Alexander Lammert

SOM230 (Pasireotide) and Temozolomide Achieve Sustained Control of Tumour Progression and ACTH Secretion in Pituitary Carcinoma with Widespread Metastases

Pituitary carcinomas are rare and neurosurgically challenging lesions, as they commonly relapse after surgical removal. Their prognosis is dismal due to their limited response to radiotherapy and chemotherapy. In recent studies, temozolomide was administered in very few patients with partial effects. We report a patient with an ACTH-secreting pituitary carcinoma and widespread intracranial, spinal and systemic metastases despite repeated surgical treatment, bilateral adrenalectomy, medical treatment and radiotherapy. Additionally to chemotherapy with temozolomide, the patient received SOM230 as salvage therapy with an improvement of the patients clinical status, and a reduction of ACTH levels. After 12 months of combination therapy a sustained tumor control was achieved and persisted upon monotherapy with SOM230 for more than 9 months thereafter. Thus, temozolomide in combination with SOM230 seems to be promising in patients with ACTH-secreting metastasized pituitary carcinoma.

Neuro-endocrine and neuropsychological outcome after aneurysmal subarachnoid hemorrhage (aSAH): a prospective cohort study.

OBJECTIVE Neuropsychological sequelae are common after aneurysmal subarachnoid hemorrhage (aSAH) and may be associated with or caused by supposed hypothalamic-pituitary dysfunction. We evaluated the incidence of neuro-endocrine and neuropsychological deficits after aSAH and their interrelations in a standardized manner. METHODS 26 patients (20 females) were prospectively screened for neuro-endocrine and neuropsychological deficits 3 and 6 months after aSAH. We measured GH, IGF-1, prolactin, LH, FSH, estradiol, TSH, fT4, total T3, testosterone, ACTH as well as cortisol before and after ACTH-stimulation. Neuropsychological analysis covered verbal comprehension, short term and working memory, visuospatial construction, figural memory, psychomotor speed, attention, and concentration. RESULTS After 3 months central hypogonadism was observed in 2 patients accompanied by central hypothyroidism in 1 male subject. Central hypogonadism resolved spontaneously after 6 months in both. After 3 months, neuropsychological deficits were detected in 57% of the examined patients (44% attention deficits, 38% memory impairment, 12% psychomotor deficits). Neuropsychological deficits were still present in 53% after 6 months. CONCLUSION We found a low prevalence of neuro-endocrine and a high prevalence of neuropsychological deficits in patients 3 and 6 months after aSAH. Thus, the absent co-incidence of central hormonal and psychological dysfunction leaves a causal association questionable.

Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study

CONTEXT Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. OBJECTIVE The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. DESIGN The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. INTERVENTION DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. RESULTS Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. CONCLUSIONS The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

Improved arteriole-to-venule ratio of retinal vessels resulting from bariatric surgery.

Obesity causes increased morbidity and mortality from metabolic and cardiovascular disease (CVD). We investigated the effect of bariatric surgery on endothelial dysfunction (ED) in retinal vessels as a marker of metabolic and cardiovascular risk in patients with obesity WHO III. Thirty consecutive patients (19/11, w/m) were evaluated by anthropometry, lipid profile, and oral glucose tolerance test before and after bariatric surgery (Mannheim Obesity Study (MOS); NCT 00770276). Risk stratification was performed by the presence of metabolic syndrome (MetS) according to ATP‐III (adult treatment panel‐III). Subclinical atherosclerosis was assessed by measurement of intima‐media thickness (IMT). Flicker light response of retinal vessels was used as measures of ED. We measured their arteriole‐to‐venule ratio (AVR) for evaluation of vascular pathology. After a median of 9 months following bariatric surgery, mean weight loss was 39.4 kg (37.3%). Remission of impaired glucose metabolism was achieved in 53.3% of affected patients. Dyslipidemia improved significantly (triglycerides −61.3 mg/dl, P < 0.0001, total cholesterol −28.2 mg/dl, P = 0.002, and low‐density lipoprotein cholesterol were reduced −24.5 mg/dl, P = 0.008). This resulted in a significant reduction of patients classified for MetS (27 vs. 9, P < 0.0001). Adiponectin increased by 2.08 µg/l (P = 0.032) and high sensitivity C‐reactive protein (hs‐CRP) and soluble intercellular cell adhesion molecule (sICAM) decreased (−7.3 mg/l, P < 0.0001 and −146.4 ng/ml, P = 0.0006). AVR improved significantly (+0.04, P < 0.0001), but neither Flicker light response nor IMT changed significantly. Retinal AVR is ameliorated after bariatric intervention. As an increased AVR results from either or both widening retinal arteriolar caliber and narrowing retinal venular caliber, an improvement in small vessel profile is evident 9 months after bariatric surgery.

