Changes in diagnosis and operative treatment of insulinoma over two decades.

PURPOSE: Most insulinomas are small solitary, benign neoplasms. Imaging and surgical techniques improved over the last 20 years. Thus, the aim of the present study was to analyze changes in diagnosis and surgery of insulinoma patients in a referral center over two decades. METHODS: Operated patients with a histologically proven insulinoma were retrieved from a prospective database. Clinico-pathological characteristics and outcomes were retrospectively analyzed with regard to the time periods 2000-2010 (group 1) and 2011-2020 (group 2). RESULTS: Sixty-one of 202 operated patients with pNEN had an insulinoma, 37 (61%) in group 1 and 24 (39%) in group 2. Of those 61 insulinomas, 49 (80%) were sporadic benign, 8 (13%) benign MEN1-associated insulinomas, and 4 (7%) sporadic malignant insulinomas. In 35 of 37 (95%) patients of group 1 and all patients of group 2, the insulinoma was preoperatively identified by imaging. The most sensitive imaging modality was endoscopic ultrasound (EUS) with correctly diagnosed and localized insulinomas in 89% of patients in group 1 and 100% in group 2. In group 1, significantly less patients were operated via minimally invasive approach compared to group 2 (19% (7/37) vs. 50% (12/24), p = 0.022). Enucleation was the most frequently performed operation (31 of 61, 51%), followed by distal resection (15 of 61, 25%) without significant differences between groups 1 and 2. The rate of relevant postoperative complications was not different between groups 1 and 2 (24% vs. 21%, p = 0.99). Two patients with benign insulinoma (1 out of each group) experienced disease recurrence and underwent a second resection. After a median follow-up of 134 (1-249) months, however, all 57 (100%) patients with benign insulinoma and 3 out of 4 patients with malignant insulinoma had no evidence of disease. CONCLUSION: Insulinoma can be preoperatively localized in almost all patients, allowing for a minimally invasive, parenchyma-sparing resection in selected patients. The long-term cure rate is excellent.

Spinal Opioid Tolerance Depends upon Platelet-Derived Growth Factor Receptor-ß Signaling, Not µ-Opioid Receptor Internalization.

Opioids are some of the most potent analgesics available. However, their effectiveness is limited by the development of analgesic tolerance. Traditionally, tolerance was thought to occur by termination of µ-opioid receptor (MOR) signaling via desensitization and internalization. Contradictory findings led to a more recent proposal that sustained MOR signaling caused analgesic tolerance. However, this view has also been called into question. We recently discovered that the platelet-derived growth factor receptor(PDGFR)-ß signaling system is both necessary and sufficient to cause opioid tolerance. We therefore propose a completely new hypothesis: that opioid tolerance is mediated by selective cellular signals and is independent of MOR internalization. To test this hypothesis, we developed an automated software-based method to perform unbiased analyses of opioid-induced MOR internalization in the rat substantia gelatinosa. We induced tolerance with either morphine, which did not cause MOR internalization, or fentanyl, which did. We also blocked tolerance by administering morphine or fentanyl with the PDGFR-ß inhibitor imatinib. We found that imatinib blocked tolerance without altering receptor internalization induced by either morphine or fentanyl. We also showed that imatinib blocked tolerance to other clinically used opioids. Our findings indicate that opioid tolerance is not dependent upon MOR internalization and support the novel hypothesis that opioid tolerance is mediated by intracellular signaling that can be selectively targeted. This suggests the exciting possibility that undesirable opioid side effects can be selectively eliminated, dramatically improving the safety and efficacy of opioids. SIGNIFICANCE STATEMENT: Classically, it was thought that analgesic tolerance to opioids was caused by desensitization and internalization of µ-opioid receptors (MORs). More recently, it was proposed that sustained, rather than reduced, MOR signaling caused tolerance. Here, we present conclusive evidence that opioid tolerance occurs independently of MOR internalization and that it is selectively mediated by platelet-derived growth factor receptor signaling. This novel hypothesis suggests that dangerous opioid side effects can be selectively targeted and blocked, improving the safety and efficacy of opioids.

