Management of primary and renal hyperparathyroidism: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: The purpose of this review is to provide updated recommendations for the surgical management of primary (pHPT) and renal (rHPT) hyperparathyroidism, formulating a new guideline of the German Association of Endocrine Surgeons (CAEK). METHODS: Evidence-based recommendations for the diagnosis and therapy of pHPT and rHPT were assessed by a multidisciplinary panel using PubMed for a comprehensive literature search together with a structured consensus dialogue (S2k guideline of the Association of the German Scientific Medical Societies, AWMF). RESULTS: During the last 20 years, a variety of new preoperative localization procedures, such as sestamibi-SPECT, 4D-CT, and various PET/CT procedures, were established for pHPT. High-resolution imaging, together with intraoperative parathyroid hormone (IOPTH) measurement, enabled focused or minimally invasive surgery to become the most favored surgical technique. Patients with pHPT and nonlocalizing imaging have a higher risk of multiglandular disease. Surgical therapy provides very high cure rates, with a clear relation to the surgeon's experience in parathyroid procedures. Reoperative parathyroidectomy, children with pHPT or familial forms, and parathyroid carcinoma are addressed and require special surgical expertise. A multidisciplinary team of experienced nephrologists, transplant, and endocrine surgeons should assess the diagnosis and treatment of renal HPT. CONCLUSION: Surgery is the only curative treatment for pHPT and should be considered for all patients with pHPT. For rHPT, a more selective approach is required, and parathyroidectomy is indicated only when conservative treatment options fail. In parathyroid carcinoma, the adequacy of local resection influences local disease control.

Surgical therapy of adrenal tumors: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: Previous guidelines addressing surgery of adrenal tumors required actualization in adaption of developments in the area. The present guideline aims to provide practical and qualified recommendations on an evidence-based level reviewing the prevalent literature for the surgical therapy of adrenal tumors referring to patients of all age groups in operative medicine who require adrenal surgery. It primarily addresses general and visceral surgeons but offers information for all medical doctors related to conservative, ambulatory or inpatient care, rehabilitation, and general practice as well as pediatrics. It extends to interested patients to improve the knowledge and participation in the decision-making process regarding indications and methods of management of adrenal tumors. Furthermore, it provides effective medical options for the surgical treatment of adrenal lesions and balances positive and negative effects. Specific clinical questions addressed refer to indication, diagnostic procedures, effective therapeutic alternatives to surgery, type and extent of surgery, and postoperative management and follow-up regime. METHODS: A PubMed research using specific key words identified literature to be considered and was evaluated for evidence previous to a formal Delphi decision process that finalized consented recommendations in a multidisciplinary setting. RESULTS: Overall, 12 general and 52 specific recommendations regarding surgery for adrenal tumors were generated and complementary comments provided. CONCLUSION: Effective and balanced medical options for the surgical treatment of adrenal tumors are provided on evidence-base. Specific clinical questions regarding indication, diagnostic procedures, alternatives to and type as well as extent of surgery for adrenal tumors including postoperative management are addressed.

Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.

Harmonic scalpel versus conventional dissection technique in pylorus-preserving partial duodenopancreatectomy.

BACKGROUND/AIMS: Pancreatic head resection is performed with low mortality, but morbidity remains high. Extensive preparation, long operating times, intraoperative blood loss and the need for blood transfusions are risk factors for postoperative morbidity. The aim of our study was to evaluate the feasibility and safety of the ultrasonic dissection device in pylorus-preserving duodenopancreatectomy (PPPD). METHODS: Fifty consecutive patients who underwent PPPD with an ultrasonic dissection device (group 1) were compared with a match-controlled group of 50 consecutive patients who underwent PPPD with conventional dissection techniques (group 2). Duration of surgery, intraoperative blood loss, blood units, complications, mortality and duration of hospital stay were analyzed. RESULTS: There was no difference in age, gender or BMI between groups. In group 1, mean blood loss (446 ± 281.8 ml, p = 0.008) and number of blood units (0.32 ± 0.86, p = 0.001) were significantly lower than in group 2 (819 ± 915.4 ml; 1.36 ± 2.83 units). Duration of surgery was shorter in group 1 (345.6 vs. 373 min, p = 0.28). The rate of postoperative complications, mortality and hospital stay were not significantly different. CONCLUSIONS: Use of an ultrasonic dissection device in PPPD might significantly reduce intraoperative blood loss and the need for blood transfusions. These results should be verified in a prospective randomized controlled trial.

Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma.

