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Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Background Pompe disease (PD) is an autosomal recessive, lysosomal storage disease due to a mutation of the acid α-glucosidase (GAA) gene. In adult patients, PD is characterized by slowly progressive limb-girdle and trunk myopathy and restrictive respiratory insufficiency. Enzyme replacement therapy (ERT) is available, improving or stabilizing muscle-function in some and slowing deterioration in other patients. Unfortunately, there is no biomarker available to indicate therapeutic efficacy and/or disease activity. Whole body MRI depicts all skeletal muscles demonstrating foci of atrophic muscles, i.e., late and irreversible pathological changes. Any method indicating the localizations of increased muscle glycogen storage, muscle inflammation and/or degradation could possibly help identifying newly afflicted tissue and may be of prognostic value. We therefore investigated 2-deoxy-2-[18]fluoro-D-glucose (FDG) PET, a biomarker for glucose-metabolism, as a tool to evaluate disease activity and prognosis in PD. Methods In a pilot study, we investigated four patients by FDG dynamic PET/CT while on ERT. One patient had FDG-PET/CT twice, before and after 12 months on ERT. Dynamic FDG-PET/CT quantifies the metabolic rate of glucose utilisation in mg/ml/min. MRI was performed in parallel with pelvic and thigh muscles semi-quantitatively scored for atrophy and disease-activity. Results None of the muscles analysed showed a focally increased FDG-uptake. Thus, quantification of muscle glucose metabolism could not be calculated. However, increased FDG-uptake, i.e., increased glucose utilisation, was observed in the respiratory muscles of one patient with severe, restrictive respiratory failure. In contrast, specific MRI sequences showed oedematous as well as atrophic muscle areas in PD. Conclusions Our pilot study demonstrates that FDG-uptake does not correlate with glycogen storage in vivo. In contrast, MRI is an excellent tool to demonstrate the extent of muscle involvement. Specific MRI sequences may even demonstrate early changes possibly allowing prognostic predictions or localization of early stages of PD.

Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS). Objective: To determine the role of LHCGR in transient, pregnancy-induced CS. Design, Setting, Patient, and Intervention: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition. Main Outcome Measures and Results: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)–increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of LHCGR, transcription factors GATA4, ZFPM2, and proopiomelanocortin (POMC), AVP receptors (AVPRs) AVPR1A and AVPR2, and downregulated melanocortin 2 receptor (MC2R) vs control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone–positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated MC2R. Coexpression of CYP11B1/CYP11B2 and AVPR1A/AVPR2 was observed in ectopic cortical cells in the medulla. hCG stimulation of the patient’s adrenal cell cultures significantly increased cyclic adenosine monophosphate, corticosterone, 11-deoxycortisol, cortisol, and androstenedione production. CTNNB1, PRKAR1A, ARMC5, and PRKACA gene mutational analyses were negative. Conclusion: Nongenetic, transient, somatic mutation-independent, pregnancy-induced CS was due to hCG-stimulated transformation of LHCGR-positive undifferentiated subcapsular cells (presumably adrenocortical progenitors) into LHCGR-positive hyperplastic cortical cells. These cells respond to hCG stimulation with cortisol secretion. Without the ligand, they persist with aberrant LHCGR expression and the ability to respond to the same stimulus., Précis: Pregnancy-induced CS due to hCG-stimulated transformation of LHCGR-positive undifferentiated subcapsular cells into LHCGR-positive hyperplastic cortical cells with hCG-stimulated cortisol secretion.