Preoperative Imaging Overestimates the Tumor Size in Pancreatic Neuroendocrine Neoplasms Associated with Multiple Endocrine Neoplasia Type 1.

BACKGROUND: Radiological tumor size of non-functioning pancreatic neuroendocrine neoplasms (Nf-pNENs) associated with multiple endocrine neoplasia type 1 (MEN1) is a crucial parameter to indicate surgery. The aim of this study was to compare radiological size (RS) and pathologic size (PS) of MEN1 associated with pNENs. METHODS: Prospectively collected data of MEN1 patients who underwent pancreatic resections for pNENs were retrospectively analyzed. RS was defined as the largest tumor diameter measured on endoscopic ultrasound (EUS), magnetic resonance imaging (MRI) or computed tomography (CT). PS was defined as the largest tumor diameter on pathological analysis. Student's t test and linear regression analysis were used to compare the median RS and PS. p < 0.05 was considered significant. RESULTS: Forty-four patients with a median age of 37 (range 10-68) years underwent primary pancreatic resections for pNENs. Overall, the median RS (20 mm, range 3-100 mm) was significantly larger than the PS (13 mm, range 4-110 mm) (p = 0.001). In patients with pNENs < 20 mm (n = 27), the size difference (median RS 15 mm vs PS 12 mm) was also significant (p = 0.003). However, the only modality that significantly overestimated the PS was EUS (median RS 14 mm vs 11 mm; p = 0.0002). RS overestimated the PS in 21 patients (21 of 27 patients, 78%). Five of 11 patients (12%) with a Nf-pNEN and a RS > 20 mm had in reality a PS < 20 mm. MRI was the imaging technique that best correlated with PS in the total cohort (r = 0.8; p < 0.0001), whereas EUS was the best correlating imaging tool in pNENs < 20 mm (r = 0.5; p = 0.0001). CONCLUSION: Preoperative imaging, especially EUS, frequently overestimates the size of MEN1-pNENs, especially those with a PS < 20 mm. This should be considered when indicating surgery in MEN1 patients with small Nf-pNENs.

GRAND-4: the German retrospective analysis of long-term persistence in women with osteoporosis treated with bisphosphonates or denosumab.

UNLABELLED: This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5-2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab. INTRODUCTION: Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse. METHODS: From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan-Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use. RESULTS: Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7-17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96-2.02, respectively; all P < 0.0001). CONCLUSIONS: Two-year persistence with denosumab was 1.5-2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.

[Pharmacogenic osteoporosis beyond cortisone. Proton pump inhibitors, glitazones and diuretics]. / Pharmakogene Osteoporose jenseits von Kortison. Protonenpumpenhemmer, Glitazone, Diuretika.

BACKGROUND: [corrected] There are many drugs which can cause osteoporosis or at least favor its initiation. The effect of hormones and drugs with antihormonal activity, such as glucocorticoids and aromatase inhibitors, on initiation of osteoporosis is well known. In addition, proton pump inhibitors, glitazones and diuretics also influence the formation of osteoporosis. MATERIAL AND METHODS: The results of currently available studies on the correlation between proton pump inhibitors, glitazones and diuretics on formation of osteoporosis were evaluated and summarized. RESULTS: Proton pump inhibitors and glitazones increase the risk for osteoporotic fractures. Loop diuretics may slightly increase fracture risk, whereas thiazides were shown to be osteoprotective by reducing fracture probability on a relevant scale. CONCLUSION: Proton pump inhibitors should not be prescribed without serious consideration and then only as long as necessary. Alternatively, the administration of the less effective H2 antagonists should be considered when possible due to the reduction of acid secretion. Because the long-term intake of thiazides is associated with a clinically relevant reduction in the risk of fractures and they are economic and well-tolerated, prescription can be thoroughly recommended within the framework of differential diagnostic considerations in an appropriate clinical context. The briefly increased risk of falling immediately after starting diuretic therapy is the only point which needs to be considered.

Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma.

