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Ectopic ACTH-syndrome is a rare cause of Cushing's disease. Despite extensive diagnostic procedures the source of ACTH secretion often remains occult. This case describes a 45-year old woman with an ectopic Cushing's syndrome. Extensive imaging procedures including CT scan of chest and abdomen, octreotide scan and MRI of the chest and pituitary did not reveal the source of ACTH secretion. In consideration of an occult source of ACTH secretion we started a therapeutic trial with cabergoline (0.5 mg/d), a dopamine receptor agonist, which has been shown to be effective in ectopic Cushing's syndrome. 2 months after cabergoline treatment had been initiated, ACTH and cortisol levels normalized in association with significant improvement of the clinical symptoms. During follow-up a [68Ga-DOTA- d Phe¹, Tyr³ ]- octreotate ([68 Ga-DOTA]-TATE) PET-CT was performed revealing a somatostatin receptor positive lesion in the right sphenoidal sinus suggesting the source of ACTH secretion. The patient was cured by transnasal resection of the polypoid lesion, which was immunohistochemically characterized as an ACTH-positive neuroendocrine tumor. This case report demonstrates the management of ectopic ACTH-syndrome by molecularly targeted therapy with dopamine receptor agonists as well as improved detection of the ectopic ACTH source by novel imaging modalities, such as [68Ga-DOTA]-TATE PET specifically targeting somatostatin receptor subtype-2 with high affinity. [ABSTRACT FROM AUTHOR]

Background: NETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression.Methods: Thirty five patients (pat.) (25 male, 10 female, 63 ± 9 years) with progressive, metastasized NET (23 small intestinal, 5 lung, 4 CUP, 1 rectal, 1 gastric and 1 paraganglioma) were included. All patients previously received 4 PRRT cycles with 177Lu-DOTATATE and showed initial response. SPECT based dosimetry was applied to determine kidney and tumor doses. Therapy response was evaluated using 68Ga-DOTATATE PET/CT (with high dose CT), CT alone or MRI (RECIST 1.1), toxicity was defined using CTCAE 5.0 criteria. 99mTc99-MAG3 scintigraphy was used to assess potential renal tubular damage. Progression free survival (PFS) and Overall survival (OS) analysis was performed with the Kaplan-Meier-method.Results: The median PFS after initial PRRT was 33 months (95% CI: 30-36). The mean cumulative dose for including salvage PRRT was 44 GBq (range 33.5-47). One pat. (2.9%) showed grade 3 hematotoxicity. Kidney dosimetry revealed a mean cumulative kidney dose after a median of 6 PRRT cycles of 23.8 Gy. No grade 3 / 4 nephrotoxicity or relevant decrease in renal function was observed. Follow-up imaging was available in 32 patients after salvage therapy. Best response according to RECIST 1.1. was PR in one patient (3.1%), SD in 26 patients (81.3%) and PD in 5 patients (15.6%). PFS after salvage therapy was 6 months (95% CI: 0-16; 8 patients censored). Mean OS after initial PRRT was 105 months (95% CI: 92-119) and 51 months (95% CI: 41-61) after start of salvage therapy. Median OS was not reached within a follow-up of 71 months after initial PRRT and 25 months after start of salvage PRRT, respectively.Conclusions: Salvage therapy with 177Lu-DOTATATE is safe and effective even in patients with extensive previous multimodal therapies during disease progression and represents a feasible and valuable therapy option for progressive NET. [ABSTRACT FROM AUTHOR]

Our retrospective single-center study aims to evaluate the impact of structured reporting (SR) using a self-developed template on report quality compared to free-text reporting (FTR) in [ 18 F]SiTATE Positron Emission Tomography/Computer Tomography (PET/CT) for the primary staging and therapy monitoring of patients diagnosed with neuroendocrine tumors (NET). In total 50 patients were included. FTRs and SRs were generated post-examination. All reports were evaluated by a radiologist and a surgeon through a questionnaire to determine their contribution to facilitating clinical decision-making and to assess their completeness, linguistic quality, and overall quality. SR significantly increased the capacity of facilitating therapy decision-making from 32% in FTR to 55% in SR (p < 0.001). Trust in the report was significantly higher in SR with a mean of 5.0 (SD = 0.5) vs. 4.7 (SD = 0.5) for FTR (p < 0.001). SR received significantly higher mean ratings regarding linguistic quality with 4.7 for SR vs. 4.4 for FTR (p = 0.004) and overall report quality with a mean of 4.9 for SR vs. 4.6 for FTR (p < 0.001). Concluding that SR enhances the overall quality of reports in [ 18 F]SiTATE-PET/CTs for NET staging, serving as a tool to streamline clinical decision-making and enhance interdisciplinary communication in the future., Competing Interests: Declarations. Competing interests: AHo reports compensation for scientific consulting by ABX advanced biochemical compounds. MB received consulting/speaker honoraria from Life Molecular Imaging, GE healthcare, and Roche, and reader honoraria from Life Molecular Imaging. All the remaining authors declare no conflict of interest. Ethics approval: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (Ethics Committee, Medical Faculty, Ludwig-Maximilians-University Munich; 20-1077; date of approval: 09 December 2020). Consent to participate: Due to the retrospective nature of the study, the Ethics Committee of the Medical Faculty at Ludwig-Maximilians-University Munich waived the need of obtaining informed consent., (© 2025. The Author(s).)