Background The obstetric risk in patients with Pompe disease (glycogen storage disease type II), a mainly skeletal muscle disorder, is unknown. Methods The clinical course and the outcome of pregnancy, and the effect of pregnancy on disease manifestations or clinical signs and symptoms in Pompe disease were analyzed retrospectively using a questionnaire. Participating women with Pompe disease were recruited by the German and the UK sections of the International Pompe Association, and by centers associated within the German Pompe Group. The data was compared with information from the German statistical almanac, perinatal registry, and perinatal quality survey. Results 66 of 136 women responded to the questionnaire (median age: 47 years, range: 18–74). In 10 of 52 women who had been pregnant, the symptoms of Pompe disease were present during pregnancy (n = 7 1st, n = 1 2nd, n = 1 3rd pregnancy). Muscle weakness worsened in 3 women, and first presented in 3 others during the first pregnancy (4.5% each). Respiratory problems deteriorated in 2/10 women during pregnancy. These 10 symptomatic women had 17 pregnancies (15 deliveries, 2 miscarriages, no abortions). The 42 asymptomatic women (63.6%) had 109 pregnancies (72.4% deliveries, 19.3% miscarriages, 7.3% abortions). There were no significant differences between the mean duration of pregnancies or the mean birth weight in symptomatic and asymptomatic women, or compared to the data from the general population. The same was true of pregnancy and delivery complications (including Cesarean section). Conclusions Our data show that women with Pompe disease do not appear to have an increased risk of pregnancy or delivery complications. However, muscle weakness and respiratory complications might manifest or worsen during pregnancy in some women.

Neuroendocrine tumours of the pancreas (pNET) are observed in 8 – 17 % of patients with von Hippel-Lindau disease (vHLD), and 11 – 20 % of these patients develop metastatic disease. MRI and CT have a very high resolution; however, their sensitivity and specificity for the detection of pNET amongst cystic lesions in the pancreas of vHLD patients are generally considered insufficient. In contrast, 68Ga-DOTATOC PET/CT demonstrates a high sensitivity for the diagnosis and staging of neuroendocrine tumours. In this study we investigated the potential role of 68Ga-DOTATOC PET/CT in screening of patients with vHLD. 68Ga-DOTATOC PET/three-phase contrast-enhanced CT was performed according to guidelines in all consecutive vHLD patients between January 2012 and November 2015. All patients underwent additional MRI imaging of the abdomen, spine, and head. Chromogranin A (CgA) was determined at the time of the PET/CT examination. A lesion seen on 68Ga-DOTATOC PET in the pancreas was defined as positive if the uptake was visually higher than in the surrounding tissues. Lesions were quantified using maximum SUV. Overall, 20 patients (8 men, 12 women; mean age 44.7 ± 11.1 years) were prospectively examined. Genetically, 12 patients had type 1 vHLD and 8 had type 2 vHLD. 68Ga-DOTATOC PET/CT detected more pNET than morphological imaging (CT or MRI): 11 patients (55 %; 8 type 1, 3 type 2) vs. 9 patients (45 %; 6 type 1, 3 type 2). The concentration of CgA was mildly elevated in 2 of 11 patients with pNET. The mean SUVmax of the pancreatic lesions was 18.9 ± 21.9 (range 5.0 – 65.6). Four patients (36.4 %) had multiple pNETs. The mean size of the lesions on CT and/or MRI was 10.4 ± 8.3 mm (range 4 – 38 mm), and 41.1 % were larger than 10 mm. In addition, somatostatin receptor-positive cerebellar and spinal haemangioblastomas were detected in three patients (SUVmax 2.1 – 10.1). One patient presented with a solitary somatostatin receptor-positive lymph node metastasis. pNETs were observed more frequently in vHLD type 1 than type 2 (66.7 % vs. 37.5 %, p = 0.089). None of the patients showed progressive disease during follow-up. In this study, 68Ga-DOTATOC PET detected pNETs in a higher proportion of patients with vHLD than found in previous studies with 111In-octreoscan, the imaging method recommended by the NCCN. We therefore suggest 68Ga-DOTATOC PET/CT as the more sensible screening tool.

Pompe disease is an autosomal recessive lysosomal storage disease characterized in adult patients by slowly progressive limb-girdle muscle weakness and respiratory insufficiency. Data on pregnancy in women with Pompe disease, intrauterine development of the fetus and parturition are rare. Here we describe a twin pregnancy followed by a second pregnancy in a 38-year-old female patient with Pompe disease. We report the impact of pregnancy on muscle and respiratory functions as well as the neurological and endocrine systems and discuss the medical consequences for anaesthetic management at parturition.