Although most pheochromocytomas (PCCs) and paragangliomas (PGLs) are sporadic, molecular genetic medicine has revealed that a considerable number of patients with apparently sporadic PCC actually have a genetic predisposition to the development of these tumors. After decades of intensive research, several genes are now known to play an important role in the pathogenesis of PCC. At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes. In addition to these ten PCC susceptibility genes, two other genes, KIF1B and PHD2, have also been associated with PCC. Studying the pathogenesis and the molecular correlation of these mutations has revealed the existence of two main transcription signatures: a pseudohypoxic cluster (VHL and SDH mutations) and a cluster rich in kinase receptor signaling and their downstream pathways (RET, NF1, TMEM127, and MAX mutations). However, the general mechanism in the pathogenesis of a syndrome does not entirely apply in the particular pathogenesis of PCC as a manifestation of that syndrome. A better understanding of the complexity and high genetic diversity of PCC and PGL may lead to more efficient diagnosis and management of the disease.

Pituitary function in patients with hereditary haemochromatosis.

Haemochromatosis may impair the function of endocrine organs, amongst others the pituitary gland. It was the aim of this study to determine pituitary function in adult patients with genetically defined hereditary haemochromatosis in a prospective diagnostic study using a standardised stimulation test. Therefore, 22 patients (7 females, 15 males; age at diagnosis of haemochromatosis 48.1 ± 7.9 years; age at study inclusion 50.7 ± 7.7 years) with genetically defined hereditary haemochromatosis were investigated by a combined pituitary stimulation test (CRH, GHRH/arginine, GnRH, TRH). In 11 patients (50% of the study population; 2 females, 9 males), pituitary insufficiencies were detected [isolated corticotrophic insufficiency (peak cortisol < 181.25 µg/l/500 nmol/l) n=10 (2 females, 8 males); combined corticotrophic and borderline gonadotrophic insufficiency (basal testosterone 2.4-3.0 µg/l without basal LH-elevation) in 1 male]. Somatotrophic pituitary insufficiencies were not found. IFG-1 concentrations below -2 standard deviations in 7 patients (32%) may be attributed to impaired hepatic IGF-1 synthesis. Hypopituitarism, particularly corticotrophic insufficiency, seems to be prevalent in a considerable number of middle-aged patients with hereditary haemochromatosis. Despite normal somatotrophic function, low IGF-1 serum concentrations may be found in a subgroup of haemochromatosis patients.

Rapid Onset and Sustained Efficacy (ROSE) study: results of a randomised, multicentre trial comparing the effect of zoledronic acid or alendronate on bone metabolism in postmenopausal women with low bone mass.

SUMMARY: The ROSE study compared a once-yearly intravenous dose of zoledronic acid with a once-weekly oral dose of alendronate in postmenopausal women. Once-yearly zoledronic acid showed a greater and faster reduction in the levels of two markers of bone turnover and may be an effective option for the treatment of osteoporosis. INTRODUCTION: The open-label Rapid Onset and Sustained Efficacy (ROSE) study was designed to compare a once-yearly intravenous (iv) dose of zoledronic acid with a once-weekly oral dose of alendronate with respect to markers of bone turnover in approximately 600 postmenopausal women in Germany. METHODS: Levels of N-telopeptide of collagen type I (NTx) and procollagen 1 C terminal extension peptide (P1NP) were assessed during the study. The primary objective was to assess if zoledronic acid was superior to alendronate in reducing serum NTx levels after 12 months' treatment. RESULTS: A significantly greater reduction in NTx levels from baseline to month 12 (as determined by the area under the curve) was observed in patients treated with zoledronic acid (n = 408) versus those receiving alendronate (n = 196; 0.282 ng/mL vs. 0.270 ng/mL; P = 0.012). The reduction in levels of P1NP after 1 year was also significantly greater in patients treated with zoledronic acid compared with those receiving alendronate (28.21 vs. 25.53 ng/mL; P = 0.0024). The overall incidence of adverse events was similar between groups; both treatments were generally well tolerated. Although post-dose symptoms, including the incidence of influenza-like symptoms, were higher with zoledronic acid than alendronate initially, the incidence was similar between groups from days 4-360. Gastrointestinal symptoms were more frequent with alendronate than zoledronic acid throughout the study. CONCLUSION: In this study, once-yearly iv zoledronic acid provided a greater and faster reduction in the levels of NTx and P1NP versus once-weekly oral alendronate.

