FDG-PET/CT in indeterminate thyroid nodules: cost-utility analysis alongside a randomised controlled trial.

PURPOSE: To evaluate cost-effectiveness of an [18F]FDG-PET/CT-driven diagnostic workup as compared to diagnostic surgery, for thyroid nodules with Bethesda III/IV cytology. [18F]FDG-PET/CT avoids 40% of futile diagnostic surgeries for benign Bethesda III/IV nodules. METHODS: Lifelong societal costs and quality-adjusted life years (QALYs) were assessed for 132 patients participating in a randomised controlled multicentre trial comparing [18F]FDG-PET/CT to diagnostic surgery. The observed 1-year trial results were extrapolated using a Markov model. The probability of cost-effectiveness was estimated using cost-effectiveness acceptability curves, taking uncertainty about sampling, imputation, and parameters into account. RESULTS: The observed 1-year cost difference of [18F]FDG-PET/CT as compared to diagnostic surgery was - €1000 (95% CI: - €2100 to €0) for thyroid nodule-related care (p = 0.06). From the broader societal perspective, the 1-year difference in total societal costs was - €4500 (- €9200 to €150) (p = 0.06). Over the modelled lifelong period, the cost difference was - €9900 (- €23,100 to €3200) (p = 0.14). The difference in QALYs was 0.019 (- 0.045 to 0.083) at 1 year (p = 0.57) and 0.402 (- 0.581 to 1.385) over the lifelong period (p = 0.42). For a willingness to pay of €50,000 per QALY, an [18F]FDG-PET/CT-driven work-up was the cost-effective strategy with 84% certainty. CONCLUSION: Following the observed reduction in diagnostic surgery, an [18F]FDG-PET/CT-driven diagnostic workup reduced the 1-year thyroid nodule-related and societal costs while sustaining quality of life. It is very likely cost-effective as compared to diagnostic surgery for Bethesda III/IV nodules. TRIAL REGISTRATION NUMBER: This trial is registered with ClinicalTrials.gov: NCT02208544 (5 August 2014), https://clinicaltrials.gov/ct2/show/NCT02208544 .

Oral versus intravenous antibiotic treatment of moderate-to-severe community-acquired pneumonia: a propensity score matched study.

Community-acquired Pneumonia (CAP) guidelines generally recommend to admit patients with moderate-to-severe CAP and start treatment with intravenous antibiotics. This study aims to explore the clinical outcomes of oral antibiotics in patients with moderate-to-severe CAP. We performed a nested cohort study of an observational study including all adult patients presenting to the emergency department of the Haga Teaching Hospital, the Netherlands, between April 2019 and May 2020, who had a blood culture drawn. We conducted propensity score matching with logistic and linear regression analysis to compare patients with moderate-to-severe CAP (Pneumonia Severity Index class III-V) treated with oral antibiotics to patients treated with intravenous antibiotics. Outcomes were 30-day mortality, intensive care unit admission, readmission, length of stay (LOS) and length of antibiotic treatment. Of the original 314 patients, 71 orally treated patients were matched with 102 intravenously treated patients. The mean age was 73 years and 58% were male. We found no significant differences in outcomes between the oral and intravenous group, except for an increased LOS of + 2.6 days (95% confidence interval 1.2-4.0, p value < 0.001) in those treated intravenously. We conclude that oral antibiotics might be a safe and effective treatment for moderate-to-severe CAP for selected patients based on the clinical judgement of the attending physician.

Using Design Thinking for Co-Creating an Integrated Care Pathway Including Hospital at Home for Older Adults with an Acute Moderate-Severe Respiratory Infection in the Netherlands.

Introduction: Acute respiratory infections are common in frail, community-dwelling older people and are accompanied by considerable diagnostic and prognostic uncertainties. Inadequately coordinated care is associated with unnecessary hospital referral and admission with potential iatrogenic harm. Therefore, we aimed to co-create a regional integrated care pathway (ICP), including a hospital at home journey. Developing the ICP: Tasked with using design thinking methodology, stakeholders from regional healthcare facilities, together with patient representatives, were assigned to different focus groups based on their expertise. The focus of each session was to co-create ideal patient journeys suitable for embedding in the ICP. Results: Based on these sessions, a regional cross-domain ICP was developed that comprises three patient journeys. The first journey included a hospital at home track, the second a tailored visit, with priority assessment, to regional emergency departments, and the third concerned referral to readily available nursing home 'recovery-beds' under the supervision of an elderly care medicine specialist. Conclusion: Using design thinking and involving end-users during the whole process, we created an ICP for community-dwelling frail older people with moderate-severe acute respiratory infections. This resulted in three realistic patient journeys, including a hospital at home track, which will be implemented and evaluated in the near future.