BACKGROUND: The study was undertaken to determine prognostic factors and the value of systematic lymphadenectomy on survival in sporadic gastrinoma. METHODS: Patients with sporadic gastrinoma who underwent initial surgery during a 21-year period in two tertiary referral centres were analysed retrospectively with respect to clinical characteristics, operative procedures and outcome. RESULTS: Forty-eight patients with a median age of 52 (range 22-73) years were analysed. Some 18 patients had pancreatic and 26 had duodenal gastrinomas, whereas the primary tumour remained unidentified in four patients. After a median postoperative follow-up of 83 (range 3-296) months, 20 patients had no evidence of disease, 13 patients were alive with disease, 11 patients had died from the disease and four had died from unrelated causes. In 41 patients who underwent potentially curative surgery, systematic lymphadenectomy with excision of more than ten lymph nodes resulted in a higher rate of biochemical cure after surgery than no or selective lymphadenectomy (13 of 13 versus 18 of 28 patients; P = 0·017), with a trend towards prolonged disease specific survival (P = 0·062) and disease-free survival (P = 0·120), and a reduced risk of death (0 of 13 versus 7 of 24 patients; P = 0·037). Negative prognostic factors for disease specific survival were pancreatic location (P = 0·029), tumour size equal to or larger than 25 mm (P = 0·003), Ki-67 index more than 5 per cent (P < 0·001), preoperative gastrin level 3000 pg/ml or more (P = 0·003) and liver metastases (P < 0·001). Sex, age, type of surgery and presence of lymph node metastases had no influence on disease free or disease specific survival. CONCLUSION: In sporadic gastrinoma, systematic lymphadenectomy during initial surgery may reduce the risk of persistent disease and improve survival.

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.

Surgery for multiple endocrine neoplasia type 1-associated primary hyperparathyroidism.

BACKGROUND: Surgery in patients with multiple endocrine neoplasia type 1 (MEN1)-associated primary hyperparathyroidism (pHPT) is difficult as the condition it is caused by asymmetrical multiple gland hyperplasia. It is uncertain which operative procedure provides the best outcome with regard to long-term normocalcaemia. METHODS: All patients who had surgery for genetically confirmed MEN1-associated pHPT between 1987 and 2009 were identified from a prospective database. Clinical data, operative procedures and outcome were analysed retrospectively. RESULTS: A total of 47 patients were identified. Twenty-three patients underwent total parathyroidectomy with thymectomy and autotransplantation (TPTX + AT), 11 patients subtotal parathyroidectomy (3-3.5 glands, SPTX) with thymectomy, and 13 patients selective gland excision (fewer than 3 glands, SGE). Rates of persistent disease, recurrent disease and permanent hypoparathyroidism after TPTX + AT were 4 per cent (1 patient), 4 per cent (1 patient) and 22 per cent (5 patients) respectively. Respective rates after SPTX were 0 per cent, 18 per cent (2 patients) and 45 per cent (5 patients), which were not statistically different from those following TPTX + AT. SGE resulted in persistent disease in 23 per cent (3 patients) and a significantly higher rate of recurrent disease (46 per cent, 6 patients; P = 0.004 versus TPTX, P = 0.210 versus SPTX), but permanent hypoparathyroidism did not occur. CONCLUSION: TPTX + AT and SPTX both seem adequate surgical procedures for the treatment of MEN1-associated pHPT and are associated with fewer recurrences than SGE.

Expression of the zinc-finger transcription factor Snail in adrenocortical carcinoma is associated with decreased survival.

In this study, we evaluate whether Snail is expressed in adrenocortical cancer (ACC) and if its expression is related to patient outcome. One of the best known functions of the zinc-finger transcription factor Snail is to induce epithelial-to-mesenchymal transition (EMT). Increasing evidence suggests that EMT plays a pivotal role in tumour progression and metastatic spread. Snail and E-cadherin expression were assessed by immunohistochemistry in 26 resected ACCs and real-time quantitative RT-PCR expression analysis was performed. Data were correlated with clinical outcome and in particular with overall patient survival. Seventeen of 26 (65%) ACC tumour samples expressed Snail when assessed by immunohistochemistry. Snail expression was neither detected in normal adrenocortical tissue, nor in benign adrenocortical adenomas. Expression levels were confirmed on the mRNA level by Real-Time-PCR. Survival rates were significantly decreased in Snail-positive tumours compared to Snail-negative tumours: 10 out of 16 vs one out of eight patients succumbed to disease after a median follow up of 14.5 and 28.5 months, respectively (P=0.03). Patients with Snail-expressing ACCs presented in advanced disease (11 out of 12 vs 6 out of 14, P=0.01) and tend to develop distant metastases more frequently than patients with negative staining (7 out of 11 vs two out of eight, P=0.19). In conclusion, we describe for the first time that Snail is expressed in a large subset of ACCs. Furthermore, Snail expression is associated with decreased survival, advanced disease and higher risk of developing distant metastases.

Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study.

OBJECTIVE: Adrenal lesion is one of the features of multiple endocrine neoplasia type 1 (MEN1). This study aimed to assess prevalence, natural course and clinical relevance of small adrenal lesions without clinical symptoms, endocrine activity, or mechanical problems and thus without clear indication for surgical therapy by endoscopic ultrasound (EUS). DESIGN AND METHODS: Forty-nine patients with familial MEN1 were studied. Twenty-seven of these with adrenal lesions were detected by EUS and at least two performed EUS examinations were included into a subgroup where changes in adrenal morphology were studied by measuring changes in the largest diameter of the dominant adrenal tumour. RESULTS: EUS detected adrenal lesions in 36 (73%) patients: 6 (12%) plump adrenals, 17 (35%) nodular hyperplasia, 12 (24%) adenomas and 1 (2%) cyst. Bilateral adrenal lesions were detected in 17 patients and unilateral in 19 patients. A change in the largest tumour diameter was found to be for nodular hyperplasia -0.02+/-1.41% per month (range -2.56 to 4.58%) and for adenomas -0.61+/-1.95% per month (range -6.25 to 1.15%). One patient had an adrenal cyst with significant growth. There was no evidence of carcinoma or metastatic disease during the study. CONCLUSIONS: The prevalence of adrenal lesions in MEN1 is higher than that reported earlier. Except one cystic lesion, no significant change in the tumour size was observed over a mean observation period of more than 2 years. In a typical situation, small adrenal lesions in MEN1 seem to be constant in their morphology.

Management of sporadic and multiple endocrine neoplasia type 1 gastrinomas.

BACKGROUND: Gastrinomas are functional endocrine duodenopancreatic tumours and are responsible for Zollinger-Ellison syndrome (ZES). Clinical presentation, localization techniques and operative management were reviewed. METHODS: An electronic search of the Medline database was undertaken for articles published in English between January 1987 and May 2007. This timeframe was chosen because of the fundamental changes in operative strategy, antisecretory therapy and localization techniques during this period. RESULTS AND CONCLUSION: Most gastrinomas are located in the 'gastrinoma triangle', comprising the head of the pancreas, and the first and second parts of the duodenum. Some 20 per cent of gastrinomas occur in association with multiple endocrine neoplasia type 1 (MEN1) and 50-60 per cent of tumours are malignant at the time of diagnosis. Biochemical evidence justifies operation of which duodenotomy is an essential part. Only complete tumour resection allows 5- and 10-year survival rates of 90 per cent. Pylorus-preserving pancreaticoduodenectomy may be the procedure of choice for MEN1-ZES.

[Adrenal incidentalomas]. / Inzidentalome der Nebenniere.

Adrenal incidentalomas are clinically inapparent masses detected incidentally with imaging studies conducted for other reasons. They are relatively common and require structured diagnostic workup. In many cases surveillance is warranted. The diagnostic workflow has to reveal whether the mass is hormonally functioning and/or if there is evidence of malignancy. If the tumor is functionally silent and not larger than 4 cm, surveillance is warranted. Functioning tumors and masses larger than 6 cm have to be resected. Fine-needle aspiration biopsy is indicated in very rare cases, but pheochromocytoma has to be ruled out first.

Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening.

BACKGROUND: Adrenal tumors are a common manifestation of the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Prevalence in recent studies varies between 9 and 45%. A genotype-phenotype correlation has been described as well as the development of adrenocortical carcinomas. Long-term prospective data are still lacking. MATERIALS AND METHODS: Thirty-eight MEN-1 patients with proven germline mutations have been prospectively observed in a regular screening program in our hospital. Adrenal glands have been screened by biochemical analysis and either by endoscopic ultrasound (EUS) or computed tomography (CT) or both. Median follow-up was 48 months (12-108 months). Age at diagnosis of MEN-1, type of adrenal tumor, genotype, therapy, and clinical characteristics have been analyzed. RESULTS: In 21 (55%) patients, adrenal involvement of the disease was detected. Adrenal lesions were detected in average 6.9 years after the initial diagnosis of MEN-1. Median tumor size was 12 mm (5-40 mm). Tumor size smaller than 10 mm was observed in 11 patients. Twelve patients had unilateral while nine had bilateral adrenal lesions. EUS detected all adrenal tumors, whereas CT failed in seven cases. In three patients, functioning tumors (one pheochromocytoma, one bilateral Cushing adenoma, and one adrenocortical carcinoma) and one nonfunctioning adenoma were diagnosed by histology and biochemical assessment. Two laparoscopic adrenalectomies and one laparoscopic subtotal resection were performed. Nonfunctioning adrenal lesions, not characterized by histology yet, were found in 18 patients. There was no statistical difference with regard to adrenal involvement between patients with germline mutations in exons 2 and 10 (12/21) and those with mutations in exons 3-9 (6/11). CONCLUSION: MEN-1-associated adrenal tumors are mostly small, benign, and nonfunctioning and much more common than previously reported. EUS was the most sensitive imaging procedure. The genotype-pheotype correlation previously suggested by our group could not be confirmed.