To determine the frequency and impact of gastrointestinal symptoms, and bowel and urinary incontinence, as this is currently unknown in adults with Pompe disease.Adult German Pompe patients and age- and gender-matched controls were asked about symptoms in the upper and lower intestinal tract as well as urinary incontinence using the Gastrointestinal Symptoms Questionnaire and the International Consultation on Incontinence Questionnaires for Bowel Symptoms and Urinary Incontinence.The overall response rate was 78%; 57 patients and 57 controls participated. The mean age of the patients was 48.3 years ±14.7 (28 female, 29 male). 84% of patients were receiving enzyme replacement therapy. Stool urgency, diarrhoea, and urinary urge incontinence were reported significantly more frequently in patients compared to the age- and gender-matched controls (55%, 56%, 33% vs. 20%, 18%, 7%). 20% of Pompe patients used loperamide daily against diarrhoea. No other gastrointestinal tract-related symptoms were reported to occur more frequently in Pompe patients than in controls.Compared to age- and gender-matched controls, both urinary and bowel incontinence occur in a higher frequency in adults with Pompe disease and have a major impact on daily life.

The binding of certain growth factors and cytokines to components of the extracellular matrix can regulate their local availability and modulate their biological activities. We show that interleukin 2 (IL-2), an important stimulator of T cell growth, preferentially binds to collagen types I, III, and VI and to a lesser degree to collagen types II, IV, and V, immobilized on polystyrene or nitrocellulose. These interactions are inhibited by denatured, single collagen chains or a subset of their cyanogen bromide peptides in a dose-dependent manner. Cross-inhibition experiments and ligand blotting of collagen-derived peptides point to a limited set of collagenous consensus sequences mediating the binding of IL-2. This interaction is saturable, with dissociation constants of approximately 10(-)(8) m, and estimated molar ratios of 4-6 molecules of IL-2 bound to one molecule of triple helical collagen. Furthermore, collagen-bound IL-2 stimulates proliferation of mouse lymphocytes. We conclude that its specific binding to the abundant interstitial collagens leads to a spatial pattern of bioavailable IL-2 which is dictated by the local organization of the collagenous extracellular matrix. This interaction may contribute to the particular phenotype of stromal lymphocytes and could be exploited for devising collagenous peptide analogues that modulate IL-2 bioactivity.

Methods A total of 29 patients with DM treated with insulin (20 men, mean age 62 ± 10 years, mean ±SD) and 10 healthy, adult subjects (4 men, mean age 54 ± 4 years) were studied using a commercial whole-body 3.0 Tesla MRI system. In 13 (45%) patients with diabetes CAD was known (mean age 62 ± 10 years); in 16 (55%) DM patients CAD was absent (mean age 62 ± 11 years). The presence of CAD was defined using a previous coronary x-ray angiogram. In each subject, the proximal segment of a coronary artery was imaged for cross-sectional area measurements using cine spiral MRI [3]. Distensibility (mmHg-1*103) was determined as (lumen max lumen min)/(pulse pressure x lumen min) x 1000. The pulse pressure was calculated as the difference between the systolic and diastolic brachial blood pressure. All continuous parameters are given as mean + one standard deviation (SD). For all tests, p

Neuroendocrine tumors (NETs) are rare neoplasms. Approximately 75% of all cases manifest in the gastroenteropancreatic (GEP) system. Because of the low incidence of NETs, limited data about the clinical outcome and prognostic variables are available. In an attempt to identify prognostic parameters, we investigated the distribution of primary tumors, pattern of metastasis formation, clinical presentation, histological classification, and outcome of therapeutic interventions in a large patient cohort cared for in a German referral center. In 254 patients with GEP-NETs, the primary tumor was of foregut, midgut, or hindgut origin in 44.1% (28.7% pancreas), 43.7% (34.7% jejunoileum), and 4.3%, respectively. No primary tumor was found in 7.9%. Metastases occurred preferentially in lymph nodes and the liver. The overall 5-year survival rate was 57.1%. In the absence or presence of metastases at initial diagnosis the 5-year survival rate was 80.0% and 51.7%, respectively. The 5-year survival rate was related to the localization of the primary and was 75.0% and 42.9% for jejunoileal and pancreatic tumors, respectively. The size of the primary tumor (