Evaluation of an integrated care pathway for out-of-hospital treatment of older adults with an acute moderate-to-severe lower respiratory tract infection or pneumonia: protocol of a mixed methods study.

INTRODUCTION: Older adults with an acute moderate-to-severe lower respiratory tract infection (LRTI) or pneumonia are generally treated in hospitals causing risk of iatrogenic harm such as functional decline and delirium. These hospitalisations are often a consequence of poor collaboration between regional care partners, the lack of (acute) diagnostic and treatment possibilities in primary care, and the presence of financial barriers. We will evaluate the implementation of an integrated regional care pathway ('The Hague RTI Care Bridge') developed with the aim to treat and coordinate care for these patients outside the hospital. METHODS AND ANALYSIS: This is a prospective mixed methods study. Participants will be older adults (age≥65 years) with an acute moderate-to-severe LRTI or pneumonia treated outside the hospital (care pathway group) versus those treated in the hospital (control group). In addition, patients, their informal caregivers and treating physicians will be asked about their experiences with the care pathway. The primary outcome of this study will be the feasibility of the care pathway, which is defined as the percentage of patients treated outside the hospital, according to the care pathway, whom fully complete their treatment without the need for hospitalisation within 30 days of follow-up. Secondary outcomes include the safety of the care pathway (30-day mortality and occurrence of complications (readmissions, delirium, falls) within 30 days); the satisfaction, usability and acceptance of the care pathway; the total number of days of bedridden status or hospitalisation; sleep quantity and quality; functional outcomes and quality of life. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee Leiden The Hague Delft (reference number N22.078) has confirmed that the Medical Research Involving Human Subjects Act does not apply to this study. The results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN68786381.

Analysis of Variation Between Diagnosis at Admission vs Discharge and Clinical Outcomes Among Adults With Possible Bacteremia.

Importance: Misdiagnosis of infection is among the most commonly made diagnostic errors and is associated with increased morbidity and mortality. Little is known about how often misdiagnosed site of infection occurs and its association with clinical outcomes. Objectives: To evaluate the discrepancy between admission and discharge site of infection diagnoses among patients with suspected bacteremia, to explore factors associated with discrepant diagnoses, and to evaluate the association with clinical outcomes. Design, Setting, and Participants: This cohort study used electronic records of 1477 adult patients who were admitted to the hospital for suspected bacteremia from April 1, 2019, to May 31, 2020, and who had blood cultures taken at the emergency department at Haga Teaching Hospital, The Hague, the Netherlands. Suspected infection sites were classified into 8 categories at admission and discharge. Misdiagnosed site was defined as a discrepancy between the suspected site of infection at admission and at discharge. Main Outcomes and Measures: Clinical outcomes were 30-day mortality, intensive care unit admission, length of hospital stay, and antibiotic use, analyzed with logistic and linear regression. Risk factors for misdiagnosed site were determined using regression analysis. Results: A total of 1477 patients (820 [55.5%] male; median [IQR] age, 68 [56-78] years) were analyzed. The rate of misdiagnosed site of infection was 11.6% (171 of 1477); 3.1% of all patients (46 of 1477) ultimately had no infection. No association was found between misdiagnosis and 30-day mortality (adjusted odds ratio [aOR], 0.8; 95% CI, 0.3-1.9; P = .60), intensive care unit admission (aOR, 1.3; 95% CI, 0.6-3.0; P = .54), and hospital length of stay (adjusted increase of stay, 15.5%; 95% CI, -3.1% to 37.7%; P = .11). Misdiagnosed site was associated with receiving broad-spectrum antibiotics (aOR, 4.0; 95% CI, 1.8-8.8; P < .001). Older age, dementia, a positive urine sediment test result without urinary symptoms, and suspicion of an intravascular, central nervous system, or bone and joint infection were risk factors for misdiagnosed site of infection. Conclusions and Relevance: In this cohort study, misdiagnosed site of infection occurred in 1 of 9 patients and was not associated with worse short-term clinical outcomes. Clinicians should be aware of risk factors associated with misdiagnosed site of infection and potential inappropriate antibiotic use.