Donor desmopressin is associated with superior graft survival after kidney transplantation.

Background. A recent randomized trial showed that pretreatment of the brain-dead donor with low-dose dopamine improves immediate kidney graft function, by limiting injury from cold storage (ClinicalTrials.gov Identifier: NCT00115115). This study determines whether donor exposure to desmopressin (1-deamino-8-d-arginine-vasopressin [DDAVP]) before organ retrieval affects renal transplant outcome. Methods. This retrospective multicenter cohort study, nested in the database of the dopamine trial, includes 264 deceased heart-beating donors with confirmed brain death and corresponding 487 renal allograft recipients transplanted at 60 European centers between March 2004 and August 2007. We assessed differences in delayed graft function, biopsy-proven acute rejections, and 2-year kidney graft survival in recipients of a DDAVP-exposed versus unexposed graft. Results. DDAVP was associated with improved graft survival (85.4% vs. 73.6%, P=0.003). This survival benefit persisted after censoring for death with functioning graft (91.1% vs. 82.0%, P=0.01) and after adjustment for confounders including covariate adjustment from propensity scoring (hazard ratio 0.40, 95% confidence interval [CI] 0.21–0.77; P=0.006). Delayed graft function (odds ratio 0.97, 95% CI 0.57–1.65; P=0.92) and biopsy-proven acute rejections (odds ratio 1.32, 95% CI 0.70–2.49; P=0.40) were unaffected. The survival effect was enhanced after a shorter cold ischemic time less than 14 hr (91.3% vs. 77.8%, P=0.008) and after dopamine pretreatment (92.7% vs. 78.6%, P=0.006). By contrast, prolonged cold ischemic time more than or equal to 14 hr (91.2% vs. 86.5%, P=0.39) and assignment to the nondopamine group (89.7% vs. 84.8%, P=0.37) abrogated the survival advantage. Conclusions. Donor DDAVP seems to improve renal allograft survival. Combined use of donor DDAVP and low-dose dopamine should receive further evaluation.

Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2

BackgroundDiabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE).MethodsDIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro- and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e.g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness.DiscussionDIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.

The CNDP1 (CTG)5 Polymorphism Is Associated with Biopsy-Proven Diabetic Nephropathy, Time on Hemodialysis, and Diabetes Duration

Considering that the homozygous CNDP1 (CTG)5 genotype affords protection against diabetic nephropathy (DN) in female patients with type 2 diabetes, this study assessed if this association remains gender-specific when applying clinical inclusion criteria (CIC-DN) or biopsy proof (BP-DN). Additionally, it assessed if the prevalence of the protective genotype changes with diabetes duration and time on hemodialysis and if this occurs in association with serum carnosinase (CN-1) activity. Whereas the distribution of the (CTG)5 homozygous genotype in the no-DN and CIC-DN patients was comparable, a lower frequency was found in the BP-DN patients, particularly in females. We observed a significant trend towards high frequencies of the (CTG)5 homozygous genotype with increased time on dialysis. This was also observed for diabetes duration but only reached significance when both (CTG)5 homo- and heterozygous patients were included. CN-1 activity negatively correlated with time on hemodialysis and was lower in (CTG)5 homozygous patients. The latter remained significant in female subjects after gender stratification. We confirm the association between the CNDP1 genotype and DN to be likely gender-specific. Although our data also suggest that (CTG)5 homozygous patients may have a survival advantage on dialysis and in diabetes, this hypothesis needs to be confirmed in a prospective cohort study.