Background: This study aimed to assess 68 Ga-DOTA-TATE (-TOC) PET/CT quantitative parameters in monitoring and predicting everolimus response in neuroendocrine tumor (NET) patients with hepatic metastases (NELM)., Patients and Methods: This retrospective analysis included 29 patients with 62 target lesions undergoing everolimus treatment and pre-therapy, and follow-up 68 Ga-DOTA-TATE (-TOC) PET/CT scans. Response evaluation utilized progression-free survival (PFS) categorized as responders (R; PFS > 6 months) and non-responders (NR; PFS ≤ 6 months). Lesion size and density, along with maximum and median standardize uptake value (SUV) in target lesions, liver, and spleen were assessed. Tumor-to-spleen (T/S) and tumor-to-liver (T/L) ratios were calculated, including the tumor-to-spleen (T/S) ratio and tumor-to-liver (T/L) ratio (using SUVmax/SUVmax, SUVmax/SUVmean, and SUVmean/SUVmean)., Results: PET/CT scans were acquired 19 days (interquartile range [IQR] 69 days) pre-treatment and 127 days (IQR 74 days) post-starting everolimus. The overall median PFS was 264 days (95% CI: 134-394 days). R exhibited significant decreases in Tmax/Lmax and Tmean/Lmax ratios compared to NR (p = 0.01). In univariate Cox regression, Tmean/Lmax ratio was the sole prognostic parameter associated with PFS (HR 0.5, 95% CI 0.28-0.92, p = 0.03). Percentage changes in T/L and T/S ratios were significant predictors of PFS, with the highest area under curve (AUC) for the percentage change of Tmean/Lmax (AUC = 0.73). An optimal threshold of < 2.5% identified patients with longer PFS (p = 0.003). No other imaging or clinical parameters were predictive of PFS., Conclusions: This study highlights the potential of quantitative SSTR-PET/CT in predicting and monitoring everolimus response in NET patients. Liver metastasis-to-liver parenchyma ratios outperformed size-based criteria, and Tmean/Lmax ratio may serve as a prognostic marker for PFS, warranting larger cohort investigation., (© 2024 Homeira Karim et al., published by Sciendo.)

Background: This study explores the predictive and monitoring capabilities of clinical and multiparametric MR parameters in assessing capecitabine and temozolomide (CAPTEM) therapy response in patients with neuroendocrine tumors (NET)., Patients and Methods: This retrospective study (n = 44) assessed CAPTEM therapy response in neuroendocrine liver metastases (NELM) patients. Among 33 monitored patients, as a subgroup of the overall study cohort, pretherapeutic and follow-up MRI data (size, apparent diffusion coefficient [ADC] values, and signal intensities), along with clinical parameters (chromogranin A [CgA] and Ki-67%), were analyzed. Progression-free survival (PFS) served as the reference. Responders were defined as those with PFS ≥ 6 months., Results: Most patients were male (75%) and had G2 tumors (76%) with a pancreatic origin (84%). Median PFS was 5.7 months; Overall Survival (OS) was 25 months. Non-responders (NR) had higher Ki-67 in primary tumors (16.5 vs . 10%, p = 0.01) and increased hepatic burden (20% vs . 5%, p = 0.007). NR showed elevated CgA post-treatment, while responders (R) exhibited a mild decrease. ADC changes differed significantly between groups, with NR having decreased ADCmin (-23%) and liver-adjusted ADCmean/ADCmean liver (-16%), compared to R's increases of ADCmin (50%) and ADCmean/ADCmean liver (30%). Receiver operating characteristic (ROC) analysis identified the highest area under the curve (AUC) (0.76) for a single parameter for ∆ ADC mean/liver ADCmean, with a cut-off of < 6.9 (76% sensitivity, 75% specificity). Combining ∆ Size NELM and ∆ ADCmin achieved the best balance (88% sensitivity, 60% specificity) outperforming ∆ Size NELM alone (69% sensitivity, 65% specificity). Kaplan-Meier analysis indicated significantly longer PFS for ∆ ADCmean/ADCmean liver < 6.9 (p = 0.024) and ∆ Size NELM > 0% + ∆ ADCmin < -2.9% (p = 0.021)., Conclusions: Survival analysis emphasizes the need for adapted response criteria, involving combined evaluation of CgA, ADC values, and tumor size for monitoring CAPTEM response in hepatic metastasized NETs., (© 2024 Maria Ingenerf et al., published by Sciendo.)

Background: This study aimed to evaluate the predictive and monitoring role of somatostatin receptor (SSTR) positron emission tomography-computed tomography (PET/CT) and clinical parameters in patients with neuroendocrine liver metastases (NELM) from pancreatic neuroendocrine tumors (pNET) receiving capecitabine and temozolomide (CAPTEM)., Patients and Methods: This retrospective study included twenty-two patients with pNET and NELM receiving CAPTEM who underwent pre- and post-therapeutic 68 Ga-DOTATATE/-TOC PET/CT. Imaging (including standardized uptake value [SUV] of target lesions [NELM and pNET], normal spleen and liver) and clinical (Chromogranin A [CgA], Ki-67) parameters were assessed. Treatment outcome was evaluated as response according to RECIST 1.1, progression free survival (PFS) and overall survival (OS)., Results: The median PFS (mPFS) was 7 months. Responders had a significantly longer mPFS compared to non-responders (10 vs . 4 months p = 0.022). Median OS (mOS) was 33 months (mOS: responders = 80 months, non-responders = 24 months p = 0.182). Baseline imaging showed higher SUV in responders, including absolute SUV, tumor-to-spleen (T/S), and tumor-to-liver (T/L) ratios (p < 0.02). All SUV parameters changed only in the responders during follow-up. Univariable Cox regression analysis identified baseline Tmax/Smean ratio and percentage change in size of pNETs as significant factors associated with PFS. A baseline Tmax/Smean ratio < 1.5 was associated with a shorter mPFS (10 vs . 4 months, (p < 0.05)). Prognostic factors for OS included age, percentage change in CgA and in T/S ratios in univariable Cox regression., Conclusions: SSTR-PET/CT can be useful for predicting response and survival outcomes in pNET patients receiving CAPTEM: Higher baseline SUV values, particularly Tmax/Smean ratios of liver metastases were associated with better response and prolonged PFS., (© 2023 Maria Ingenerf et al., published by Sciendo.)