Mit feucht-kalten Gebuschen, staubigen Kohlenkellern, mit Ruinen beim Hamburger Heiligengeistfeld, am Rand von St. Pauli setzen die Erinnerungen an fruhpubertare Abenteuer im Schreiben Hubert Fichtes ein. Kurz nach der Geburt war seine Mutter mit ihrem unehelichen Sohn von Perleberg, Westprignitz, zu den Groseltern nach Hamburg umgezogen. Sein judischer Vater galt als auf der Flucht vor den Nazis verschollen. Wahrend des Zweiten Weltkrieges wurde der halbjudische, evangelische Halbwaise von der Mutter in einer bayrischen Klosterschule untergebracht. In seinem ersten Roman Das Waisenhaus (1965) beschreibt Hubert Fichte jene traumatischen Spannungen, die in einem sechsjahrigen Jungen zwischen Internat und Pfarrkirche entstehen: Wahrend der Priester von der Kanzel den »Herrn« beschwort, dessen Sohn dahinter blutuberstromt am Kreuz hangt, terrorisieren die Zoglinge als Teufelsgestalten den Neuling mit latent sadomasochistischen Spielen. Die anstaltsinternen Hierarchien unter den Kindern sind in einem System korperlicher Abhangigkeit manifestiert, deren Schauplatz die wenigen intimen Orte sind, die den kontrollierenden Blicken der Nonnen verborgen bleiben: der Waschraum, der Schlafsaal, der Platz unter der Bettdecke. Regiert dort zunachst die pure Angst, so verwandelt sie sich schlieslich in erregte Aufmerksamkeit, in ein Beobachten und Phantasieren des eigenen Korpers und der Korper der anderen, um sich selbst im Kontext des neuen Sozialgefuges orientieren zu konnen. Im allgegenwartigen Verdikt des Sexuellen entfalten die Jungen des katholischen Waisenhauses ein stilles Gesprach der Korper, dessen Grammatik von jenen Orten ausgeht, die der offiziellen Sprachlosigkeit anheimfallen: Es ist ein Diskurs des Analen, in dem sich die Waisenhauszoglinge orientieren, in dem ihre Angste und ihr Begehren um das »Unkeusche« kreisen, wahrend ihre Phantasien eben jenes verbotene Terrain erkunden, das es aus dem Bewustsein zu verdrangen gilt. »Detlev sah Joachims Rucken. Joachim hatte einen schwarzen Schwanz, unter dem Schwanz ein groses schwarzes Loch. Das Loch verbreiterte sich, bis es den halben Rucken einnahm. Blut flos daraus hervor.«

Background Increased left ventricular (LV) mass is a strong predictor of cardiovascular events and mortality and is common among patients with type 2 diabetes. Carotid intima-media thickness (CIMT) is commonly used to monitor progression of coexisting atherosclerosis. However, the relationship between the progression of LV mass and vascular changes in the carotid and coronary arteries remains poorly understood. The purpose of this study was to investigate that relationship in patients with type 2 diabetes. Methods Cardiovascular magnetic resonance (CMR) imaging was performed at baseline and at 2-year follow-up in 95 patients with type 2 diabetes (57 men, mean age 61±9 years), of whom 86 had adequate image quality for common carotid artery and 37 for coronary artery vessel wall measurements. LV-septal and lateral wall thickness was assessed and LV mass index (LVMI) was determined by indexing LV mass to body surface area. For both vascular territories lumen area and total vessel area were assessed and vessel wall area, wall thickness and vessel wall ratio (vessel wall area/body surface area) were calculated. CIMT was measured by ultrasound. Results All patients were under optimal medical treatment. At 2-year follow-up HbA1c significantly improved (HbA1c at baseline 7.88±1.76% vs. HbA1c at follow up 6.86±0.83% (p