Quality of life and health status with zoledronic acid and generic alendronate--a secondary analysis of the Rapid Onset and Sustained Efficacy (ROSE) study in postmenopausal women with low bone mass.

SUMMARY: The ROSE study compared annual infusion with zoledronic acid and weekly generic alendronate. No significant differences in quality of life or health status between treatment groups were observed. Adherence to alendronate during the study was high, with 80.9% of patients achieving adequate adherence. INTRODUCTION: A secondary analysis to evaluate quality of life, health status, adherence to alendronate and therapy preference in postmenopausal women with low bone mass who received treatment with zoledronic acid or alendronate was conducted. METHODS: Postmenopausal women with low bone mass were randomised 2:1 to receive an annual infusion of zoledronic acid or weekly oral generic alendronate in this open-label, multicentre study. Changes in quality of life and health status were assessed using questionnaires at baseline and month 12. Adherence to alendronate was assessed by the investigator and/or study personnel, and subjective therapy preference was assessed using a questionnaire at month 12. RESULTS: Patients were randomised to zoledronic acid (n = 408) and alendronate (n = 191). Overall, there were no significant differences in quality of life between zoledronic acid and alendronate. However, improvements in quality of life with zoledronic acid versus alendronate could be detected by posthoc analysis in patients with previous fractures. There were no significant differences in health status between patients receiving zoledronic acid or alendronate. Adherence to alendronate during the study was high, with 80.9% of patients achieving adequate adherence. A total of 81% of patients who had received zoledronic acid indicated that they would prefer to continue with that treatment, and 43% of the patients who received oral alendronate would like to switch to zoledronic acid. CONCLUSIONS: There were no significant differences in quality of life between patients receiving zoledronic acid or alendronate.

Variation of the baseline characteristics and treatment parameters over time: an analysis of 15 years of growth hormone replacement in adults in the German KIMS database.

The purpose of this study is to examine potential implications of changes in the approach to adult growth hormone (GH) replacement (GHR) over the last 15 years. Therefore, we analysed the German KIMS database as one of the largest single country pharmacoepidemiological databases on adult GH deficiency (GHD). Based on the date of their first GH application patients were assigned to three intervals (1995-1999, 2000-2004, 2005-2009). A multivariate analysis of variance with interval and sex as independent variables was conducted. Differences were analysed with respect to IGF-I standard deviation score (SDS), quality of life, latency between GHD diagnosis and first GH dose, body mass index, waist-hip ratio, lipid profile, and GH dose. All analyses were conducted at baseline, 1 year, and 3 years of GHR. We detected significant associations between time interval and patient characteristics at baseline and with treatment effects. Recently, patients with less severe GHD (mean IGF-I SDS: -2.1, -1.6, -1.0 in the 1st, 2nd and 3rd interval; p = 0.000) are treated with lower GH starting doses (mean 0.30, 0.19, 0.21 mg/day in the 1st, 2nd and 3rd interval; p = 0.000). In the first time interval, IGF-I SDS was not normalized in females after 3 years of GHR. The results of our analysis demonstrate prominent changes in patient characteristics and handling of GHR. They highlight that approach to therapy and patient inclusion criteria change over time and may represent an important confounder for any analysis in epidemiological surveillance surveys.

Peripheral bone mineral density in correlation to disease-related predisposing conditions in patients with multiple endocrine neoplasia type 1.