Effects of therapy with [177Lu-DOTA 0,Tyr 3]octreotate on endocrine function.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes. METHODS: Hormone levels were measured and adrenal function assessed at baseline and up to 24 months of follow-up. RESULTS: In 35 men, mean serum inhibin B levels were decreased at 3 months post-therapy (205 +/- 16 to 25 +/- 4 ng/l, p < 0.05) and follicle-stimulating hormone (FSH) levels increased (5.9 +/- 0.5 to 22.7 +/- 1.4 IU/l, p < 0.05). These levels returned to near baseline levels. Total testosterone and sex hormone binding globulin (SHBG) levels decreased (15.0 +/- 0.9 to 10.6 +/- 1.0 nmol/l, p < 0.05 and 61.8 +/- 8.7 to 33.2 +/- 3.7 nmol, p < 0.05), respectively, whereas non-SHBG-bound T did not change. An increase (5.2 +/- 0.6 to 7.7 +/- 0.7 IU/l, p < 0.05) of luteinizing hormone (LH) levels was found at 3 months of follow-up returning to baseline levels thereafter. In 21 postmenopausal women, a decrease in levels of FSH (74.4 +/- 5.6 to 62.4 +/- 7.7 IU/l, p < 0.05) and LH (26.8 +/- 2.1 to 21.1 +/- 3.0 IU/l, p < 0.05) was found. Of 66 patients, 2 developed persistent primary hypothyroidism. Free thyroxine (FT(4)) levels decreased (17.7 +/- 0.4 to 15.6 +/- 0.6 pmol/l, p < 0.05), whereas thyroid-stimulating hormone (TSH) and triiodothyronine (T(3)) levels did not change. Reverse triiodothyronine (rT(3)) levels decreased (0.38 +/- 0.03 to 0.30 +/- 0.01 nmol/l, p < 0.05). Before and after therapy adrenocorticotropic hormone (ACTH) stimulation tests showed an adequate response of serum cortisol (> 550 nmol/l, n = 18). Five patients developed elevated HbA(1c) levels (> 6.5%). CONCLUSION: In men (177)Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non-SHBG-bound T levels remained unaffected. In the long term, gonadotropin levels decreased significantly in postmenopausal women. Only a few patients developed hypothyroidism or elevated levels of HbA(1c). Therefore, PRRT with (177)Lu-octreotate can be regarded as a safe treatment modality with respect to short- and long-term endocrine function.

Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas.

OBJECTIVE: Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age- and gender-specific standard deviations (SD) scores (Z-scores) of QoL parameters in patients treated for pituitary adenomas. PATIENTS AND METHODS: We determined Z-scores for health-related questionnaires [the Hospital Anxiety and Depression Scale (HADS), Multidimensional Fatigue Inventory (MFI)-20, Nottingham Health Profile (NHP), and Short Form Health Survey (SF-36)] in patients during long-term follow-up (13 +/- 8 years) after treatment for pituitary adenomas. Z-scores were calculated by comparing the data for 403 patients with acromegaly (n = 118), Cushing's disease (CD; n = 58), prolactinoma (n = 128), and nonfunctioning macroadenoma (n = 99) with a control population (n = 440) for each subscale of the questionnaires and for total QoL score. RESULTS: All subscales of the questionnaires and the total QoL score were negatively affected in patients compared to controls. Comparing the Z-scores, patients treated for acromegaly reported more impairment in physical ability and functioning and more bodily pain compared to patients treated for nonfunctioning macroadenoma and those treated for prolactinoma. Patients with CD reported impairment in physical functioning compared to patients treated for nonfunctioning macroadenoma. Linear regression analysis, with correction for age and gender, confirmed these findings. Additionally, CD was associated with increased anxiety. Hypopituitarism negatively influenced multiple aspects of QoL. CONCLUSION: QoL is impaired in patients during long-term follow-up after treatment of pituitary adenomas. Patients with pituitary adenomas should be informed of these persistent adverse effects of their disease on QoL to prevent inappropriate expectations with respect to the long-term results of treatment.

Bolus administration of obestatin does not change glucose and insulin levels neither in the systemic nor in the portal circulation of the rat.