Minoxidil for Treatment of Resistant Hypertension in Chronic Kidney Disease––A Retrospective Cohort Analysis

Resistant hypertension is still a challenge and reserve antihypertensive agents are often necessary to achieve blood pressure control. One reserve antihypertensive is minoxidil, a direct vasodilator that is known for its strong blood pressure–lowering effect, but contemporary studies are sparse. The authors retrospectively analyzed 54 inpatients with uncontrolled hypertension despite the combined use of current antihypertensive agents. To investigate the effect of minoxidil when added to other antihypertensive agents, blood pressure was evaluated at the time minoxidil treatment was initiated and at discharge. Minoxidil treatment was associated with a significant reduction in blood pressure from 162.4±15.1/83.2±12.7 mm Hg to 135.8±12.2/72.8±6.9 mm Hg (P<.0001). This effect was sustained across all analyzed subgroups. Although the well‐known adverse events of minoxidil limit its widespread use, these data show that minoxidil as a reserve antihypertensive agent still has a niche indication in the particular subgroup of patients with treatment‐resistant or uncontrolled hypertension.

Adipokines and endothelial dysfunction in obesity WHO°III.

Obesity is closely associated with the metabolic syndrome (MetS) and subsequent low-grade inflammation links to endothelial dysfunction (ED) and cardiovascular disease. The impact of adipokines on retinal ED is not fully understood, in particular not in severe obesity. The aim of the study was to identify the association of the MetS and prespecified adipokines on retinal ED in obesity WHO°III. 92 obese patients (obesity WHO°III) were assessed for the MetS (IDF), neck circumference, adipokines and inflammatory markers (hsCRP, TNFα, Il-6, MCP-1, sICAM, sVCAM, IGF-BP3, RBP 4 and adiponectin). Retinal ED as determined by the arterio-venous-ratio (AVR) and retinal vessel diameters (CRAE, CRVE) was measured using retinal photographs. Obese subjects with MetS (MetS+ group) differed from the MetS- by neck circumference, fasting plasma glucose, insulin, HOMA-IR, triglycerides and HDL-C. Importantly, IL-6, sICAM and adiponectin were significantly different between groups, while measures of retinal ED showed no differences. Univariate linear regression revealed a significant association between neck circumference and ED for patients with MetS, and a significant association between adiponectin and CRAE for patients without MetS. This study shows that ED in obesity WHO°III is independent of MetS or inflammation and that neck circumference has an impact on ED in obesity WHO°III.

Healthy obese and post bariatric patients - metabolic and vascular patterns.

OBJECTIVE Obesity and the metabolic syndrome (MetS) are associated with endothelial dysfunction (ED). An established method to determine ED is retinal vessel analysis. Obesity is associated with MetS, but obese patients not matching all criteria of the MetS and therefore defined as metabolically healthy obese subjects (MHOS) exist. Bariatric surgery may be an appropriate option to treat morbid obesity. The aim of this study was to compare MetS, MHOS and post bariatric patients in adipocytokine -patterns and ED. METHODS Arterio-venous ratio (AVR) and vessel diameters from retinal photographs (IMEDOS™), parameters of MetS (IDF) and obesity-associated factors (hsCRP, TNF, Il-6, MCP-1, sICAM, sVCAM, IGF-BP3, RBP 4 and adiponectin) were assessed in 51 obese patients with MetS, 20 obese patients without MetS and 21 patients pre and post bariatric surgery. RESULTS Bariatric surgery improved ED as reflected by AVR and venous diameters (p<0.05 for both). These improvements were associated with lower levels of fasting plasma glucose, insulin, HOMA-IR, LDL-C, triglycerides, cholesterol, hsCRP, sICAM, and higher levels of adiponectin and RBP4 (p<0.05 for each parameter). MHOS differed from MetS by neck circumference, fasting plasma glucose, HOMA-IR, triglycerides, HDL-C, sICAM, and adiponectin (p<0.05), but not by RRs, RRd, insulin, LDL-C, hsCRP, Il-6, TNF, MCP-1, sVCAM, RBP-4, IGF-BP3, and retinal ED. CONCLUSION These data indicate that improved insulin-sensitivity and reduced inflammatory mediators characterize the metabolic outcome of postbariatric patients in comparison to MHOS. Thus, MHOS characterizes an intermediate state between MetS and postbariatric patients.