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123/131I-MIBG scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma however with low sensitivity due to low spatial resolution. 124I-MIBG PET may overcome this limitation to improve the staging of patients with (suspected) pheochromocytoma. Methods: We analyzed the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of 124I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathological (n = 25) and clinical validation (n = 18) as standard of truth. Furthermore, we compared 124I-MIBG PET versus contrast enhanced CT (CE-CT) per-patient and per-lesion detection rate of 124I-MIBG PET in 13 additional patients with known metastatic malignant pheochromocytoma (MMP). Results:124I-MIBG PET/CT was positive in 19/43 (44%) patients with suspected pheochromocytoma. Presence of pheochromocytoma was confirmed in 22/43 (51%). 124I-MIBG PET/CT sensitivity, specificity, PPV, NPV were 86%, 100%, 100%, 88%, respectively. 124I-MIBG PET was positive in 11/13 (85%) MMP patients. Combined 124I-MIBG PET and CE-CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on 124I-MIBG PET and CE-CT, respectively. Discussion:124I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and high detection rate at re-staging. Superior diagnostic performance aids guidance of surgical and medical management including personalized 131I-MIBG therapy.

Contains fulltext : 245825.pdf (Publisher’s version ) (Closed access) BACKGROUND: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy. METHODS: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression. FINDINGS: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5-3473·1), abdominal or pelvic tumour location (11·3; 1·5-1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8-13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery). INTERPRETATION: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes. FUNDING: US National Institutes of Health.

Background Surgery for catecholamine-producing tumours can be complicated by intraoperative and postoperative haemodynamic instability. Several perioperative management strategies have emerged but none has been evaluated in randomized trials. To assess this issue, contemporary perioperative management and outcome data from 21 centres were collected. Methods Twenty-one centres contributed outcome data from patients who had surgery for phaeochromocytoma and paraganglioma between 2000 and 2017. The data included the number of patients with and without α-receptor blockade, surgical and anaesthetic techniques, complications and perioperative mortality. Results Across all centres, data were reported on 1860 patients with phaeochromocytoma or paraganglioma, of whom 343 underwent surgery without α-receptor blockade. The majority of operations (78·9 per cent) were performed using minimally invasive techniques, including 16·1 per cent adrenal cortex-sparing procedures. The cardiovascular complication rate was 5·0 per cent overall: 5·9 per cent (90 of 1517) in patients with preoperative α-receptor blockade and 0·9 per cent (3 of 343) among patients without α-receptor blockade. The mortality rate was 0·5 per cent overall (9 of 1860): 0·5 per cent (8 of 517) in pretreated and 0·3 per cent (1 of 343) in non-pretreated patients. Conclusion There is substantial variability in the perioperative management of catecholamine-producing tumours, yet the overall complication rate is low. Further studies are needed to better define the optimal management approach, and reappraisal of international perioperative guidelines appears desirable.

Objective To screen for CLCN2 mutations in apparently sporadic cases of aldosterone-producing adenomas (APAs). Description Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (ClC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured. Conclusion In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.

Objective To evaluate the prevalence of low anterior resection syndrome (LARS) in patients with debulking surgery for primary advanced epithelial ovarian cancer and to identify potential risk factors for development of LARS. Methods We reviewed data on 552 consecutive patients with primary epithelial ovarian cancer (EOC), who underwent upfront or interval cytoreductive surgery including low anterior resection at two different academic institutions (Kliniken-Essen-Mitte, Germany, and Medical University of Vienna, Austria). Intestinal dysfunction was assessed by the validated LARS-questionnaire via telephone call. We performed descriptive statistics and a binary logistic regression model to evaluate risk factors for LARS. Results In total, 341 patients were eligible and 206 (60.4%) were successfully contacted and provided complete information. Major LARS was observed in 78 (37.9%) patients, minor LARS in 44 (21.4%) patients, and no LARS in 84 (40.8%) patients. The prevalence rate of major LARS was not influenced by time interval between surgery and LARS assessment, type of cytoreductive surgery, and recurrent disease at the time of assessment. In multivariate analyses, number of anastomosis was independently associated with an increased risk for presence of major LARS (OR 3.76 [1.95–7.24]). In the present cohort, 25.2% patients had more than one bowel anastomosis. Conclusions LARS in general and major LARS in particular seem to be a frequent long-term complication after debulking surgery including low anterior resection in primary advanced EOC patients. Particularly EOC patients with more than one bowel anastomosis during surgery seem to be at an increased risk for major LARS.