Obestatin is a second peptide derived from the preproghrelin polypeptide. It was originally thought to have anorexigenic effects, thereby functioning as an antagonist of ghrelin. However, this has been a subject of debate ever since. Since acylated ghrelin strongly induces insulin resistance, it could be hypothesized that obestatin plays a role in glucose homeostasis as well. In the present study we evaluated the effect of obestatin on glucose and insulin metabolism in the systemic and portal circulation. Obestatin 200 nmol/kg was administered systemically as a single intravenous bolus injection to fasted pentobarbital anesthetized adult male Wistar rats. Up to 50 min after administration, blood samples were taken to measure glucose and insulin concentrations, both in the portal and in the systemic circulation. The effect of obestatin was evaluated in fasted and in glucose-stimulated conditions (IVGTT) and compared to control groups treated with saline or IVGTT, respectively. Intravenous administration of obestatin did not have any effect on glucose and insulin concentrations, neither systemic nor portal, when compared to the control groups. Only the glucose peak 1 min after administration of IVGTT was slightly higher in the obestatin treated rats: 605.8+/-106.3% vs. 522.2+/-47.1% in the portal circulation, respectively (NS), and 800.7+/-78.7% vs. 549.6+/-37.0% in the systemic circulation, respectively (P<0.02), but it can be debated whether this has any clinical relevance. In the present study, we demonstrated that intravenously administered obestatin does not influence glucose and insulin concentrations, neither in the portal nor in the systemic circulation.

Intravenous glucose administration in fasting rats has differential effects on acylated and unacylated ghrelin in the portal and systemic circulation: a comparison between portal and peripheral concentrations in anesthetized rats.

Ghrelin is produced by the gastrointestinal tract, and its systemic concentrations are mainly regulated by nutritional factors. Our aim was to investigate: 1) endogenous portal and systemic acylated and unacylated ghrelin levels (AG and UAG, respectively); 2) whether an iv glucose tolerance test (IVGTT) modifies AG and UAG; and 3) whether the liver passage plays a role in regulating systemic AG and UAG. To elucidate this, we evaluated the effects of IVGTT or saline injection on endogenous portal and systemic concentrations of glucose, insulin, AG, and UAG in anesthetized fasting rats. Hepatic extraction of insulin, AG, and UAG and the ratio of AG to UAG were also measured. IVGTT suppressed both portal (P < 0.03) and peripheral (P < 0.05) UAG, whereas it only blunted prehepatic, but not peripheral, AG. During fasting, hepatic clearance of UAG was 11%, and it was decreased to 8% by IVGTT. AG was cleared by the liver by 38% but unaffected by glucose. The AG to UAG ratio was higher in the portal than the systemic circulation, both in the saline (P < 0.004) and IVGTT (P < 0.0005) rats. In conclusion, this study shows that: 1) the ratio of AG to UAG is very low in the portal vein and decreases further in the systemic circulation; 2) IVGTT in anesthetized fasting rats inhibits UAG, whereas it only blunts prehepatic, but not systemic, AG; and 3) hepatic clearance of AG is much higher than that of UAG. Thus, our results suggest that peripheral AG metabolic regulation and action are mainly confined within the gastrointestinal tract.

Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly.

BACKGROUND: We previously reported the efficacy of a combined treatment of active acromegaly with both long-acting somatostatin analogs (SSA) and pegvisomant (PEG-V). OBJECTIVE: Our objective was to assess long-term efficacy and safety in a larger group of acromegalic patients after a period of 138 (35-149) wk [median (range)]. DESIGN: PEG-V was added to high-dose SSA treatment in 32 subjects (13 females) who had not shown a normalization in serum IGF-I concentrations during SSA monotherapy. PEG-V dosage was increased until IGF-I concentration normalized. The maximal dose was 80 mg twice weekly. RESULTS: After dose finding, IGF-I remained within the normal range in all subjects with PEG-V administered once (n = 24) or twice (n = 8) weekly, on a total weekly dose of 60 (40-160) mg. Baseline IGF-I levels were positively correlated with the required dosage of PEG-V (r = 0.48; P = 0.006). PEG-V-dependent liver enzyme disturbances were observed in 11 (6 diabetic) subjects, of which symptomatic gallstones explained two cases. These liver enzyme disturbances were transient in all subjects without discontinuation or dose adaptation of PEG-V. In our series, diabetic patients had a 5.1 times (odds ratio) (confidence interval, 1.02-25.54; P < 0.05) higher risk for developing liver enzyme disturbances. These liver enzyme disturbances seemed to occur earlier. Pituitary adenoma size decreased in four patients. No increase in tumor size was observed in any of the patients. CONCLUSION: Long-term combined treatment with long-acting SSA and (twice) weekly PEG-V for active acromegaly seems to be effective and safe. Patients with acromegaly and diabetes seem to have a higher risk of developing transient liver enzyme disturbances.