BACKGROUND AND AIM: Patients with multiple endocrine neoplasia type 1 (MEN1) often have low bone mineral density (BMD) attributed to primary hyperparathyroidism (pHPT). However, in MEN1 patients, other endocrine dysfunctions and conditions such as hypercortisolism, hypogonadism, and GH deficiency due to pituitary manifestation, and surgery on the upper gastrointestinal tract may affect BMD. SUBJECTS AND METHODS: In 23 patients with MEN1 (10 females, 13 males; 46±12 yr), BMD was determined by quantitative computed tomography at the forearm (pqCT), compared to a reference population and related to different conditions suspected to affect bone metabolism in MEN1. RESULTS: In this cohort, Z-score for trabecular BMD was -0.85±1.18 and for total BMD -1.16±1.04. There was a similar trend towards lower BMD in uncontrolled hyperparathyroidism, hypercortisolism, hypogonadism/GH deficiency and the state after surgery at the upper gastrointestinal tract. CONCLUSIONS: These data while confirming previous observations on reduced BMD in patients with MEN1, however, challenge its only or even predominant association with pHPT. Other conditions such as hypercortisolism, somatotrophic/ gonadotrophic pituitary insufficiency, and previous upper gastrointestinal surgery seem to be factors contributing to the risk of developing osteoporosis.

[Hereditary neuroendrocrine tumors. Multiple endocrine neoplasia type 1 and 2]. / Hereditäre neuroendokrine Tumoren. Multiple endokrine Neoplasien Typ 1 und 2.

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal-dominant hereditary disease characterized by the occurrence of tumors of the parathyroids, duodenum and/or pancreas, and anterior pituitary. The syndrome is caused by germline mutations of the MEN1 tumor suppressor gene. The identification of the causative mutations is of paramount importance for the long-term management of affected individuals and their relatives. Multiple endocrine neoplasia type 2 (MEN2) is less frequent than MEN1 and represents a cancer syndrome caused by autosomal-dominant inherited mutations of the RET proto-oncogene, and displays a genotype-phenotype correlation of remarkable clinical relevance. Major components of MEN-2 comprise medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism. Since 25-30% of patients with MTC display a hereditary background, genetic testing is indicated once MTC is diagnosed. Occurrence of MTC can be avoided by prophylactic thyroidectomy in early childhood in gene carriers. Early diagnosis and therapy of simultaneous pheochromocytoma avoids the development of complications caused by acute or chronic hypertension.

Listeria monocytogenes-induced bacterial peritonitis caused by contaminated cheese in a patient with haemochromatosis.

Infections with Listeria monocytogenes can present clinically with a wide range of different organ manifestations such as gastroenteritis, meningoencephalitis or osteomyelitis, posing a serious threat, particularly to immunocompromised patients. We present the case of a 76-year-old female patient with advanced liver disease due to underlying haemochromatosis, who was admitted to the hospital with increasing abdominal pain. She was diagnosed with spontaneous bacterial peritonitis caused by infection with Listeria monocytogenes, which she had acquired after consuming contaminated cheese from a local supermarket chain. To the best of our knowledge, this is the first case to describe Listeria-induced spontaneous bacterial peritonitis in a patient with haemochromatosis. Both end-stage liver disease and hereditary haemochromatosis on their own impair the local and systemic immune response, thereby representing predisposing factors for acquiring Listeria monocytogenes infection. This case demonstrates a rare organ manifestation of Listeria monocytogenes infection, which can be life-threatening if not diagnosed and treated adequately, and underlines the need to identify possible sources of infection in order to apply measures to prevent the further spread of the contaminated food.

Prevalence of CYP450 gene variations in patients with type 2 diabetes.

