Silke Klose

Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients.

Purpose: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are ∼

The Role of Surgery in the Management of Recurrent Adrenocortical Carcinoma

3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. Experimental Design: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Results: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. Conclusions: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations. (Clin Cancer Res 2009;15(20):6378–85)

Detection of Neuroendocrine Tumors of the Small Bowel by Double Balloon Enteroscopy

CONTEXT Surgery is the standard of care for localized adrenocortical carcinomas, but its role for recurrent disease is not well defined. OBJECTIVE Our objective was to evaluate clinical outcome after surgery for recurrence. DESIGN We conducted a retrospective analysis in 154 patients with first recurrence after initial radical resection from the German Adrenocortical Carcinoma Registry. MAIN OUTCOME MEASURES We evaluated progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method and identified prognostic factors by Cox regression analysis. RESULT A total of 101 patients underwent repeated surgery (radical resection, n = 78), and 99 received (additional) nonsurgical therapy. After a median of 6 (1-221) months, 144 patients (94%) experienced progression. Multivariate analysis adjusted for age, sex, tumor burden, time to first recurrence (TTFR), surgery for recurrence (including resection status), and additional therapy indicated that only two factors were significantly associated with shorter PFS [hazard ratio for progression: for TTFR ≤ 12 months, 1.8 (95% confidence interval = 1.3-2.6) vs. TTFR > 12 months; for macroscopically incomplete resection, 3.4 (1.5-7.9), and for no surgery, 3.4 (1.6-7.0) vs. microscopically complete (R0)-resection and OS [hazard ratio for death: for TTFR > 12 months, 3.1 (2.0-4.7) vs. TTFR ≤ 12 months; for macroscopically incomplete resection, 2.7 (1.1-6.9), and no surgery, 4.2 (1.8-9.6) vs. R0-resection]. Patients who had both TTFR over 12 months and R0-resection of recurrent tumors (n = 22) had the best prognosis (median PFS, 24 months; median OS, >60 months). CONCLUSIONS The best predictors of prolonged survival after first recurrence are TTFR over 12 months and R0-resection. Our data suggest that patients with longer TTFR and tumors amenable to radical resection should be operated, whereas individualized treatment decisions are needed for patients with short TTFR or with not completely resectable tumors.

Insulin Affects the Neuronal Response in the Medial Temporal Lobe in Humans

Background Neuroendocrine tumors (NET) account for one-third of all small bowel neoplasms. The search for the primary tumor in NET is important, even though it is difficult to localize, as its surgical excision leads to a better prognosis, even in metastasized stages of the disease. The objective of this study was to evaluate the use of double balloon enteroscopy (DBE) for the detection of the primary tumor in patients with NET. Methods Twelve consecutive patients (eight women, four men) with suspected carcinoid syndrome, either metastatic to the liver (n = 5), symptoms of a neuroendocrine tumor with elevated tumor markers (n = 5), or obscure gastrointestinal bleeding (n = 2) underwent DBE for the search of the primary tumor or the source of bleeding. All patients underwent abdominal sonography and a computed tomography (CT) scan, esophagogastroduodenoscopy (EGD), ileocolonoscopy, and octreotide scintigraphy prior to DBE. Capsule endoscopy was performed in four patients. Results A total of 17 DBE were performed in the 12 patients. The CT scan and sonography of the abdomen as well as EGD and ileocolonoscopy were unable to detect the primary tumor in any patient. A submucosal tumor of the ileum or the jejunum could be detected by DBE was detected in seven patients (58%) (anal route, n = 4; oral route, n = 3). In four of these patients (33%) this finding could be confirmed by the surgical resection of a NET. In two patients (17%) with a submucosal ileum protrusion suspicious for NET, laparotomy and intraoperative endoscopy did not confirm the tumor. Conclusions In this study, the diagnostic yield of DBE for primary tumor search in patients with metastatic or suspected NET was 33%. Although endoscopic small bowel investigation by DBE seems to enrich the diagnostic possibilities for the diagnosis of small bowel-NET, at the present time DBE should only be performed in selected cases, possibly based on a positive previous work-up.

