined. Both the AT1 and AT2 receptors appear to mediate the proangiogenic effects of ang II.