BACKGROUND: Drug degradation in the human organism is driven by detoxification mechanisms that can be affected in their efficiency by genetic mutations. The purpose of this pilot investigation was to investigate whether Type 2 diabetes is associated with mutations in prominent members of the CYP 450 isoenzyme family. METHODS: Genomic DNA was isolated from EDTA blood samples of 203 Caucasian subjects (101 patients with Type 2 diabetes and 102 non-diabetic subjects, age (mean +/- STD): 49 +/- 16 years) was analyzed. Genomic DNA was isolated from EDTA blood. Mutation analysis for CYP2C8 (*2/*3/*4), CYP2C9 (*2/*3), CYP2C19 (*2/*3), CYP2D6 (*3/*4/*5/*6) and PPARgamma (P12A) was performed by means of real-time PCR methods (Light-Cycler, Roche Diagnostics, Indianapolis, IN, USA). RESULTS: The genotyping revealed the following allele frequency distributions for the two investigated groups: CYP2C8: *2 (type 2 diabetes 3% vs. 1%, n.s.), *3 (16% vs. 3%, n.s.), *4 (15% vs. 2%, p < 0.05), CYP2C9: *2 (20% vs. 24%, n.s.), *3 (22% vs. 21%, n.s.), CYP2C19: *2 (23% s. 33%, n.s.), *3 (0% vs. 0%, n.s.), CYP2D6: *3 (3% vs. 4%, n.s.), *4 (40% vs. 37%, n.s.), *5 (3% vs. 2%, n.s.), *6 (0% vs. 0%, n.s.), PPARgamma P12A (15% vs. 21%, n.s.), i.e. all but one mutation (CYP2C8*4) were found with equal prevalence in the two cohorts. CONCLUSIONS: In this pilot investigation, we found an increased prevalence of the CYP2C8*4 mutation in the Type 2 diabetic patient group. This may result in a modification of drug degradation and drug efficacy in these patients and may have an influence, e.g. on the choice of anti-diabetic drugs. However, further trials are necessary in order to confirm our findings.

Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.

OBJECTIVE: Familial pancreatic cancer (FPC) accounts for approximately 3% of all pancreatic cancer (PC) cases. It has been suggested that high-risk individuals (HRIs) should be offered a screening programme. AIM: To evaluate the diagnostic yield of a prospective screening programme in HRIs from families with FPC over a period of 5 years. METHODS: HRIs of families with FPC of the National German Familial Pancreatic Cancer Registry (FaPaCa) were counselled and enrolled in a prospective, board-approved PC screening programme. Screening included clinical examination, laboratory tests, endoscopic ultrasound (EUS) and MRI with magnetic resonance cholangiopancreaticography (MRCP) and MR angiography. RESULTS: Between June 2002 and December 2007, 76 HRIs of families with FPC took part in the screening programme with a total of 182 examination visits. Twenty-eight patients revealed abnormalities in EUS (n = 25) and/or MR/MRCP (n = 12). In 7 patients fine needle aspiration cytology was performed. Operative pancreatic explorations were performed in 7 individuals, resulting in limited resections in 6 cases. Histopathological examination of the resected specimens showed serous oligocystic adenomas (n = 3), pancreatic intraepithelial neoplasia 1 (PanIN1) lesions with lobular fibrosis (n = 1), PanIN2 lesions (n = 1) and PanIN1 lesion plus a gastric type intraductal papillary mucinous neoplasm (IPMN) (n = 1). CONCLUSIONS: In FPC an EUS/MR/MRCP-based screening programme leads to the detection of potential precursor lesions of PC. However, the yield of an extensive screening programme is low, especially since the tumourigenic value of low grade PanIN lesions is not yet defined. Taking into account the enormous psychological stress for the tested individual and the high costs, a general PC screening in HRIs is not justified.

Changes in insulin resistance and cardiovascular risk induced by PPARgamma activation have no impact on RBP4 plasma concentrations in nondiabetic patients.

