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2.
Clin Pharmacol Ther ; 96(2): 182-91, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24781527

ABSTRACT

Prospective studies on epidermal growth factor receptor (EGFR) inhibitors in African Americans with non-small cell lung cancer (NSCLC) have not previously been performed. In this phase II randomized study, 55 African Americans with NSCLC received 150 mg/day erlotinib or a body weight-adjusted dose with subsequent escalations to the maximum-allowable dose, 200 mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower than those observed in previous studies, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics showed only two EGFR mutations, EGFR amplification in 17/47 samples, eight KRAS mutations, and five EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease-control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Low incidence of toxicity and low erlotinib exposure suggest standardized and maximum-allowable dosing may be suboptimal in African Americans.


Subject(s)
Black or African American/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Quinazolines/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/metabolism , Erlotinib Hydrochloride , Female , Humans , Lung Neoplasms/metabolism , Male , Middle Aged , Pharmacogenetics , Prospective Studies , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Quinazolines/pharmacokinetics
5.
Exp Clin Endocrinol Diabetes ; 118(2): 98-100, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19834872

ABSTRACT

Impaired glucose tolerance and diabetes have been associated with depression, and antidepressant treatment is assumed to improve impaired glucose tolerance. However, antidepressant treatment is also considered as a risk factor for the development of diabetes. Reports about glucose tolerance under antidepressant treatment frequently lack appropriate control groups. We conducted the oral glucose tolerance test (OGTT) in 10 healthy controls selected from an epidemiological sample with a negative lifetime history of mental Axis I disorder. Controls were carefully matched to a sample of inpatients with major depression that participated in an OGTT before and after antidepressant treatment with mirtazapine. All participants underwent a standard OGTT protocol. In patients, a second (after 2 weeks) and a third (after 4-6 weeks) OGTT was performed under treatment with mirtazapine. Compared to healthy controls, we observed significantly impaired glucose tolerance in acutely depressed patients. Effect size calculation indicated a moderate to large effects on glucose and insulin concentrations in response to an OGTT. Although glucose tolerance improved under mirtazapine treatment, insulin sensitivity was still impaired and remained significantly lower in patients compared to controls.


Subject(s)
Depressive Disorder/complications , Depressive Disorder/metabolism , Glucose Intolerance/complications , Glucose/metabolism , Mianserin/analogs & derivatives , Adult , Aged , Antidepressive Agents, Tricyclic/therapeutic use , Area Under Curve , Depressive Disorder/drug therapy , Female , Glucose Intolerance/metabolism , Glucose Tolerance Test , Humans , Inpatients , Male , Mianserin/therapeutic use , Middle Aged , Mirtazapine
7.
Cancer Chemother Pharmacol ; 63(6): 1073-82, 2009 May.
Article in English | MEDLINE | ID: mdl-18795290

ABSTRACT

PURPOSE: Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies. PATIENTS-METHODS: Initially, patients received MMC on day 1 and irinotecan on days 2, 8, 15 and 22, every 6 weeks. MMC dose was fixed at 6 mg/m(2) and cumulative doses of >36 mg/m(2) were not permitted. Irinotecan was escalated in 25 mg/m(2) increments. Due to late-onset diarrhea, the schedule was subsequently shortened to 4 weeks, omitting irinotecan on days 15 and 22. In the second part of the study, celecoxib 400 mg orally twice daily was added to irinotecan/MMC regimen. Potential pharmacokinetic interactions and Topo-1 and DT-diaphorase (NQ01) gene expressions in peripheral-mononuclear cells were evaluated. RESULTS: Forty-five patients were enrolled. Irinotecan 125 mg/m(2) on days 2 and 8 in combination with MMC 6 mg/m(2) on day 1 every 4 weeks is recommended for future studies; myelosuppression and diarrhea are dose-limiting. The addition of celecoxib resulted in unacceptable toxicities despite reductions on irinotecan's dose. No relevant pharmacokinetic interactions occurred between irinotecan and MMC, and mean increases in Topo-1, were observed. Sixteen of 36 patients evaluable for response-assessment had discernable anti-tumor activity, including 1 complete, 4 partial, 10 minor and 1 tumor marker response. Four patients had prolonged (>4 months) disease-stability (stable disease, not included in CR or PR). Patients experiencing complete and partial responses had higher increments in Topo-1 expression. CONCLUSIONS: Modulation of irinotecan by MMC is feasible, devoid of pharmacological interactions and active in solid malignancies. The lack of improvement in therapeutic index does not support the addition of celecoxib.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/pharmacokinetics , Celecoxib , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Irinotecan , Male , Middle Aged , Mitomycin/administration & dosage , Mitomycin/adverse effects , Mitomycin/pharmacokinetics , Neoplasms/metabolism , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Treatment Outcome , Young Adult
8.
Exp Clin Endocrinol Diabetes ; 115(8): 509-17, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17853334

ABSTRACT

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.