Diagnostic imaging of dopamine receptors in pituitary adenomas.

Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using (123)I-S-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenzamide ((123)I-IBZM) and (123)I-epidepride. (123)I-epidepride is generally superior to (123)I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However, (123)I-IBZM and (123)I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with (11)C-N-raclopride and (11)C-N-methylspiperone.

Unacylated ghrelin is active on the INS-1E rat insulinoma cell line independently of the growth hormone secretagogue receptor type 1a and the corticotropin releasing factor 2 receptor.

Both unacylated ghrelin (UAG) and acylated ghrelin (AG) exert metabolic effects. To investigate the interactions between AG and UAG on ghrelin receptors we evaluated the effects of AG and UAG on INS-1E rat insulinoma cells, using insulin secretion after 30min static incubation as a read-out. A possible involvement of the growth hormone secretagogue receptor type 1a (GHS-R1a) or the corticotropin-releasing factor 2 (CRF2) receptor (CRF2R), as a putative receptor for UAG, was also studied determining their mRNA expression and the functional effects of receptor antagonists on insulin release. Both UAG and AG stimulated insulin release dose-dependently in the nanomolar range. The AG-induced insulin output was antagonized by two GHS-R1a antagonists ([d-Lys(3)]GHRP-6 and BIM28163), which did not block UAG actions. These effects occurred in the presence of low levels of GHS-R1a mRNA. Neither CRF2R expression nor effects of the CRF2R antagonist (astressin(2)B) on insulin output were observed. In conclusion, we provide a sensitive and reproducible assay for specific effects of UAG, which in this study is responsible for insulin release by INS-1E cells. Our data support the existence of a specific receptor for UAG, other than the CRF2R and GHS-R1a. The stimulatory effect on insulin secretion by AG in this cell line is mediated by the GHS-R1a.

Dopamine agonist therapy of clinically non-functioning pituitary macroadenomas. Is there a role for 123I-epidepride dopamine D2 receptor imaging?

OBJECTIVE: Clinically non-functioning pituitary adenomas (NFPAs) can express functional dopamine D2 receptors. Therapy with dopamine (DA) agonists may result in a NFPA size reduction. However, DA agonist-sensitive and -resistant NFPAs are clinically indistinguishable. We have studied the correlation between in vivo imaging of D2 receptors using (123)I-epidepride and the radiological response of NFPA to DA in 18 patients. METHODS: Patients were treated with either cabergoline (1-2 mg/week) or quinagolide (150-300 mug/day) for a mean period of 89.7 months (range, 34-187 months). RESULTS: Pituitary uptake of (123)I-epidepride varied from slight uptake classified as grade 0 to very high classified as grade 3. Grade 0 uptake was found in four patients; grade 1 in three; grade 2 in ten, and grade 3 in one. NFPA stabilization or shrinkage with DA agonist therapy showed no significant difference between grade 0, 1, and 2 tumors (mean tumor stabilization or shrinkage: 31, 30, and 36% respectively). However, when we considered a decrease in tumor size ranging from 0 to 20% as tumor stabilization and >20% decrease in tumor size as true shrinkage, one out of four NFPAs with grade 1 uptake, two out of three with grade 1 uptake, and eight out of ten with grade 2 uptake showed tumor shrinkage. CONCLUSION: In conclusion, there is limited clinical usefulness of dopamine D2 receptor imaging for predicting the clinical efficacy of DA agonist in selected patients with NFPAs. DA agonist therapy in NFPAs can result in tumor stabilization and shrinkage.

Somatostatin receptor imaging for neuroendocrine tumors.

Tumors and metastases that express the somatostatin receptor subtypes sst2 sst3 or sst5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs, like (111)In-pentetreotide. (111)In-pentetreotide scintigraphy also allows for more accurate staging of the disease by demonstrating tumor sites, which were not shown by conventional imaging. (111)In-pentetreotide scintigraphy may also detect resectable tumors that would have remained unrecognized using conventional radiological imaging techniques; it may prevent surgery with curative intent in those patients whose tumors have metastasized to a greater extend than could be detected with conventional radiological imaging and it may be used to select patients for treatment with the currently available octapeptide somatostatin analogs or with tumor targeted radioactive treatment with radiolabelled somatostatin analogs. (111)In-pentetreotide scintigraphy has also been used to select patients with pituitary tumors for medical treatment with octapeptide analogs, but its clinical usefulness for this purpose seems to be limited. It further allows scar tissue to be differentiated from tumor recurrence after the pituitary surgery or radiotherapy. However, a large variety of lesions in and around the pituitary region also express somatostatin receptors and, therefore, can be visualized by (111)In-pentetreotide scintigraphy.