Modulation of the redox system in cancer cells has been considered a promising target for anti-cancer therapy. The novel MTH1 inhibitor TH588 proved tremendous potential in terms of cancer cell eradication, yet its specificity has been questioned by recent reports, indicating that TH588 may also induce cancer cell death by alternative mechanisms than MTH1 inhibition. Here we used a panel of heterogeneous neuroendocrine tumor cells in order to assess cellular mechanisms and molecular signaling pathways implicated in the effects of TH588 alone as well as dual-targeting approaches combining TH588 with everolimus, cytotoxic 5-fluorouracil or γ-irradiation. Our results reflect that TH588 alone efficiently decreased the survival of neuroendocrine cancer cells by PI3K-Akt-mTOR axis downregulation, increased apoptosis and oxidative stress. However, in the dual-targeting approaches cell survival was further decreased due to an even stronger downregulation of the PI3K-Akt-mTOR axis and augmentation of apoptosis but not oxidative stress. Furthermore, we could attribute TH588 chemo- and radio-sensitizing properties. Collectively our data not only provide insights into how TH588 exactly kills cancer cells but also depict novel perspectives for combinatorial treatment approaches encompassing TH588.

Objectives: To quantify the additional value of 68 Ga-DOTA-TATE PET/CT in comparison with contrast-enhanced CT alone for primary tumour detection in neuroendocrine cancer of unknown primary (CUP-NET)., Methods: In total, 38 consecutive patients (27 men, 11 women; mean age 62 years) with histologically proven CUP-NET who underwent a contrast-enhanced 68 Ga-DOTA-TATE PET/CT scan for primary tumour detection and staging between 2010 and 2014 were included in this IRB-approved retrospective study. Two blinded readers independently analysed the contrast-enhanced CT and 68 Ga-DOTA-TATE PET datasets separately and noted from which modality they suspected a primary tumour. Consensus was reached if the results were divergent. Postoperative histopathology (24 patients) and follow-up 68 Ga-DOTA-TATE PET/CT imaging (14 patients) served as the reference standards and statistical measures of diagnostic accuracy were calculated accordingly., Results: The majority of confirmed primary tumours were located in the abdomen (ileum in 19 patients, pancreas in 12, lung in 2, small pelvis in 1). High interobserver agreement was noted regarding the suspected primary tumour site (Cohen's k 0.90, p < 0.001). 68 Ga-DOTA-TATE PET demonstrated a significantly higher sensitivity (94 % vs. 63 %, p = 0.005) and a significantly higher accuracy (87 % vs. 68 %, p = 0.003) than contrast-enhanced CT., Conclusions: Ga-DOTA-TATE PET/CT compared with contrast-enhanced CT alone provides an improvement in sensitivity of 50 % and an improvement in accuracy of 30 % in primary tumour detection in CUP-NET., Key Points: • 68 Ga-DOTA-TATE PET augments the sensitivity of contrast-enhanced CT by 50 % • 68 Ga-DOTA-TATE PET augments the accuracy of contrast-enhanced CT by 30 % • Somatostatin receptor-targeted hybrid imaging optimizes primary tumour detection in CUP-NET.

Neuroendocrine neoplasms of the gastroenteropancreatic system are classified according to the WHO classification system 2010 into neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC). The proliferation index Ki-67 and the grading of NETs is essential for the prognosis and therapy plan. Also NET tumor biology and therapeutic options may differ depending on the primary NET tumor location. Palliative therapy of inoperable NETs involves local ablative methods in cases of primary liver metastasis, peptide receptor radionuclide therapy (PRRT) in NETs expressing somatostatin receptors and different options for medicinal therapy. This manuscript reviews the current role of biotherapy with somatostatin analogues and interferon-alpha for symptom and tumor control. In addition conventional chemotherapy regimens and novel molecular targeted therapeutic options, such as sunitinib or everolimus in NET of the pancreas are reviewed. Possible therapeutic algorithms are discussed.

Unlabelled: We hypothesized that (68)Ga-DOTATATE uptake of neuroendocrine tumors is sensitive to therapy with a nonradioactive somatostatin analog., Methods: (68)Ga-DOTATATE PET/CT was used to examine 105 patients, 35 of whom had been pretreated with long-acting octreotide. The maximum standardized uptake value (SUV(max)) of target tissues, as well as metastases, was compared between the groups of patients with (group 1) and without (group 2) octreotide treatment., Results: The SUV(max) of the spleen and liver was significantly lower in group 1 than in group 2 (both P < 0.001). There were no significant group differences in SUV(max) for primary tumors (28.6 ± 6.8 vs. 32.9 ± 31.5) or metastases in the liver (27.2 ± 14.8 vs. 25.7 ± 10.7), lymph nodes (41.4 ± 19.5 vs. 25.0 ± 6.3), or skeleton (39.5 ± 22.0 vs. 15.4 ± 7.8). In 9 patients available for intraindividual comparison, tumor uptake was unaffected by treatment with somatostatin analogs (21.7 vs. 20.6; P = 0.93)., Conclusion: Treatment with a long-acting somatostatin analog did not significantly reduce (68)Ga-DOTATATE binding in neuroendocrine tumors but tended to improve the tumor-to-background ratio.