Subject(s)
Mass Screening/methods , Multiple Endocrine Neoplasia Type 1/epidemiology , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Child , DNA/blood , DNA/genetics , Female , Genotype , Germany/epidemiology , Humans , Male , Middle Aged , Multiple Endocrine Neoplasia Type 1/genetics , Nuclear Family , Phenotype , Polymerase Chain Reaction
9.
Eur J Endocrinol ; 155(4): 553-7, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16990654

ABSTRACT

OBJECTIVE: Patients with traumatic brain injury (TBI) are at moderate risk of GH deficiency (GHD), requiring a diagnostic test with high specificity. The GHRH + arginine (GHRH + ARG) test has been recommended as a reliable alternative to the insulin-tolerance test (ITT) as a standard test with a cutoff level of 9 ng/ml. However, it has recently been questioned for its low specificity in obese subjects, and now BMI-dependent cut-off levels are available. In this study, we compared the ITT and GHRH + ARG test in patients with TBI. DESIGN: A cross-sectional study METHODS: We performed an ITT and a GHRH + ARG test in 21 patients with TBI (6 women, 15 men; mean age 40.2 +/- 12.1 years; BMI 30.7 +/- 6.2). The number of patients classified discordantly as GH deficient by the ITT and the GHRH + ARG test with both classical and BMI-dependent cut-off levels was assessed. RESULTS: Using the GHRH + ARG test with the classical cut-off ( 3 ng/ml), and one patient as GH sufficient who had a blunted GH response to ITT (discordance rate 61.9%). All patients discordantly classified as GH deficient by the GHRH + ARG test had a BMI of >or= 28. With the BMI-dependent cut-offs (4.2, 8.0, and 11.5 ng/ml in obese, overweight, and lean subjects respectively), only 3 of the 21 patients were discordantly classified (discordance rate 14.3%). CONCLUSIONS: Our results discourage the use of a cut-off level of 9 ng/ml for the GHRH + ARG test in obese subjects. The diagnostic reliability of this test is improved with the BMI-dependent cut-offs.


Subject(s)
Arginine/analysis , Brain Injuries/complications , Diagnostic Techniques, Endocrine , Growth Hormone-Releasing Hormone/analysis , Human Growth Hormone/deficiency , Insulin Resistance , Adult , Body Mass Index , Brain Injuries/blood , Cross-Sectional Studies , Diagnostic Techniques, Endocrine/statistics & numerical data , Female , Humans , Male , Middle Aged
10.
MMW Fortschr Med ; 148(26): 37-40, 2006 Jun 29.
Article in German | MEDLINE | ID: mdl-16875377

ABSTRACT

Affective disorders increase the risk for the occurrence of type 2 diabetes, and the presence of type 1 or type 2 diabetes may contribute to the development of an affective disorder. Certain antidepressants and behavioral therapy seem to improve blood sugar levels in patients suffering from depression and type 2 diabetes, although these antidepressants may lead to weight gain. However, some antipsychotics unfavorably affect weight development and carbohydrate metabolism. In diabetic patients, the physician should be particularly alert to affective symptoms, and in mentally ill patients, he should look out for metabolic changes that may be caused by diabetogenic psychopharmacological medication.


Subject(s)
Antidepressive Agents/therapeutic use , Antipsychotic Agents/therapeutic use , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Mood Disorders/complications , Antidepressive Agents/adverse effects , Antipsychotic Agents/adverse effects , Blood Glucose/analysis , Cognitive Behavioral Therapy , Depression/blood , Depression/complications , Depression/therapy , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 2/blood , Glucose Tolerance Test , Humans , Meta-Analysis as Topic , Mood Disorders/blood , Mood Disorders/therapy , Randomized Controlled Trials as Topic , Weight Gain
12.
Internist (Berl) ; 47(4): 427, 429-33, 2006 Apr.
Article in German | MEDLINE | ID: mdl-16470359

ABSTRACT

A 62 year-old patient was admitted to hospital with rapid progressive edema, low potassium and hypertension. This symptoms are caused by Cushing's syndrome through ectopic paraneoplastic ACTH-production. Primary neoplasm is a small cell cancer. A Sertoli-cell-tumor of the testis was diagnosed as an additional carcinoma. Palliative chemotherapy and adrenostatic agents did not improve the clinical findings and the patient died eight weeks after admission.