The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5.

OBJECTIVE: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing's disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst(1), sst(2), sst(3) and sst(5) was recently introduced. We compared the in vitro effects of the sst(2)-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells. METHODS: By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied. RESULTS: Corticotroph adenomas expressed predominantly sst(5) mRNA (six out of six adenomas), whereas sst(2) mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range -30 to -40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (- 28%). In AtT20 cells, expressing sst(2), sst(3) and sst(5), SOM230 inhibited ACTH secretion with high potency (IC(50) 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst(5) is relatively resistant to negative control by glucocorticoids. CONCLUSIONS: The selective expression of sst(5) receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing's disease.

Long-term predictive value of postsurgical cortisol concentrations for cure and risk of recurrence in Cushing's disease.

We assessed the value of postoperative plasma cortisol concentrations to predict cure and recurrence of Cushing's disease after transsphenoidal surgery (TS). Seventy-eight of 80 consecutive patients treated by TS for Cushing's disease were evaluated. TS cured 72% (n = 56) of the patients. Two weeks after surgery, patients with plasma cortisol levels below 138 nmol/liter (n = 50; three macroadenomas) and eight (27%) of 30 patients (nine macroadenomas) with cortisol greater than 138 nmol/liter were cured. Six (five with a macroadenoma) of these eight patients had cortisol values less than 50 nmol/liter 3 months after surgery. Therefore, the optimal cut-off value of cortisol predicting remission was 138 nmol/liter, measured 3 months after surgery (positive and negative predictive values 87 and 90%, respectively). Five patients (9%) had recurrent Cushing's disease during a median follow-up of 7 yr. Recurrence occurred in four of 24 (17%) patients with a follow-up of more than 10 yr. Therefore, cortisol levels above 138 nmol/liter, obtained 2 wk after TS, should be repeated, because they do not predict persistent Cushing's disease in 27% of those patients. Postoperative cortisol levels do not positively predict recurrence of disease during long-term follow-up of initially cured patients.

ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11ß-hydroxylase.

BACKGROUND: Adrenal Cushing's syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in vivo and in vitro. METHODS: In vivo cortisol responses to hormonal stimuli were studied in 35 patients with ACTH-independent bilateral adrenal enlargement and (sub-)clinical hypercortisolism. In vitro, the effects of these stimuli on cortisol secretion and steroidogenic enzyme mRNA expression were evaluated in cultured AIMAH and other adrenocortical cells. Arginine-vasopressin (AVP) receptor mRNA levels were determined in the adrenal tissues. RESULTS: Positive serum cortisol responses to stimuli were detected in 27/35 AIMAH patients tested, with multiple responses within individual patients occurring for up to four stimuli. AVP and metoclopramide were the most prevalent hormonal stimuli triggering positive responses in vivo. Catecholamines induced short-term cortisol production more often in AIMAH cultures compared to other adrenal cells. Short- and long-term incubation with AVP increased cortisol secretion in cultures of AIMAH cells. AVP also increased steroidogenic enzyme mRNA expression, among which an aberrant induction of CYP11B1. AVP type 1a receptor was the only AVPR expressed and levels were high in the AIMAH tissues. AVPR1A expression was related to the AVP-induced stimulation of CYP11B1. CONCLUSIONS: Multiple hormonal signals can simultaneously induce hypercortisolism in AIMAH. AVP is the most prevalent eutopic signal and expression of its type 1a receptor was aberrantly linked to CYP11B1 expression.

Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype.