Manifestation eines Cushing-Syndroms und osteoporotischer Frakturen in der Schwangerschaft einer Patientin mit Carney-Komplex

In recent years, clear evidence has accumulated that insulin affects central nervous functions. Besides controlling metabolic processes such as energy homeostasis by the regulation of food intake through hypothalamic receptors, the peptide hormone also appears to be capable of modulating cognitive functions. Experimental and clinical evidence for insulin supports effects on learning and memory. This study explores the impact of insulin on neuronal activity using a picture encoding task in a functional magnetic resonance imaging approach. Ten subjects performed two independent scanning sessions, each session divided into one part of four baseline runs and a second part of four runs during either insulin or saline was infused. A hyperinsulinemic- euglycemic clamp technique was applied to keep the blood glucose concentrations normal during insulin infusion. Contrast images between the two parts revealed identical activation patterns during baseline and saline conditions while during the insulin condition a higher level of activation was detected within the fusiform gyrus in both hemispheres. Shorter reaction times during the insulin condition underlined the cognitive benefit. For the first time, we were able to demonstrate that insulin enhances neuronal activity within the medio-temporal lobe and increased performance in humans under in-vivo conditions.

Serum cathepsin K levels are not suitable to differentiate women with chronic bone disorders such as osteopenia and osteoporosis from healthy pre- and postmenopausal women.

ZusammenfassungAnamnese und klinischer Befund: Aufgrund von therapierefraktären Lendenwirbelsäulenbeschwerden wurde bein einer 31-jährigen Patientin nach einer Sectio caesarea eine Röntgenuntersuchung veranlasst, die Frakturen von L2 und L3 bei stark erhöhter Strahlentransparenz zeigte. Neben den klinischen Zeichen des Hypercortisolismus waren bei der Untersuchung auch zahlreiche Hyperpigmentationen im Gesichtsbereich unter Einbeziehung des Lippenrots und der rechten Konjunktiva auffällig, so dass ein Carney-Komplex vermutet wurde. Untersuchungen: Ein nicht supprimierbares Cortisol bestätigte in der endokrinologischen Diagnostik einen Hypercortisolismus. Die selektive Venenkatheteruntersuchung ergab den Verdacht auf eine bilaterale Cortisolmehrproduktion. Auch in der CT-Untersuchung der Nebennieren fanden sich knotige Veränderungen rechts und eine Hyperplasie links. Therapie und Verlauf: Bei der bilateralen Adrenalektomie konnte histologisch die Verdachtsdiagnose einer primär pigmentierten nodulären Hyperplasie bestätigt werden. Die Zeichen des Hypercortisolismus bildeten sich rasch zurück. Schlussfolgerung: Die Diagnose eines Cushing-Syndroms bei Carney-Komplex wurde bei unserer Patientin erst nach Beendigung der Schwangerschaft gestellt, obgleich die Zeichen des Hypercortisolismus schon lange vor Beginn der Schwangerschaft bestanden. An die seltene Diagnose eines Carney-Komplexes sollte bei klinischen Symptomen des Hypercortisolismus und charakteristischen phänotypischen Veränderungen (Hyperpigmentationen) gedacht werden.AbstractHistory and Clinical Findings: In a 31-year-old patient a conventional X-ray was performed due to persistend pain at the lumbar spine level after a cesarean section. It revealed compression fractures of L2 and L3. Besides very clear clinical signs of hypercortisolism, multiple hyperpigmentations and naevi in the patients face including the lips and the conjunctiva of the right eye were visible, suggesting a Carney complex. Investigations: Insuppressible cortisol levels confirmed an adrenal origin of hypercortisolism. A selective catheterization of adrenal veins supported the presence of bilateral adrenal cortisol production. The computed tomography showed nodular lesions in the right and a hyperplasia of the left adrenal gland. Treatment and Course: A bilateral adrenalectomy was performed and a primary pigmented nodular adrenal hyperplasia was confirmed histologically. Clinical signs of hypercortisolism rapidly resolved after adrenalectomy. Conclusions: The diagnosis of Cushings syndrome as a part of Carney complex was diagnosed at the end of a pregnancy although signs of hypercortisolism were present a long time before. The rare diagnosis of Carney complex should be considered in patients exhibiting symptoms of hypercortisolism and the typical clinical signs (hyperpigmentations).

