Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1.

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.     

Lung injury in acute experimental pancreatitis in rats. I. Morphological studies.

The pathogenesis of pancreatitis-related pulmonary injury was studied at the light- and electronmicroscopic level. Experimental pancreatitis was induced in rats by infusion of supramaximal doses of cerulein for 12 h. Investigations were carried out 3, 6, and 12 h after the start of infusion and 12, 48, and 72 h after the end of pancreatitis induction. Initial manifestations of pancreatitis-associated lung injury revealed a pronounced clustering of polymorphonuclear leukocytes in pulmonary microvessels, followed by severe damage of alveolar endothelial cells. Consecutively, the increase in vascular permeability of the lung resulted in interstitial edema formation. Structural changes were maximal after 12 h and reversed completely after 84 h. In conclusion, the structural appearance of pulmonary injury in cerulein-induced pancreatitis was similar to that reported in early stages of the adult respiratory distress syndrome (ARDS). It is suggested that polymorphonuclear granulocytes play a crucial role in the pathogenesis of pancreatitis-related lung injury.     

Effects of overnight fasting on working memory‐related brain network: An fMRI study

Glucose metabolism serves as the central source of energy for the human brain. Little is known about the effects of blood glucose level (BGL) on higher‐order cognitive functions within a physiological range (e.g., after overnight fasting). In this randomized, placebo‐controlled, double blind study, we assessed the impact of overnight fasting (14h) on brain activation during a working memory task. We sought to mimic BGLs that occur naturally in healthy humans after overnight fasting. After standardized periods of food restriction, 40 (20 male) healthy participants were randomly assigned to receive either glucagon to balance the BGL or placebo (NaCl). A parametric fMRI paradigm, including 2‐back and 0‐back tasks, was used. Subclinically low BGL following overnight fasting was found to be linked to reduced involvement of the bilateral dorsal midline thalamus and the bilateral basal ganglia, suggesting high sensitivity of those regions to minimal changes in BGLs. Our results indicate that overnight fasting leads to physiologically low levels of glucose, impacting brain activation during working memory tasks even when there are no differences in cognitive performance. Hum Brain Mapp 36:839–851, 2015. © 2014 Wiley Periodicals, Inc.     

Clinical course of haemodialysis patients with malignancies and dose-adjusted chemotherapy.

BACKGROUND: Chemotherapy is not given routinely to patients with malignancies receiving chronic haemodialysis because evidence of a clear benefit is still lacking and severe side effects are feared. The aim of our retrospective study was to analyse the methods of dose adjustment and the clinical course of chronic haemodialysis patients with malignancies treated by chemotherapy. METHODS: Between 1985 and 2001, a total of 48 cycles of 21 chemotherapy protocols were administered to 16 dialysis patients with nine haemoblastic and seven solid malignancies. We compared the dose actually administered with that theoretically derived from the proportional dose reduction rule of Dettli and the rule of Giusti and Hayton, using published pharmacokinetic parameters. RESULTS: Kaplan-Meier estimates of median survival time were 30 months in patients with haemoblastic malignancies and 10 months for patients with solid malignancies. Eleven chemotherapies were administered in standard dosages and 10 chemotherapies in reduced dosages (39-80% of the regular dose); in all therapies, however, the dose was significantly higher than proposed by the Dettli rule (P<0.01). CONCLUSION: Chemotherapy in patients with haemodialysis is feasible. Individual dose adjustment should be performed on the basis of pharmacokinetic data and the general condition of the patient, but it is still a matter of expert judgement, as there is no formal evidence available.     

Menin mutations in the diagnosis and prediction of multiple endocrine neoplasia type 1