Retinol binding protein 4 (RBP4) has recently been suggested as a good biomarker for insulin resistance and the metabolic syndrome. With this study, we wanted to investigate the effect of pioglitazone (PIO) and simvastatin (SIMVA) on insulin resistance and RBP4 plasma concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications. The prospective, parallel, randomized, double-blind clinical trial was performed with 125 nondiabetic patients with increased cardiovascular risk (78 females, 47 males, age (mean+/-STD): 58.6+/-7.8 years, BMI: 30.8+/-4.2 kg/m (2)). They were randomized to either receive PIO (45 mg)+placebo, SIMVA (40 mg)+placebo, or PIO+SIMVA for 3 months. Key outcome measures were the HOMA (IR)-Score, an oral glucose tolerance test, adiponectin, hsCRP, and RBP4 at baseline and endpoint. No correlation could be detected between the HOMA (IR) values or the impaired fasting glucose tolerance status and RBP-4. Treatment with PIO alone or in combination with SIMVA resulted in a significant improvement of the HOMA (IR)-Score and the adiponectin values, while no change in HOMA (IR) and a decrease in adiponectin (p<0.05) were observed with SIMVA monotherapy. Reductions of hsCRP were seen in all three treatment arms (p<0.001). No changes of the plasma RBP4 concentrations were observed in any of the treatment groups (PIO: 35.6+/-7.2/36.3+/-8.7 ng/ml, PIO+SIMVA: 36.5+/-10.8/36.5+/-8 ng/ml, SIMVA: 36.1+/-8.1/36.6+/-11.1 ng/ml, all n.s. vs. baseline). Despite a partial or comprehensive improvement in insulin resistance and/or cardiovascular risk indicators in all treatment arms, no change in RBP4-levels could be observed. The regulation of RBP4 expression and secretion occurs through biochemical pathways independent from those influenced by pioglitazone or simvastatin.

Color-coded duplex endoscopic ultrasound of the adrenals.

Imaging of the adrenals by endoscopic ultrasound (EUS) is a valuable technique for detection and localization of adrenal lesions, but endosonomorphological tumor distinction remains difficult. In this single-center study, the amount of blood flow in common adrenal lesions, such as adrenal adenomas, adrenal hyperplasia, and pheochromocytomas, was visualized by color-coded duplex EUS (CD-EUS) and was retrospectively analysed. Therefore, we reviewed our EUS database to evaluate and correlate the perfusion patterns of common adrenal lesions with histologically confirmed diagnosis, possible malignancy, and endosonomorphological features such as echogeneity, echostructure, and tumor size. CD-EUS was performed using an endosonoscope Pentax FG 32 UA with a longitudinal 7.5 MHz sector array and Hitachi EUB 525 ultrasound system. In 38 consecutive patients (male=19; female=19; age: mean 53+/-16 yr SD), perfusion patterns of 46 histologically confirmed adrenal, para- or extra-adrenal lesions of adrenal origin (adenoma: no.=20; nodular hyperplasia: no.=11; pheochromocytoma: no.=15; diameter 26+/-15 mm, range 6-70 mm) were analyzed and classified semiquantitatively as "not" (no.=24), "slightly" (no.=12), "moderately" (no.=4) or "highly" (no.=6) hypervascularized. Compared to adenomas (p=0.003) and nodular hyperplasia (p=0.047), pheochromocytomas showed a significantly higher grade of perfusion. There was no relationship between perfusion patterns and localization of pheochromocytomas (adrenal: 8; paraadrenal: 3; extra-adrenal: 4). Vascularization was not statistically associated with tumor echogeneity, echostructure, malignancy or tumor size. CD-EUS is an additional tool for adrenal endosonographic tumor distinction and seems to improve the endosonographic detection of pheochromocytomas by visualization of hypervascularization. As an overlap of perfusion patterns exists, CD-EUS findings must be interpreted in the context of clinical, laboratory and chemical results.

Malignant and unclear histological findings in incidentalomas.

BACKGROUND: The management of incidentalomas with tumor size 3 cm and larger is still under controversial discussion. STUDY DESIGN: Clinical charts of 65 patients who underwent adrenalectomy for an incidentaloma were reviewed. RESULTS: Sixty-five patients were operated. There were 28 men and 37 women with a median age of 56.9 years. Median size of all resected lesions was 4.1 cm. Indications for surgery were tumor size equal and larger than 3 cm, recurrent pain, hormone status and patients' fear of malignancy. In 45 patients, the adenomas did not meet the defined criteria of malignancy. There were 9 cases of adrenal hyperplasia, and two cysts and two hematomas were found in 4 patients. Moreover, 1 schwannoma and 1 myelolipoma were removed. In 3 patients, a primary adrenocortical carcinoma of 3.4, 4.0, and 5.0 cm in diameter, respectively, was identified. In 1 patient, an adrenal cortical carcinoma of 10.0 cm in diameter was operated. In 1 patient, the status (size: 4.5 cm) could not be determined conclusively. CONCLUSION: Hormonal activity should be determined independent of the size, and lesions with hormonal activity should be resected; in the presence of hormonally inactive masses, removal of tumors of 3 cm and larger in size is recommended.