Subject(s)
Cushing Syndrome/etiology , Edema/etiology , Hypertension/etiology , Hypokalemia/etiology , Sertoli Cell Tumor/complications , Testicular Neoplasms/complications , Testicular Neoplasms/diagnosis , Cushing Syndrome/diagnosis , Diagnosis, Differential , Disease Progression , Edema/diagnosis , Humans , Hypertension/diagnosis , Hypokalemia/diagnosis , Male , Middle Aged , Sertoli Cell Tumor/diagnosis
13.
Exp Clin Endocrinol Diabetes ; 113(4): 219-24, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15891958

ABSTRACT

OBJECTIVE: For patients in whom acromegaly persists despite pituitary surgery or drug treatment, gamma-knife surgery represents an additional treatment option. Considering carefully the different reported biochemical outcomes, the central point is whether gamma-knife radiosurgery has advantages compared to conventional radiotherapy or, furthermore, to newer medical therapies, such as long-acting somatostatin analogues or growth hormone receptor antagonists. DESIGN AND METHODS: We report the outcome of 44 patients with acromegaly, who received gamma-knife surgery with the Leksell gamma knife. The median follow-up time was 1.9 years (0.5-4.3 years) post-radiosurgery. 43 of 44 patients had previously undergone pituitary surgery. RESULTS: Immediately prior to gamma-knife surgery, median xULN of patients' serum IGF-I was 1.9 times above upper limit of normal (range: 0.5-8.9 xULN [multiple of upper limit of normal range]). There was a significant decline of serum IGF-I at patients' final follow-up. We found a normal age-adjusted IGF-I in 21/44 patients (xULN of IGF-I<1). Furthermore, as the number of treated patients increased, we found an improvement in remission rate, which let us assume that there was a learning effect for the gamma-knife performing team over time. In addition, the median adenoma size decreased from 1.5 ml (0.1-6.9 ml) prior to gamma-knife therapy to 0.3 ml (no rest vol. detectable-2.4 ml) at patients' last visit. CONCLUSION: We have shown that pituitary gamma-knife surgery is effective in lowering serum IGF-I levels. At the end of the follow-up period, 48 % of our cohort had normal age-adjusted IGF-I levels.


Subject(s)
Acromegaly/surgery , Insulin-Like Growth Factor I/metabolism , Radiosurgery , Acromegaly/blood , Adenoma/surgery , Adult , Aged , Biomarkers/blood , Female , Follow-Up Studies , Humans , Male , Middle Aged , Pituitary Neoplasms/surgery , Reference Values , Retrospective Studies , Time Factors
14.
J Neuroendocrinol ; 17(3): 152-60, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15796767

ABSTRACT

Members of the Toll receptor (Tlr) family have a crucial role in the innate immune response following bacterial infection. The effects of Gram-negative bacteria-derived endotoxins (lipopolysaccharide, LPS) are predominantly mediated by Tlr4, and we have recently shown that pituitary folliculostellate cells express functional Tlr4. In the present study, we investigated whether Tlr4 is also present in normal and transformed endocrine epithelial pituitary cell types. By reverse transcriptase-polymerase chain reaction, Tlr4 mRNA expression was found in some pituitary epithelial tumour cell lines (AtT20, HP75), whereas others were negative (GH3, alphaT3-1). Tlr4 protein was detected by immunohistochemistry in a few epithelial cells in normal human anterior pituitaries and in 26 out of 67 human pituitary tumours analysed. LPS had no effect on adrenocorticotropic hormone secretion in Tlr4-positive AtT20 cells, but it suppressed the growth of these cells in a dose-dependent manner. As expected, neither hormone secretion, nor growth of Tlr4-negative GH3 cells was affected by LPS. In cell cultures of Tlr4-positive pituitary adenomas, LPS dose-dependently stimulated the production of interleukin (IL)-6, which is known to induce growth and hormone production in pituitary tumours. The LPS-induced IL-6 production was blocked by the specific p38alphaMAP kinase inhibitor, SB203580, and by the synthetic glucocorticoid, dexamethasone. The data suggest that, during Gram-negative bacteria-induced infections or inflammatory processes, LPS could affect pituitary tumour pathophysiology and progression in the subset of Tlr4-expressing pituitary adenomas.