In patients with carcinoid syndrome, there has always to be considered cardiac impairment. We report about two patients with hepatic and bone metastases of a neuroendocrine tumor of the midgut, who suffered from progressive dyspnea. This was caused in both cases by a right-to-left atrial shunt, in case 1 based on a patent foramen ovale (PFO), in case 2 based on a secundum atrial septal defect. Symptoms were significantly reduced by percutaneous closure of PFO and ASD, respectively. Right-to-left atrial shunt was facilitated by right-sided carcinoid induced endocardial fibrosis with the consequence of severe tricuspid regurgitation, leading to an increase of right atrial pressure.

Two patients aged 24 and 64 years presented at our hospital with similar symptoms including bone pain and muscle weakness. Basic laboratory tests and urinary diagnostics, bone densitometry and bone histology revealed severe osteomalacia with renal phosphate wasting. After the exclusion of other causes an extensive tumor search was performed due to suspected tumor-induced osteomalacia. In one patient a mesenchymal tumor was found in the thigh and completely resected. After surgery the patient showed a rapid recovery from osteomalacia. Because the search was unsuccessful in the other patient phosphorus supplementation in combination with calcitriol was started. Despite continuing renal phosphate wasting a significant increase in bone mineral density was observed.

Neuroendocrine tumours (NET) differ appreciably with regard to their biological behaviour from tumours of epithelial origin. In general this leads to a better 5-year survival rate. Liver metastases per se and also in cases of NET result in a significantly poorer survival in comparison to tumours without metastases. In contrast to those with epithelial tumours, about (2/3) of the NET patients already have liver metastases at the time of diagnosis. Thus, in spite of the rarity of these tumours, the surgeon is frequently confronted with this tumour entity. Among other factors the prognosis depends on the primary localisation of the NET (pancreatic NET poorer than non-pancreatic NET) as well as the staging and grading (proliferation index Ki-67) of the tumours. In this article, we characterise the surgical and ablative therapies for liver metastases from NET of the gastrointestinal tract from both curative and palliative points of view on the basis of the recently published guidelines of the ENETS (European Neuroendocrine Tumour Society). Furthermore, the various options for conservative therapy are discussed and assessed for their relative values. For localised tumour disease, also of both liver lobes, the resection of liver metastases (single or multi-stage operation, if necessary in combination with RFA) remains the standard therapy. Liver resections as debulking operations (target: resection of > 90 % tumour volume) with good preoperative planning can also be carried out under palliative criteria. For diffuse liver metastases with more than 50 % tumour volume in the liver, orthotopic liver transplantation, if necessary even as a multivisceral transplantation, may be considered in individual cases. For inoperable metastases, depending on the tumour load in the liver, the tumour localisation (intrahepatic versus intra- and extrahepatic), the tumour grading (proliferation index Ki-67), the dynamics of tumour growth, and the primary localisation of the tumour, differentiated biotherapy with somatostatin analogues, peptide-mediated radioreceptor therapy (PRRT), transarterial chemoembolisation (TACE) and selective intraarterial radiotherapy (SIRT), chemotherapy and new molecular target-directed therapy options can be employed. The utilities of these treatment options are presented and discussed., ((c) Georg Thieme Verlag Stuttgart-New York.)

As a consequence of recent studies the treatment of gastrointestinal cancers has become challenging and is undergoing constant changes on the basis of the results of new trials. The steering committee of the working group on gastrointestinal cancers of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten has decided to summarise and present recent updates of the current treatment guidelines and recommendations for the most relevant gastrointestinal malignancies. In this review we have included recent findings from large trials on esophageal, gastric, pancreatic, cholangiocellular and liver cancers, as well as colorectal cancers, neuroendocrine tumours and lymphomas. This includes an update on the combination with novel targeted agents and the introduction of potential predictive biomarkers in the selection of the appropriate treatment strategy.

ACTH-independent macronodular bilateral adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome. Here, massive bilateral adrenal enlargement is accompanied by ACTH-independent hypercortisolism. The detection of ectopic hormone receptors which, according to a new concept, control the cortisol production in AIMAH, offers the opportunity of normalizing the hypercortisolism by pharmacologically influencing the receptor or its ligand. We here present the case of a 46 year old male patient. Using clinical and pharmacological tests we found evidence of ectopic receptors in the AIMAH. After suspicion was erroneously raised that a malignant lesion could be inside of the right adrenal mass, the decision was made to resect both adrenals instead of trying to treat the hypercortisolism by pharmacological means. This surgical approach (bilateral adrenalectomy) has been the standard way of treatment for AIMAH until the new concept of the ectopic receptors was developed.