Preoperative diagnosis of insulinoma: low body mass index, young age, and female gender are associated with negative imaging by endoscopic ultrasound.

OBJECTIVE: Endoscopic ultrasound (EUS) is a highly reliable procedure to localize insulinomas preoperatively. It has been considered to be important in planning surgical strategy, especially considering a minimal invasive approach. However, even under ideal conditions experienced examiners miss about 10-20% of insulinomas by EUS imaging. DESIGN AND METHODS: This retrospective study aimed to identify factors associated with negative EUS imaging. Twenty-nine consecutive patients (24 benign and 5 malignant) with sporadic pancreatic insulinomas confirmed by successful surgery and positive histopathology were included. All EUS examinations were performed by one single experienced examiner over a period of one decade. RESULTS: Three of the tumors were not detected by preoperative EUS as they were isoechoic to the surrounding healthy pancreatic tissue; 25 could be detected as hypoechoic lesions, (including all malignant tumors), and one lesion was hyperechoic. Low body mass index (P=0.053) and young age (P=0.037) were associated with negative EUS imaging. All patients with negative imaging were females. The position on the examiner's learning curve, the diameter and location of insulinoma, and endocrine parameters (insulin concentrations and insulin-glucose ratios in the prolonged fasting test) had no influence on the success of EUS imaging. CONCLUSIONS: Some insulinomas are missed by preoperative EUS imaging as they are completely isoechoic. A low body mass index, female gender, and young age might be risk factors for negative imaging.

Short stature and decreased insulin-like growth factor I (IGF-I)/growth hormone (GH)-ratio in an adult GH-deficient patient pointing to additional partial GH insensitivity due to a R179C mutation of the growth hormone receptor.

OBJECTIVE: Genetic factors play an expanding role in understanding growth hormone (GH) disorders, therefore the German KIMS Pharmacogenetics Study was initiated with the aim of genotyping various GH-/IGF-I-axis-related genes of GH-deficient adult patients to investigate genotype:phenotype relationships and response to GH therapy. PATIENTS AND METHODS: 129 consecutively enrolled GH-deficient adult patients were genotyped for variant 1 (V1) of the alternatively spliced noncoding exons in the 5'-untranslated region and for the nine coding exons of the GH receptor (GHR) gene, which obviously play a striking role in the function of the GH-IGF-I-axis. After detection of a heterozygous, non-synonymous mutation R179C in exon 6 in one single patient with acquired GH-deficiency (GHD) in late adulthood, analysis of her clinical data followed, leading to the diagnosis of mild short stature (-1.5SD). For further endocrine evaluation, five pituitary stimulation tests (arginine) of this patient were statistically compared to stimulation tests (arginine) of ten GH-deficient control patients, retrospectively. RESULTS: The formerly in patients with Laron syndrome and idiopathic short stature reported mutation R179C leads to an amino acid change from an arginine residue (codon CGC) to a cysteine residue (codon TGC) in position 179 of the extracellular domain of the GHR. Statistical analysis revealed significant decreased IGF-I/GH(0) ratio (p=0.004) and IGF-I/GH(max) ratio (p=0.001) of the index patient compared to the control patients, implying growth hormone resistance of the index patient at the level of the GHR, according to the detected R179C mutation. CONCLUSIONS: This study reports on the unusual case of a patient with mild short stature, who acquired GHD in late adulthood due to a non-secreting pituitary adenoma and get additionally diagnosed for pre-existing growth hormone insensitivity due to a formerly in two short statured patients described, single, heterozygous, non-synonymous mutation in the GHR. Our findings support the theory that heterozygous mutations in the GHR gene can have mild phenotypical consequences.