Subject(s)
Adenoma/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/immunology , Membrane Glycoproteins/metabolism , Pituitary Neoplasms/metabolism , Prolactinoma/metabolism , Receptors, Cell Surface/metabolism , Adenoma/genetics , Adenoma/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Cell Proliferation , Cells, Cultured , Epithelial Cells/immunology , Epithelial Cells/metabolism , Female , Gene Expression Regulation, Neoplastic/immunology , Humans , Immunohistochemistry , Interleukin-6/genetics , Male , Membrane Glycoproteins/genetics , Middle Aged , Pituitary Neoplasms/genetics , Pituitary Neoplasms/immunology , Prolactinoma/genetics , Prolactinoma/immunology , RNA, Messenger/analysis , Receptors, Cell Surface/genetics , Reference Values , Toll-Like Receptor 4 , Toll-Like Receptors , Tumor Cells, Cultured
15.
J Endocrinol ; 183(2): 385-94, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15531726

ABSTRACT

The oncogenic effects of epidermal growth factor (EGF) have long been established. EGF receptor (EGFr) is overexpressed in many types of tumors and constitutes a target for cancer treatment. The pituitary gland is a target of EGF action and it is very likely that EGFr plays a role in pituitary tumor formation and progression. However, there is a controversy in the literature concerning EGFr expression in the different types of pituitary adenomas. In the present study we investigated the expression pattern of the wild type EGFr (EGFrWT) and the constitutively active variant III (EGFrvIII) at the mRNA and protein levels in a large series of pituitary tumors. EGFrWT was found in a high percentage of hormone-secreting tumors, but only in a small fraction of non-functioning pituitary adenomas, while no expression of the EGFrvIII could be detected by nested RT-PCR in any tumor. Among the hormone-secreting adenomas, the highest incidence of EGFr expression was found in Cushing's pituitary adenomas. Furthermore, immunohistochemistry for the phosphorylated EGFr revealed the presence of activated EGFr in most Cushing's adenomas, compared with most pituitary adenomas. Taking into account that downregulation of p27/Kip1 plays a significant role in corticotrope tumorigenesis and that EGFr mitogenic signaling results in decreased p27/Kip1, we searched for a correlation between EGFr expression and p27/Kip1 levels in corticotropinomas. Low p27/Kip1 immunoreactivity was observed in corticotropinomas expressing EGFr. On the other hand, somatotropinomas expressing EGFr had high p27/Kip1 immunoreactivity. These data suggest a corticotrope-specific phenomenon and indicate that EGFr may have a role in the unbalanced growth of corticotrope tumoral cells.


Subject(s)
Adenoma/metabolism , Adrenocorticotropic Hormone/biosynthesis , Cushing Syndrome/metabolism , ErbB Receptors/metabolism , Pituitary Neoplasms/metabolism , Cell Cycle Proteins/analysis , Cell Cycle Proteins/metabolism , Cyclin-Dependent Kinase Inhibitor p27 , Epidermal Growth Factor/metabolism , ErbB Receptors/analysis , ErbB Receptors/genetics , Humans , Immunohistochemistry/methods , Phosphorylation , Pituitary Gland/chemistry , Pituitary Gland/metabolism , Protein Binding , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins/analysis , Tumor Suppressor Proteins/metabolism
16.
Endocr Relat Cancer ; 11(2): 333-44, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15163308

ABSTRACT

Pituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC).


Subject(s)
Adenoma/metabolism , Neoplasm Invasiveness/pathology , Pituitary Neoplasms/metabolism , Proto-Oncogene Proteins/metabolism , Adenoma/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Genes, Tumor Suppressor , Humans , Immunoenzyme Techniques , Male , Middle Aged , Pituitary Gland/metabolism , Pituitary Gland/pathology , Pituitary Neoplasms/pathology
18.
Dtsch Med Wochenschr ; 129(13): 689-92, 2004 Mar 26.
Article in German | MEDLINE | ID: mdl-15026965

Subject(s)
Gastrinoma/therapy , Insulinoma/therapy , Multiple Endocrine Neoplasia Type 1/therapy , Pancreatic Neoplasms/therapy , Anti-Ulcer Agents/administration & dosage , Anti-Ulcer Agents/therapeutic use , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Catheter Ablation , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Clinical Trials as Topic , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Etoposide/administration & dosage , Etoposide/therapeutic use , Gastrinoma/drug therapy , Gastrinoma/mortality , Gastrinoma/surgery , Gastrointestinal Agents/administration & dosage , Gastrointestinal Agents/therapeutic use , Humans , Insulinoma/drug therapy , Insulinoma/surgery , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Interferon-alpha/therapeutic use , Multiple Endocrine Neoplasia Type 1/drug therapy , Multiple Endocrine Neoplasia Type 1/surgery , Neoplasm Metastasis , Octreotide/administration & dosage , Octreotide/therapeutic use , Omeprazole/administration & dosage , Omeprazole/therapeutic use , Palliative Care , Pancreatectomy , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/surgery , Prospective Studies , Proton Pump Inhibitors , Randomized Controlled Trials as Topic , Somatostatin/analogs & derivatives , Streptozocin/administration & dosage , Streptozocin/therapeutic use , Time Factors , Zollinger-Ellison Syndrome/surgery
19.
Exp Clin Endocrinol Diabetes ; 112(1): 18-23, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14758567