Background: Measurement of late-night salivary cortisol concentrations is increasingly used as a screening test in suspected Cushing's syndrome. Cortisol concentrations are typically extremely low in late-night samples and discordant assay-specific reference ranges have been reported. Therefore, the aim of our study was to assess the analytical performance of the first automated cortisol immunoassay specified for salivary measurements and to establish late-night sampling reference-range data for this test., Methods: Salivary cortisol was measured using the Roche Cobas Cortisol assay (Roche Diagnostics). Five salivary pools in different concentration ranges were used to assess the inter-assay imprecision of this test in a two-centre evaluation protocol including two reagent lots. Linearity was tested by serial dilution. Salivary samples were obtained at 23:00 h from 100 apparently healthy volunteers using a commercially available salivary sampling device (Salivette, Sarstedt). A subset of 20 samples was used for method comparison with isotope dilution liquid chromatography-tandem mass spectrometry., Results: Inter-assay coefficients of variation (n=20) between 11.6% and 40.4% were found for mean cortisol concentrations between 12.9 and 2.6 nmol/L, with an estimated functional sensitivity of approximately 5.0 nmol/L. The test also gave linear results in the lowest concentration range between 1.0 and 8.3 nmol/L. Mean late-night salivary cortisol of 5.0 nmol/L was found for healthy individuals; the absolute range was 1.4-16.7 nmol/L, and the 95th percentile was 8.9 nmol/L. Substantially lower concentrations were found with isotope dilution LC-MS/MS compared to immunoassay results (mean concentrations 1.8 and 4.4 nmol/L, respectively)., Conclusions: The automated assay investigated was found to offer acceptable analytical performance in the very low concentration range required for late-night salivary cortisol, despite a very short turn-around time. Using this assay, late-night salivary cortisol concentrations below 8.9 nmol/L are typically found in healthy volunteers.

Background: Recent studies have shown that immunocompetent cells synthesize and express growth hormone (GH), growth hormone receptors (GH-R), insulin-like growth factor I (IGF-I), IGF-I receptors (IGF-I-R) and different insulin-like growth factor binding proteins (IGFBPs). The aim of the current study was to evaluate the regulation of IGFBP and IGF-I secretion from immunocompetent cells by different mitogens., Methods/results: We studied the in vitro secretion pattern of IGFBPs and IGF-I from human peripheral blood mononuclear cells (PBMC), derived from 10 normal adults and 8 GH-deficient patients with adult onset. In serum-free conditioned medium of unstimulated PBMC, derived from normal adults, Western ligand blotting (1D-WLB) revealed a 24-kD, a 34-kD and a 39/43-kD doublet band to be most prominent. According to their molecular weight and two-dimensional Western ligand blot analysis (2D-WLB), these bands are deglycosylated IGFBP-4, IGFBP-2 and IGFBP-3, respectively. When the cells were treated with the T-cell mitogen phytohemagglutinin (PHA) (10 microg/ml), a differential stimulation of IGFBPs was found with a 2.57 +/- 0.48-fold increase of IGFBP-4 (p < 0.01), a 1.55 +/- 0.13-fold increase of IGFBP-2 (p < 0.01), and a 1.35 +/- 0.19-fold increase of IGFBP-3 (n.s.). In contrast, treatment with the B-cell mitogen pokeweed mitogen (PWM) (10 microg/ml) caused only a modest 1.40 +/- 0.07-fold increase of IGFBP-4 (p < 0.01). Treatment with rhGH (100 ng/ml) or rhIGF-I (200 ng/ml) caused no significant induction of any specific band, respectively. In contrast to the secretion pattern of IGFBPs, IGF-I secretion of the PBMC was not stimulated by either PHA or PWM, but showed a significant increase after GH incubation (p < 0.01). A similar differentiated secretion pattern of IGFBPs and IGF-I was also observed in the conditioned medium of PBMC, derived from GH-deficient patients., Conclusion: In summary, at least three different IGFBPs are secreted by human PBMC. Secretion of IGFBPs by PBMC is differentially regulated by different lymphocyte mitogens. Secretion of IGFBPs by PBMC is independent of GH or IGF-I, whereas the secretion of IGF-I is stimulated by GH. PBMC derived from normal adults and GH-deficient patients show similar patterns of IGF-I and IGFBPs secretion, thus indicating that the paracrine/autocrine IGF-I-IGFBPs interactions of the PBMC are not altered by pituitary GH deficiency., (Copyright 2002 S. Karger AG, Basel)