Significance of a Single-Time-Point Somatostatin Receptor SPECT/Multiphase CT Protocol in the Diagnostic Work-up of Gastroenteropancreatic Neuroendocrine Neoplasms

OBJECTIVES Cathepsin K (CatK) is expressed in high levels in osteoplasts and therefore plays an important role in bone resorption. Thus CatK serum levels may be useful in the diagnosis of chronic bone disorders such as osteopenia and osteoporosis. Therefore we aimed at studying CatK levels in women putatively free of known skeletal disorders. STUDY DESIGN In total, 121 voluntary women, 27 premenopausal women aged between 20 and 45 years, and 94 postmenopausal women aged 59-81 years, all free of known skeletal disorders were included. All women underwent bone density measurement, routine labor parameter and measurement of serum CatK levels. MAIN OUTCOME MEASURES Based on WHO criteria, women were stratified in four groups (premenopausal: healthy; postmenopausal: healthy, osteopenia, osteoporosis), and their CatK levels were statistically analyzed. RESULTS Using WHO criteria 21 postmenopausal women had normal bone mineral density (BMD), 49 had osteopenia and 24 had osteoporosis. All 27 premenopausal women had normal BMD. There were no significant differences in CatK between these groups. ROC analysis resulted in poor diagnostic validity of CatK, where the area under curve was 0.544. There was no correlation neither between CatK and other biomarkers as C-telopeptide crosslaps (CTX) or bone-specific alkaline phosphatase (BAP) nor between CatK and age. CONCLUSIONS Serum levels of CatK are not suitable to differentiate women with osteoporosis from healthy subjects.

Multiparameter analysis of serum levels of C-telopeptide crosslaps, bone-specific alkaline phosphatase, cathepsin K, osteoprotegerin and receptor activator of nuclear factor κB ligand in the diagnosis of osteoporosis

This prospective study compared a 1-d SPECT/CT protocol with the commonly used 3-d protocol for somatostatin receptor scintigraphy in patients with gastroenteropancreatic neuroendocrine neoplasms. Additionally, the influence of SPECT/CT on patient management was evaluated. Methods: From October 2011 to October 2012, all gastroenteropancreatic neuroendocrine neoplasm patients undergoing restaging with somatostatin receptor scintigraphy on a modern SPECT/CT device were enrolled in this study. The protocol consisted of planar imaging at 4, 24, and 48 h; low-dose SPECT/CT at 24 and 48 h; diagnostic CT at 24 h using a triple-phase delay after administration of contrast; and diagnostic SPECT/CT at 24 h. All components of the imaging data were reassessed by 3 masked interpreters. The results were compared with a reference standard based on all clinical, imaging, and histopathology follow-up data available (follow-up range, 24–36 mo; mean, 29.9 mo). The reference standard was defined by a study-specific interdisciplinary tumor board that also reassessed treatment decisions. Results: Thirty-one patients were eligible for analysis (18 men and 13 women; mean age, 60.4 y). Ten had no imaging signs of disease and remained disease-free during follow-up. Twenty-one had persistent or recurrent disease (82 lesions: 24 in the liver, 21 in the lymph nodes, 16 in bone, 12 in the pancreas, and 9 in other locations). The respective lesion detection rates for interpreters 1, 2, and 3 were 51.9%, 49.4%, and 71.6% for low-dose SPECT/CT at 24 h; 51.9%, 55.6%, and 67.9% for low-dose SPECT/CT at 48 h; 63.0%, 70.4%, and 85.2% for diagnostic CT; and 77.8%, 84.0%, and 88.9% for diagnostic SPECT/CT. Interobserver agreement was moderate for diagnostic SPECT/CT (κ = 0.44), diagnostic CT (κ = 0.43), low-dose SPECT/CT at 48 h (κ = 0.61), and low-dose SPECT/CT at 24 h (κ = 0.55). For planar imaging, interobserver agreement was fair after 48 h (κ = 0.36) and 24 h (κ = 0.38) and moderate after 4 h (κ = 0.42). Every lesion detectable on planar imaging or low-dose SPECT/CT was also detectable on diagnostic SPECT/CT. The CT and SPECT components of diagnostic SPECT/CT strongly complemented each other, as 34 of 82 lesions (41.4%) were detected on only the CT component or only the SPECT component. Therapeutic management was influenced by the diagnostic SPECT/CT interpretation in 8 of 31 patients (25.8%). Conclusion: The highest detection rates were achieved by diagnostic SPECT/CT. Thus, a more patient-friendly 1-d protocol is feasible. Furthermore, multiphase SPECT/CT affected management in about a quarter of patients.