Obesity is associated with local T-cell abnormalities in adipose tissue. Systemic obesity-related abnormalities in the peripheral blood T-cell compartment are not well defined. In this study, we investigated the peripheral blood T-cell compartment of morbidly obese and lean subjects. We determined all major T-cell subpopulations via six-color flow cytometry, including CD8+ and CD4+ T cells, CD4+ T-helper (Th) subpopulations, and natural CD4+CD25+FoxP3+ T-regulatory (Treg) cells. Moreover, molecular analyses to assess thymic output, T-cell proliferation (T-cell receptor excision circle analysis), and T-cell receptor-ß (TCRB) repertoire (GeneScan analysis) were performed. In addition, we determined plasma levels of proinflammatory cytokines and cytokines associated with Th subpopulations and T-cell proliferation. Morbidly obese subjects had a selective increase in peripheral blood CD4+ naive, memory, natural CD4+CD25+FoxP3+ Treg, and Th2 T cells, whereas CD8+ T cells were normal. CD4+ and CD8+ T-cell proliferation was increased, whereas the TCRB repertoire was not significantly altered. Plasma levels of cytokines CCL5 and IL-7 were elevated. CD4+ T-cell numbers correlated positively with fasting insulin levels. The peripheral blood T-cell compartment of morbidly obese subjects is characterized by increased homeostatic T-cell proliferation to which cytokines IL-7 and CCL5, among others, might contribute. This is associated with increased CD4+ T cells, with skewing toward a Treg- and Th2-dominated phenotype, suggesting a more anti-inflammatory set point.

Effects of methimazole on the elimination of irinotecan.

PURPOSE: To study the possible pharmacokinetic and pharmacodynamic interactions between irinotecan and methimazole. METHODS: A patient treated for colorectal cancer with single agent irinotecan received methimazole co-medication for Graves' disease. Irinotecan pharmacokinetics and side effects were followed during a total of four courses (two courses with and two courses without methimazole). RESULTS: Plasma concentrations of the active irinotecan metabolite SN-38 and its inactive metabolite SN-38-Glucuronide were both higher (a mean increase of 14 and 67%, respectively) with methimazole co-medication, compared to irinotecan monotherapy. As a result, the mean SN-38 glucuronidation rate increased with 47% during concurrent treatment. Other possible confounding factors did not change over time. Specific adverse events due to methimazole co-treatment were not seen. CONCLUSIONS: Additional in vitro experiments suggest that these results can be explained by induction of UGT1A1 by methimazole, leading to higher SN-38G concentrations. The prescribed combination of these drugs may lead to highly toxic intestinal SN-38 levels. We therefore advise physicians to be very careful in combining methimazole with regular irinotecan doses, especially in patients who are prone to irinotecan toxicity.

Medical therapy of acromegaly: efficacy and safety of somatostatin analogues.

Acromegaly is a chronic disease with signs and symptoms due to growth hormone (GH) excess. The most frequent cause of acromegaly is a GH-producing pituitary adenoma. Chronic GH excess is accompanied by long-term complications of the locomotor (arthrosis) and cardiovascular (atherosclerosis, cardiomyopathy) systems and is, when untreated, associated with an increased mortality. The aim of treatment of acromegaly is to improve symptoms, to achieve local tumour mass control, and to decrease morbidity and mortality. Treatment options include surgery, medical therapy and radiotherapy. Transsphenoidal surgery is the first choice of treatment when a definitive cure can be achieved, particularly in the case of microadenomas and when decompression of surrounding structures (optic chiasm, ophthalmic motor nerves) is indicated. Primary medical therapy has been increasingly applied in recent years, especially when a priori chances of surgical cure are low (because of adenoma size and localization) and in patients with advanced age and/or serious co-morbidity. In addition, preoperative primary medical therapy may result in tumour shrinkage, facilitating tumour resection, and may reduce perioperative complications due to GH excess. Within the spectrum of medical therapy, long-acting somatostatin analogues (somatostatins) are considered as first-line treatment. Treatment with somatostatin analogues results in GH control in approximately 60% of patients. In addition, somatostatin analogues induce tumour shrinkage in 30-50% of patients, particularly when applied as primary therapy. Prolonged treatment with somatostatin analogues appears to be safe and is usually well tolerated. The currently available somatostatin analogues, octreotide and lanreotide, seem to be equally effective; however, this should still be evaluated in prospective, randomized trials evaluating efficacy with respect to GH control and tumour shrinkage. In patients with an insufficient clinical and biochemical response to somatostatin analogues, combination therapy with dopamine receptor agonists or the GH receptor antagonist pegvisomant usually leads to disease control. New developments in the medical therapy of acromegaly include the universal somatostatin receptor agonist pasireotide, which has a broader affinity for all somatostatin receptor (sst) subtypes compared with the currently available somatostatin analogues with preferential affinity for the sst2 receptor, and chimeric compounds that interact with both somatostatin and dopamine receptors with synergizing effects on GH secretion.