ABSTRACT

Estrogens are considered to be critically involved in lactotroph and lactosomatotroph pituitary tumor development. In addition to direct effects, estradiol-induced tumor formation may involve alterations in growth factor and cytokine production. We have studied whether estradiol stimulates the production of the angiogenic vascular endothelial growth factor and the potential tumor progression factor interleukin-6 in 5 lactotroph (LA) and 5 lactosomatotroph (LSA) human pituitary adenoma cell cultures. All tumors secreted heterogenous basal amounts of VEGF (18.0 +/- 1.4 to 425 +/- 26 pg/ml per 24 h) and IL-6 (18.1 +/- 1.5 to 604 +/- 17 pg/ml per 24 h). Estradiol (100 nM) significantly enhanced VEGF release in all LA and LSA cell cultures (47 to 168 % above basal). IL-6 secretion was stimulated in 3 out of 5 LA and in all LSA cell cultures (31 to 287 % above basal). In cell cultures obtained from tumors from which sufficient cells could be isolated, a dose-dependent effect of estradiol (1 to 100 nM) on VEGF and IL-6 production was observed. Stimulation of IL-6 and/or VEGF secretion by estradiol in the majority of human lactotroph and lactosomatotroph adenoma cell cultures studied, suggests that estrogens may contribute to adenoma expansion through the stimulation of these auto-/paracrine-acting adenoma progression factors.


Subject(s)
Estradiol/pharmacology , Interleukin-6/biosynthesis , Pituitary Neoplasms/metabolism , Prolactinoma/metabolism , Vascular Endothelial Growth Factor A/biosynthesis , Adult , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interleukin-6/metabolism , Male , Middle Aged , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A/metabolism
20.
Exp Clin Endocrinol Diabetes ; 111(5): 278-82, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12951634

ABSTRACT

Circulating concentrations of leptin are exceedingly low in severe malnutrition as seen in the acute state of anorexia nervosa (AN). During refeeding therapy plasma leptin levels increase to normal and in some cases peak at values in excess of the BMI of matched controls even before a normal body weight has been achieved. Peak leptin levels are possibly the cause of an increased energy expenditure during this stage of the disorder and might predispose to renewed weight loss (rebound phenomenon). In this study we investigated the role of leptin fluctuations as a prognostic factor of therapeutic success in AN. In 11 anorectic female patients serum leptin levels, BMI and body fat percentage were evaluated in four-week intervals during a conventional refeeding program over three months (group 1). The results of the first two measurements were used to determine a range of increases in leptin levels in relation to increases in BMI. The values between the 25th and 75th percentiles determined the reference range. In a second group of 9 anorectic female patients serum leptin levels, BMI, body fat percentage and the increase in the leptin level in relation to the BMI of each subject were investigated for three months every two weeks. These patients were also treated according to the same conventional refeeding program, but the caloric intake was reduced or increased (+/-250 kcal/d) if the increase in the leptin level, in relation to the increase in the BMI, had exceeded or fallen short of the reference range. During the refeeding therapy every subject of each group experienced increases in serum leptin levels, BMI and body fat percentage. Six subjects of group 1 and six subjects of the second group had an increase in leptin levels in relation to the increase of the BMI out of the reference range at least once. To investigate the therapeutic outcome of leptin monitoring and the following alteration of caloric intake, weight gain of the patients of both groups during the whole treatment was compared. No significant difference was found. Our results probably do not support the findings that high leptin levels predispose to a renewed loss of weight. The outcome in our patients whose caloric intake was modified due to their serum leptin levels was not significantly improved.


Subject(s)
Anorexia/blood , Anorexia/diet therapy , Leptin/blood , Adipose Tissue/anatomy & histology , Biomarkers/blood , Body Mass Index , Body Weight , Energy Intake , Fasting , Female , Humans , Monitoring, Physiologic , Predictive Value of Tests , Prognosis , Reference Values , Time Factors , Weight Gain/physiology
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