Kaum eine Spur durchzieht das Werk Hubert Fichtes so deutlich wie die des Blutes. Erganzt durch die Fotobande von Leonore Mau zu den Buchern uber die afroamerikanischen Religionen — Xango und Petersilie —, bleiben die Texte und Bilder blutuberstromter Korper im Gedachtnis haften. Das rituelle Blutbad, um dessen beschreibende Erforschung es unter anderem geht, betrifft hier zuerst und vor allem den Kopf. Es ist die symbolische Uberschwemmung des Bewustseins, das hinabfliesende Blut, das zum Schliesen der Augen zwingt. „Ich trage dich wie eine Wunde auf der Stirn, die sich nicht schliest …” Das Benn-Zitat als Motto der Geschichte der Nanā verknupft den Blutschwall, der die Objektivitat unterbricht, mit der Mutterfigur. Nach den reflexartig geschlossenen Augen, im Moment der temporaren Blindheit, stellt sich der Geschmack von Blut im Mund ein. Ob dies nun das eigene Blut oder das fremde ist, last sich kaum unterscheiden — zumal nach der Geburt, wenn der Korper des Kindes noch gezeichnet ist vom Blut der Mutter und mit der Abnabelung die Gemeinsamkeit zweier Blutbahnen erst noch zertrennt werden mus. Die Bilder von den blutigen Korpern bei den rituellen Blutbadern, die fester Bestandteil einer inszenierten Wiedergeburt sind, erinnern an diesen Moment kurz nach der Entbindung.

14684 Background: Vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs) are important mediators of tumor growth and metastasis. Since NEC of the gastroenteropancreatic system are ...

14074 Background: Oxaliplatin in combination with 5-fluorouracil and folinic acid is an antitumoral agent with relatively low toxicity and satisfactory efficacy in several gastrointestinal neoplasms. However, it has not been studied in malignant gastrointestinal neuroendocrine carcinomas (NEC) for which platinum-based chemotherapy is a standard treatment with considerable toxicity. Methods: 16 patients (6 female, 10 male; mean age 57) with documented progress of histologically proven, irresectable, malignant NEC were retrospectively analyzed for safety and efficacy of cytotoxic treatment (from october 2001 to december 2005) according to the FOLFOX-4 regimen. Primary tumors were in the foregut in 9 (2 bronchial, 5 pancreas, 2 stomach), in the midgut in 3 (1 ileum, 2 coecum), and in the hindgut in 2 (1 colon, 1 rectum) patients. The primary tumor was unknown in 2 patients. No patient had clinical signs of hormone hypersecretion. NEC were low-grade malignant in 8 and high grade malignant in the remaining 8 cases. The ki67-index was ≥ 10% in 13 cases (81.3%). Results: A mean of 7.25 cycles (range 1–19) of FOLFOX-4 were administered. Stable disease for a minimum of 9 weeks was observed in 62.5% (10/16) for a mean duration of 19.4 weeks; overall mean time to progression (TTP) as measured by imaging studies was 17.8 weeks (range 2–70 weeks). Reasons for discontinuation of treatment included documented tumor progression in 8 cases (50%) and adverse events in 4 cases (25%) (grade II neurotoxicitiy in 3 cases and grade III neutropenia in 2 cases). 2 patients died during treatment due to tumor progression. 4 patients currently still receive FOLFOX-4 after a mean treatment period of 16 weeks. Side effects according to CTC-NCI-criteria include mild anemia (grade I: n=15), thrombocytopenia (I: n=4, II: n=1), neutropenia (I: n=1, III: n=2), increased serum creatinine (I: n=2), nausea (I: n=4, II: n=4, III: n=1), vomiting (I: n=2, II: n=2), and neurotoxicity (I: n=1, II: n=4). Conclusions: The FOLFOX-4 regimen was well tolerated and effective in progressive malignant NEC with increased proliferative potential. Response may be comparable to current standard regimens. FOLFOX-4 should be evaluated in a prospective controlled clinical trial. No significant financial relationships to disclose.

4086 Background Only few data exist on long-term outcome and independent prognostic factors of neuroendocrine tumors (NET) of the gastroenteropancreatic (GEP) system. Low incidence, heterogeneous c...

Background Arterial distensibility can be measured non-invasively by cardiovascular magnetic resonance (CMR) in various arterial territories. However, no information is available comparing distensibility in different anatomical territories in individual patients. Therefore, we sought to compare CMR measurements of the distensibility of the coronary and carotid artery, and ascending aorta (AA) in patients with type 2 diabetes mellitus (DM). Methods