We recently characterized leukemia inhibitory factor (LIF) as an important modulator of hypothalamo-pituitary-adrenal (HPA) axis activity. We now describe the role of interleukin (IL)-11, another member of the IL-6 cytokine family, in the neuro-immuno-endocrine modulation of the HPA axis. In murine hypothalamus, pituitary and corticotroph AtT-20 cells, IL-11 messenger RNA (mRNA) was detectable by RT-PCR only, whereas IL-11R mRNA transcripts were demonstrated by Northern blot. Using RT-PCR, IL-11 and IL-11R gene expression were also detected in normal human pituitaries, as well as in corticotropic and nonfunctioning pituitary adenomas. Incubation of AtT-20 cells for 24 h with 10(-9) M IL-11 stimulated ACTH secretion 1.4 +/- 0.1-fold (P < 0.01), whereas LIF at the same concentration caused a 1.5 +/- 0.1-fold increase (P < 0.001). POMC mRNA expression was induced by IL-11 (0.5 x 10(-9) M) and LIF (0.5 x 10(-9) M) 1.5 +/- 0.18-fold (P < 0.05) and 1.7 +/- 0.13-fold (P < 0.01), respectively. POMC promoter activity, assayed by a -706/+64 rat POMC promoter-luciferase construct, was stimulated by 0.5 x 10(-9) M IL-11 (1.9 +/- 0.06-fold; P < 0.001) and 5 mM Bu2cAMP (7.1 +/- 0.52-fold, P < 0.001), and combined treatment of IL-11 plus Bu2cAMP caused a synergistic 11.7+/-0.71-fold increase ofluciferase activity (P < 0.001 vs. Bu2cAMP alone). Gene expression of SOCS-3, an intracellular inhibitor of cytokine action, peaked as early as 60 min after incubation with IL-11 (0.5 x 10(-9) M) and was induced 3.5-fold. In comparison to mock-transfected AtT-20 cells (AtT-20M), stable overexpression of SOCS-3 (AtT-20S) resulted in significant inhibition of ACTH secretion induced by IL-11 alone (1.5 +/- 0.09 vs. 1.1 +/- 0.04-fold induction, P < 0.01) and IL-11 plus Bu2cAMP (2.1 +/- 0.21 vs. 1.5 +/- 0.06-fold, P < 0.05), but not by Bu2cAMP alone (1.5 +/- 0.12 vs. 1.4 +/- 0.06). In summary, human and murine pituitary express IL-11 and IL-11R transcripts. In murine corticotroph AtT-20 cells, IL- 11 induces POMC gene transcription and ACTH secretion. IL-11 induction of SOCS-3 indicates an intracellular negative feedback control of cytokine-induced POMC expression and ACTH secretion. Thus, IL-11 regulates the HPA axis similarly to LIF, providing further evidence for a redundant cytokine network in the neuro-immuno-endocrine regulation of the HPA axis.

As pituitary leukemia-inhibitory factor (LIF) mediates neuroimmune signals to the hypothalamo-pituitary-adrenal axis, we tested the role of intracellular SOCS-3 in corticotroph function. SOCS-3, a cytokine-inducible protein of the suppressor of cytokine signaling (SOCS) family, is expressed in the murine pituitary in vivo. After i.p. injection of LIF (5.0 micrograms/mouse) or interleukin-1 beta (0.1 microgram/mouse) pituitary SOCS-3 mRNA was stimulated 9-fold and 6-fold, respectively. Also, in corticotroph AtT-20 cells LIF and interleukin-1 beta both potently stimulated SOCS-3 mRNA expression. In AtT-20 cells, stable overexpression of SOCS-3 inhibits basal and LIF-stimulated ACTH secretion in comparison to mock-transfected AtT-20 cells (basal: 4426 +/- 118 vs. 4973 +/- 138 pg/ml, P < 0.05; LIF-induced: 5511 +/- 172 vs. 9308 +/- 465 pg/ml, P < 0.001). Stable overexpression of SOCS-3 cDNA in AtT-20 cells also resulted in a significant 50% decrease of LIF-induced POMC mRNA levels (P < 0.05) and POMC promoter activity (P < 0.001), respectively. Western blot analysis revealed an inhibition of LIF-stimulated gp130 and STAT-3 phosphorylation in SOCS-3 overexpressing AtT-20 cells. Thus, SOCS-3 inhibits the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathway, which is known to mediate LIF-stimulated ACTH secretion and POMC gene expression. In conclusion, SOCS-3 functions as an intracellular regulator of POMC gene expression and ACTH secretion, acting as a negative feedback mediator of the cytokine-mediated neuro-immuno-endocrine interface.

We have shown that leukemia inhibitory factor (LIF) is expressed in corticotroph cells and stimulates POMC gene expression and ACTH secretion in vivo and in vitro. We therefore examined the regulation of in vitro and in vivo pituitary LIF expression by cytokines known to stimulate the hypothalamo-pituitary-adrenal axis. In the corticotroph cell line AtT-20/D16v-F2, recombinant murine interleukin-1beta (IL-1beta; 0.1-10.0 ng/ml) caused a 5- to 10-fold increase in LIF messenger RNA (mRNA) levels. LIF mRNA expression was induced as early as 1 h, peaked at 2 h, and still persistently elevated above the baseline after 8 h. This effect of IL-1beta on LIF mRNA expression was abolished by preincubation with human IL-1 receptor antagonist (100 ng/ml) or antimurine IL-1beta antibody (10 microg/ml). Tumor necrosis factor-alpha (20 ng/ml) only modestly increased LIF mRNA, but was synergistic with IL-1beta (up to 2.5-fold). In contrast, IL-2 and IL-6 did not alter LIF mRNA. In C57BL/6 mice, i.p. injection of 100 ng IL-1beta increased plasma ACTH and corticosterone levels after 1 h (P < 0.02). In addition, pituitary LIF mRNA content was increased for up to 2 h in response to IL-1beta. In comparison to wild-type (+/+) B6D2F1 mice, LIF knockout mice with a deleted LIF gene (-/-) exhibited decreased plasma ACTH (631 +/- 61 vs. 376 +/- 50 pg/ml; P < 0.01) and corticosterone (783 +/- 85 vs. 433 +/- 51 ng/ml; P < 0.01) levels 1 h after i.p. IL-1beta administration. In conclusion, corticotroph LIF mRNA expression is specifically stimulated by IL-1beta and tumor necrosis factor-alpha. The attenuated hypothalamo-pituitary-adrenal response to IL-1beta in LIF knockout mice indicates that the effect of IL-1beta on ACTH secretion is modulated by LIF. Thus, LIF appears to function as an immune-neuroendocrine modulator signaling the hypothalamo-pituitary-adrenal axis.