Smooth muscle tumours of the uterine corpus: a clinicopathologic study with immunohistochemical aspects.

BACKGROUND: Based on a clinicopathologic study conducted at the University of Rostock, Germany, between 1/1997 and 6/2003, the histological records of 1761 patients who had been hysterectomized were evaluated. 1422 of these patients were suffering from smooth muscle tumours: 1389 were diagnosed as multiple leiomyomas, 26 as leiomyomas of uncertain malignant potential and 7 as leiomyosarcomas. PATIENTS AND METHODS: The data about the microscopic findings were obtained by use of both conventional histology (HE and Giemsa) and immunohistochemistry with markers for leiomyosarcomas (desmin, actin, sm-actin, myoglobin, vimentin, MIB1) and evaluated by statistical methods. Three case reports are also presented: 2 patients with leiomyosarcoma and 1 patient with an UMP tumour. RESULTS: The statistical evaluation included the frequencies of the different tumours subdivided into age groups, their localizations (with 23 distinctions), the associated microscopic findings (with 12 distinctions and most important combinations) and, finally, the number of tumours per patient and their (grouped) sizes. The case reports showed the presence of nuclear atypia, a heightened mitotic index and tumour cell necrosis. Immunohistochemical methods confirmed the histological diagnosis of a leiomyosarcoma. CONCLUSION: In accordance with earlier studies, more than 95% of the smooth muscle tumours were leiomyomas. Leiomyosarcomas were rare (<1% in our study). In 3 out of 7 cases, a leiomyosarcoma had its origin in a leiomyoma.

Influence of low power cm-/mm-microwaves on cardiovascular function.

The present study has been designed to investigate physiological effects of short (15 min) exposure to low level energy microwaves (< 10 microW cm(-2)). To this end heart rate, PQ, QS and ST (electrocardiography), respiration (conductive stretch band around the thorax), skin temperature (thermocouple), skin conductance (Ag/AgCl electrodes), systolic and diastolic blood pressure (automatic cuff) were continuously recorded in a group of 50 test persons before, during and after a 15 min exposure to 3 microW cm(-2) high frequency (77 GHz) microwaves. After an equilibration period of 30 min the first group of test persons and after additional 30 min the second group of test persons were exposed. The study has been performed in a strict double blind design. While significant effects on the measured parameters were observed depending on time ('calming' effect), no significant difference was observed between exposure and sham exposure to microwaves. In view of the small scatter of the data the present study rules out physiologically relevant effects of low level energy on the autonomic nervous system and cardiovascular function.

Enzyme behaviour and molecular environment. The effects of ionic strength, detergents, linear polyanions and phospholipids on the pH profile of soluble cytochrome oxidase.

The activity vs. pH profile for the oxidation of ferrocytochrome c by purified cytochrome oxidase (ferrocytochrome c:oxygen oxidoreductase, EC 1.9.3.1) was investigated as a function of ionic strength (from 10 to 200 mM) in the absence and in the presence of various perturbants: Tween 20, linear polyanions (RNA, heparin, polyglutamic acid) and phospholipids (asolectin, phosphatidylcholine, phosphatidic acid and cardiolipin). The activation induced by Tween 20 and "zero net charge" phospholipid liposomes was not pH dependent. On the other hand, linear polyanions and polyanionic liposomes strongly perturbed the pH profile, mostly at low ionic strength, by shifting the pH optimum about 1.7 pH units towards alkaline pH values. This effect was reversed by increasing ionic strength. These observations are interpreted in the light of polyelectrolyte theory. Since these results show striking with membrane-bound enzyme, it is concluded that in vivo cytochrome oxidase is located within polyanionic sites of the micochondrial membrane. The activation broght about by phospholipids may result from two posible processes: creation of a hydrophobic environment by the non-polar tails, preventing autoaggregation; and creation of a suitable polyelectrolytic environment by the polar heads (of non zero net charge), increasing the intrinsic reaction rate.