Comparative Clustering of Plantar Pressure Distributions in Diabetics with Polyneuropathy May Be Applied to Reveal Inappropriate Biomechanical Stress

OBJECTIVES C-telopeptide crosslaps (CTX) and bone-specific alkaline phosphatase (BAP) do not provide sufficient sensitivity and specificity for diagnosis of osteoporosis. Cathepsin K (CatK), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (total (t) and soluble (s) RANKL) play an important role in bone metabolism. Thus serum levels of biochemical markers, each or in combination, may be useful in diagnosis of osteoporosis. STUDY DESIGN In total, 121 healthy women, 27 premenopausal women aged between 20 and 45 years, and 94 postmenopausal women aged 59-81 years, all free of known skeletal disorders were included. They underwent bone density measurement and measurement of biochemical markers. MAIN OUTCOME MEASURES Based on WHO criteria, women were stratified in four groups (premenopausal: healthy; postmenopausal: healthy, osteopenia, osteoporosis), and their levels of CatK, OPG, RANKL, CTX and BAP were analyzed. RESULTS Using WHO criteria 21 postmenopausal women had normal bone mineral density (BMD), 49 had osteopenia and 24 had osteoporosis. There were no significant correlations of CatK, OPG and RANKL with BMD (T-score) in age-adjusted analysis, but for BAP and CTX. ROC analyses resulted in poor diagnostic validity of all parameters. The best result - also confirmed by discriminant analysis - was yielded by BAP (AUC=0.646 [0.510; 0.781]). A combination of variables did not significantly improve the diagnostic power. CONCLUSIONS Baseline serum levels of BAP, CTX, CatK, OPG, sRANKL or tRANKL alone or in combination are not suitable to distinguish osteoporotic from non-osteoporotic postmenopausal women with sufficient accuracy.

Diabetisches Koma und perioperative Diabetestherapie

In diabetic patients, excessive peak plantar pressure has been identified as major risk factor for ulceration. Analyzing plantar pressure distributions potentially improves the identification of patients with a high risk for foot ulceration development. The goal of this study was to classify regional plantar pressure distributions. By means of a sensor-equipped insole, pressure recordings of healthy controls (n = 18) and diabetics with severe polyneuropathy (n = 25) were captured across eight foot regions. The study involved a controlled experimental protocol with multiple sessions, where a session contained several cycles of pressure exposure. Clustering was used to identify subgroups of study participants that are characterized by similar pressure distributions. For both analyzed groups, the number of clusters to best describe the pressure profiles was four. When both groups were combined, analysis again led to four distinct clusters. While three clusters did not separate between healthy and diabetic volunteers the fourth cluster was only represented by diabetics. Here the pressure distribution pattern is characterized by a focal point of pressure application on the forefoot and low pressure on the lateral region. Our data suggest that pressure clustering is a feasible means to identify inappropriate biomechanical plantar stress.