Recently, we have shown that human fetal pituitary, mouse corticotroph AtT20 cells, and murine hypothalamus and pituitary express leukemia inhibitory factor (LIF). LIF knockout mice (LIFKO), heterozygous and wild type (wt), of B6D2F1 genetic background were used to examine whether LIF may play a role in the regulation of the hypothalamo-pituitary-adrenal axis in vivo. Resting levels of plasma ACTH and corticosterone were similar in all three genotypes. However, LIFKO mice did not respond to 30-min restraint and 45-min immobilization stress with increased plasma ACTH. Increased circulating ACTH was only observed in LIFKO mice after very short immobilization stress (15 min), but this ACTH level was lower than in wt animals (P < 0.05). Injection of mycobacterial adjuvant resulted in a 2-fold increase of corticosterone levels 7 days after treatment in wt, but not LIFKO, mice (P < 0.05). Pituitary POMC messenger RNA (mRNA) levels were very low in LIFKO animals. Although 15 and 45 min of immobilization stress resulted in enhanced POMC mRNA content in all three groups, this elevation was lowest in LIFKO mice. Injection of 12 microg murine LIF to LIFKO and normal C57BL/6 animals resulted in increased plasma ACTH and corticosterone levels and elevated pituitary POMC mRNA levels in both LIF-repleted and LIF-depleted mice. Thus, LIF appears to play an important role in activating the hypothalamo-pituitary-adrenal axis during stress and inflammation.

Human growth hormone (GH) and insulin-like growth factor I (IGF-I) are known to bind to, and exert modulatory effects on, different immunocompetent cells, including CD16+/CD3- natural killer (NK) cells. NK cells are involved in various non-major-histocompatibility-complex-restricted actions of the immune system. Although no clinically significant defect in tumour or virus defence has been reported in GH-deficient patients, the data available indicate decreased NK cell activity in these patients. In most studies, the absolute number and percentage of NK cells have been found to be normal. Substitution with GH has been reported to normalize the decreased NK cell activity in GH-deficient patients. In a cross-sectional study in GH-deficient adults, decreased basal and interferon-beta (IFN-beta)-stimulated NK cell activity in vitro. Preliminary data on GH binding to NK cells indicate enhanced binding in GH-deficient patients when compared with normal controls.

We have identified and characterized insulin-like growth factor (IGF)-I and IGF-II/mannose-6-phosphate (IGF-II/M6P) receptors in normal adult human adrenocortical tissue. Furthermore, we investigated the IGF-I receptor concentration and binding characteristics in benign and carcinomatous adrenocortical tumors. Membrane preparations of 14 normal adrenocortical glands showed a mean specific 125I-IGF-I binding (SB) of 5.0 +/- 0.5% and a competition by unlabeled ligands which is characteristic of the IGF-I receptor. The Scatchard analysis revealed a single class of high affinity binding sites with a dissociation constant (Kd) of 0.16 +/- 0.03 nmol/l, and a receptor concentration (RC) of 19.2 +/- 2.5 nmol/kg protein. Affinity cross-linking experiments with normal and tumorous adrenocortical tissue displayed a band at an apparent molecular mass of 135 kDa, corresponding to the size of the normal alpha-subunit of the IGF-I receptor. In agreement, 125I-IGF-II binding to normal adult human adrenocortical membranes was characteristic for the IGF-II/M6P receptor, and the Scatchard analysis revealed the presence of a single class of high affinity binding sites (SB 7.5 +/- 0.5%, RC 1137 +/- 265 nmol/kg protein, Kd 2.20 +/- 0.46 nmol/l, n = 6). The identity of the IGF-II/M6P receptor in adrenocortical tissue was further confirmed by Western blotting showing a specific band at 220 kDa. When 125I-IGF-I binding in adrenocortical hyperplasias (SB 4.1 +/- 0.4%, RC 19.6 +/- 2.0 nmol/kg protein, Kd 0.19 +/- 0.04 nmol/l, n = 4) and adenomas (SB 4.0 +/- 1.1%, RC 17.5 +/- 3.1 nmol/kg protein, Kd 0.21 +/- 0.04 nmol/l, n = 4) was compared with the 125I-IGF-I binding in normal adrenocortical tissue, similar IGF-I receptor concentration and binding kinetics were found. In contrast, three out of four hormonally active adrenocortical carcinomas showed a strongly elevated specific 125I-IGF-I binding with a 3- to 4-fold increase in IGF-I receptor concentration, as compared with normal adrenocortical tissue. This resulted in a significantly higher mean specific binding and receptor concentration in adrenocortical carcinomas, while the binding kinetics and the size of the alpha-subunit of the IGF-I receptor remained unaltered (n = 4, SB 13.8 +/- 4.2%, RC 72.2 +/- 21.3 nmol/kg protein, Kd 0.17 +/- 0.02 nmol/l). In summary, we show that intact IGF-I and IGF-II receptors are present in normal adult human adrenocortical tissue. While the abundance of the IGF-I receptor in adrenocortical hyperplasias and adenomas was similar to normal tissue, a strong overexpression of the intact IGF-I receptor was found in three out of four adrenocortical carcinomas.