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the development of multiple endocrine adenomas, typically in the pancreas, anterior pituitary, and parathyroid glands. The disease is associated with germ-line mutations of the menin gene, a putative tumor-suppressor gene located on human chromosome 11q13. Methods: To facilitate the diagnosis and prediction of MEN1 in patients and their relatives, we developed a molecular two-step strategy to screen for menin gene mutations. DNA fragments covering the entire menin coding sequence are generated from patient cDNA by polymerase reaction (PCR) and subsequently analyzed by single-strand conformational polymorphism electrophoresis (SSCP). Fragments with aberrant SSCP migration are DNA-sequenced to directly characterize menin mutations. In a second diagnostic step, genomic DNA of healthy relatives of the corresponding MEN1 index patient is analyzed by PCR, with only the specific exon amplified harboring the family-specific mutation. Mutation-specific restriction enzyme digestion of this PCR product finally allows the identification of mutation carriers through pathological restriction fragment patterns. Results: Using this approach, we identified an in-frame deletion mutation (Δ Tyr Met) located in menin exon 4 (codon 227 – 228) that co-segregates with the disease phenotype in a large MEN1 family from Southern Germany. Conclusion: It is likely that the direct molecular analysis of menin gene mutations will replace the genetic and biochemical screening tests currently used in the clinical management of MEN1 families. In addition, these studies may provide clues to the tumor biology of both sporadic and MEN1-associated endocrine adenomas. Received: 2 January 1998     

Kalzitoninbestimmung zur Frühdiagnose des medullären Schilddrüsenkarzinoms

Calcitonin is considered to be a sensitive marker for medullary thyroid cancer (MTC) therefore early detection and surgical treatment may help to improve the clinical prognosis of MTC. Routine calcitonin measurement has therefore been recommended in the diagnostic evaluation of patients with nodular thyroid disease. In the case of elevated serum calcitonin (>20 pg/ml) stimulation testing is recommended to improve the predictive power for MTC particularly in patients with small nodules. Serum calcitonin measurement cannot reliably discriminate between micro-MTC (<10 mm) and C cell hyperplasia. In patients with stimulated calcitonin levels exceeding 100 pg/ml thyroidectomy is recommended because of a high inherent risk of MTC. Highly elevated basal and stimulated serum calcitonin levels are strongly suggestive of MTC with practical implications for surgical management.     

Clinical value of 18F-fluorodihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA PET/CT) for detecting pheochromocytoma

Purpose

In detecting pheochromocytoma (PHEO), positron emission tomography (PET) with the radiolabelled amine precursor ¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-DOPA) offers excellent specificity, while computed tomography (CT) provides high sensitivity and ability to localize lesions; therefore, the combination of these modalities could be advantageous in this setting. The aim of this study was to investigate whether combined ¹⁸F-DOPA PET/CT more accurately detects and localizes PHEO lesions than does each modality alone.

Methods

¹⁸F-DOPA PET, CT and ¹⁸F-DOPA PET/CT images of 25 consecutive patients undergoing diagnostic scanning of suspected sporadic or multiple endocrine neoplasia type 2 syndrome-associated PHEO were reviewed retrospectively in randomized sequence. Two blinded observers scored the images regarding the likelihood of PHEO being present and localizable. Results were correlated with subsequent clinical history and, when available, histology.

Results

Of the 19 lesions detected by all three modalities, PET identified each as positive for PHEO, but was unable to definitively localize 15 of 19 (79%). CT could definitively localize all 19 lesions, but could not definitively diagnose or exclude PHEO in 18 of 19 (95%) lesions. Furthermore, CT falsely identified as negative for PHEO one lesion which was judged to be positive for this tumor by both PET and PET/CT. Only in PET/CT scans were all 19 lesions accurately characterized and localized. On a per-patient basis, the sensitivity of ¹⁸F-DOPA PET/CT for PHEO was 100% and the specificity 88%, with a 100% positive predictive value and an 88% negative predictive value.

Conclusion

¹⁸F-DOPA PET/CT more accurately diagnoses and localizes adrenal and extra-adrenal masses suspicious for PHEO than do ¹⁸F-DOPA PET or CT alone.     

Schilddrüsenkarzinom – Klinik und Diagnostik

The diagnostics of thyroid cancer in Germany is part of the differential diagnostic management of thyroid nodules which are detectable at very high prevalence in this region. Clinical data, ultrasonography, laboratory tests including calcitonin measurement and thyroid scintigraphy all provide valuable information for the initial assessment of the malignancy risk. When used in the context of rational diagnostic algorithms these methods help to select patients requiring further diagnostic assessment by fine needle biopsy. The ultimate goal of fine needle cytology is to improve the pre-operative distinction of benign and malignant thyroid lesions in order to reduce the high rate of diagnostic surgical interventions.