1. Morphine suppresses the release of pancreatic polypeptide, a hormone under vagal cholinergic control. The intention of the study was to detect whether the mu-opiate receptor agonist loperamide is also able to inhibit pancreatic polypeptide release, and to define its site of action. 2. In groups of healthy subjects (n = 6 each) stimulation of pancreatic polypeptide was assessed in five different tests: (i) insulin-hypoglycaemia; (ii) modified sham feeding; (iii) intravenous infusion of the cholecystokinin analogue ceruletide; (iv) injection of corticotropin releasing hormone; (v) infusion of the muscarinic acetylcholine agonist bethanechol. All tests were performed after oral application of either a placebo or loperamide (16 mg), tests (ii) and (iii) were repeated with loperamide in smaller doses (2 and 6 mg), with loperamide plus naloxone, with naloxone alone, and with infusion of atropine. Plasma concentrations of pancreatic polypeptide were measured radioimmunologically. 3. Release of pancreatic polypeptide in test (i) to (iv) was completely blocked by 16 mg loperamide, whereas bethanechol-stimulated release (test 5) was not influenced. Tests (ii) and (iii) showed that the inhibition was dose-dependent and could be attenuated by naloxone. The inhibitory effect of loperamide was comparable with that of atropine. 4. We conclude that loperamide causes a dose-dependent inhibition of pancreatic polypeptide release mediated by vagal-cholinergic pathways, but does not have an atropine-like peripheral action.

Growth hormone-releasing hormone (GHRH), growth hormone (GH), prolactin (PRL) and insulin-like growth factor I (IGF-I) are synthesized and secreted by various immunocompetent cells. In addition, GHRH, GH, PRL and IGF-I receptors are expressed on immune cells. Growth hormone, PRL and IGF-I stimulate the proliferation of immunocompetent cells and modulate humoral and cellular immune functions, i.e. immunoglobuline secretion of B cells, thymulin secretion of thymic epithelial cells, natural killer cell activity, phagocytosis, oxidative burst and killing capacity of neutrophils and macrophages. No clinically significant cellular or humoral immunodeficiency has been found in GH-deficient patients. However, several immunological parameters and functions are altered in GH-deficient patients when compared to normal controls. The data available to date indicate that endocrine and pleiotropic para- and autocrine mechanisms of action are involved in a neuropeptide immune network, including GH, PRL and IGF-I as modulators of immune function.

Ceruletide, a cholecystokinin-8-like peptide, was recently reported to stimulate ACTH secretion in man. The aim of this study was to investigate the effect of the mu-opiate agonist, loperamide, and the opiate antagonist, naloxone, on ceruletide-induced ACTH secretion in man. In 6 normal subjects, basal ACTH and cortisol plasma levels were significantly suppressed 3 h after loperamide administration (16 mg, orally) from 5 +/- 0 to 2 +/- 0 pmol/l and from 356 +/- 44 to 154 +/- 16 nmol/l. After stimulation with 8 ng ceruletide/kg body weight/min over a period of 5 min, the maximum ACTH levels (at 7.5 min) were significantly reduced by loperamide from 26 +/- 7 to 6 +/- 1 pmol/l and the maximum cortisol levels (at 30 min) were significantly reduced from 676 +/- 47 to 392 +/- 58 nmol/l. Furthermore, the ACTH peak (delta = 7.5 min) was significantly blunted by loperamide from 21 +/- 7 to 5 +/- 1 pmol/l and the integrated area under the curve from 0 to 120 min (delta AUC) of ACTH was significantly reduced from 40 +/- 11 to 14 +/- 4 pmol x 120 min/l. The cortisol peak (delta = 30 min) and the AUC of cortisol were not significantly diminished. The suppressive effect of loperamide on basal and ceruletide-induced ACTH and cortisol secretion was completely reversed by the administration of 0.8 mg naloxone, 20 min before and during infusion of ceruletide. The administration of naloxone itself had no significant effect on ACTH or cortisol levels. In conclusion, ACTH is released by peripherally administered ceruletide within a short period.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of the antidiarrheal drug loperamide, a mu-opiate agonist, on ACTH secretion and biosynthesis, cAMP generation and phosphoinositide turnover was studied in rat anterior pituitary cell cultures. The cAMP-dependent protein kinase A pathway was stimulated with both corticotropin-releasing hormone (CRH; 2-5 nM) and the membrane-permeable Bu(2)cAMP (0.5-2.5 mM). The protein kinase C pathway was stimulated with 1 microM arginine vasopressin (AVP) and 1-10 nM phorbol 12-myristate 13-acetate (PMA). After 3.5 h, loperamide (10 microM) had no effect on basal ACTH levels but significantly suppressed CRH-induced ACTH release, in a dose-dependent manner, to 60 +/- 4% of control (100%) (p < 0.0001). After 24 h, basal proopiomelanocortin mRNA was significantly decreased to 50% of control by loperamide (p < 0.05). The suppressive effect of loperamide on CRH-induced ACTH secretion was not reversible by naloxone (0.1-1,000 microM). Morphine (0.01-10 microM) had no effect on basal and CRH-induced ACTH secretion. Loperamide did not influence basal and CRH-induced adenylate cyclase activity in anterior pituitary cell membrane preparations, but it significantly blunted Bu(2)cAMP-induced ACTH secretion in cell culture from 100 +/- 4 to 77 +/- 4% (p < 0.05). In Ca(2+)-depleted medium (Ca2+ < 0.1 mM), loperamide had no suppressive effect on CRH-induced ACTH secretion. AVP-induced ACTH secretion was significantly suppressed by loperamide from 100 +/- 5 to 74 +/- 3% (p < 0.0001), while basal and AVP-induced inositol 1-phosphate generation and PMA-induced ACTH secretion were not affected by loperamide.(ABSTRACT TRUNCATED AT 250 WORDS)