A positive and concordant result of at least two diagnostic modalities is generally recommended prior to focused parathyroidectomy. The aim of this study was to analyze the results of surgery and the accurateness of preoperative ultrasonography (US) as single localization modality in patients who underwent parathyroidectomy without the adjunct of intraoperative Parathormone (PTH) measurement. The cases with a preoperative US as the only localization technique, who underwent parathyroidectomy between 10/1999 and 12/2017, were selected from a prospectively maintained database. Therefore, a total number of 242 patients with a mean age of 58.6 ± 13.7 years were included in the present study. US was performed by referral endocrinologist or by the surgeon during office visits. The overall “cure rate” was 99.2% (240 out of 242 patients). In 228/242 patients (94.2%), a drop of perioperative PTH levels consistent with the definition of cure was observed on the day of surgery. In four of the remaining 14 patients, healing was confirmed by PTH level dropping into the normal range on the first postoperative day. Eight patients were cured after a reoperation was performed at our department. Postoperative complications included one case of permanent recurrent laryngeal nerve palsy (0.4%). If performed by an experienced endocrinologist and/or endocrine surgeon, a positive US could be the only preoperative localization study in patients with pHPT. Moreover, the add-value of intraoperative PTH is limited. Major advantages of US are a very high accuracy, the ease of performance (accessibility) and its cost-effectiveness compared with Sesta-MIBI scintigraphy.

Introduction: Nowadays, the standard procedures of removing benign adrenal tumors are minimally invasive surgical techniques using the laparoscopic or the retroperitoneoscopic route. In ad...

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.

Sarcopenia was reported as a prognostic factor in cancer patients. Using computed tomography (CT), we analyzed the impact of sarcopenia on overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). Preoperative CT scans of consecutive EOC patients (n = 323) were retrospectively assessed for skeletal muscle index (SMI) and muscle attenuation (MA; Hounsfield units [HU]). The optimal cut-off point for MA (32 HU) was calculated using the Martingale residuals method, and previously reported cut-offs for SMI were used. Logistic regression was used to determine univariate and multivariate factors associated with OS. Sarcopenia defined as SMI 0 (13.2 vs. 3.1%), comorbidity (age-adjusted Charlson Comorbidity Index [ACCI] ≥ 4; 36.8 vs. 13.3%), median body mass index (BMI; 27 vs. 24 kg/m2), International Federation of Gynecology and Obstetrics (FIGO) stage, histology (high-grade serous 95.6 vs. 84.7%), and complete resection (38.2 vs. 68.2%). MA

We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center. Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB–IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0–1), intermediate (2–3), and high (≥4), and postoperative surgical complications were graded according to the Clavien–Dindo classification (CDC). The Fisher’s exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS. Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3–5; odds ratio 3.27, 95% confidence interval 1.97–5.43, p

Objective To identify risk factors for anastomotic leakage (AL) in patients undergoing primary advanced ovarian cancer surgery and to evaluate the prognostic implication of AL on overall survival in these patients. Methods We analyzed our institutional database for primary EOC and included all consecutive patients treated by debulking surgery including any type of full circumferential bowel resection beyond appendectomy between 1999 and 2015. We performed logistic regression models to identify risk factors for AL and log-rank tests and Cox proportional hazards models to evaluate the association between AL and survival. Results AL occurred in 36/800 (4.5%; 95% confidence interval [3%–6%]) of all patients with advanced ovarian cancer and 36/518 (6.9% [5%–9%]) patients undergoing bowel resection during debulking surgery. One hundred fifty-six (30.1%) patients had multiple bowel resections. In these patients, AL rate per patient was only slightly higher (9.0% [5%–13%]) than in patients with rectosigmoid resection only (6.9% [4%–10%]), despite the higher number of anastomosis. No independent predictive factors for AL were identified. AL was independently associated with shortened overall survival (HR 1.9 [1.2–3.4], p=0.01). Conclusion In the present study, no predictive pre- and/or intraoperative risk factors for AL were identified. AL rate was mainly influenced by rectosigmoid resection and only marginally increased by additional bowel resections.

Background Results of the PreOperative therapy in Esophagogastric adenocarcinoma Trial (POET) showed some benefits when including radiotherapy into the preoperative treatment. This article is reporting long-term results of this phase III study. Patients and methods Patients with locally advanced adenocarcinomas of the oesophagogastric junction (Siewert types I–III) were eligible. Randomisation was done to chemotherapy (group A) or induction chemotherapy and chemoradiotherapy (CRT; group B) followed by surgery. Results The primary end-point of the study was overall survival at 3 years. The study was closed early after 119 patients having been randomised and were eligible. Local progression-free survival after tumour resection was significantly improved by CRT (hazard ratio [HR] 0.37; 0.16–0.85, p = value 0.01) and 20 versus 12 patients were free of local tumour progression at 5 years (p = 0.03). Although the rate of postoperative in-hospital mortality was somewhat higher with CRT (10.2% versus 3.8%, p = 0.26), more patients were alive at 3 and 5 years after CRT (46.7% and 39.5%) compared with chemotherapy (26.1% and 24.4%). Thus, overall survival showed a trend in favour of preoperative CRT (HR 0.65, 95% confidence interval [CI] 0.42–1.01, p = 0.055). Conclusion Although the primary end-point overall survival of the study was not met, our long-term follow-up data suggest a benefit in local progression-free survival when radiotherapy was added to preoperative chemotherapy in patients with locally advanced adenocarcinoma of the oesophagogastric junction.

The distribution of malignant tumors is strongly related to gender due to sex-related organ and tissue differentiation. Neoplasias of the adrenal glands are relatively common and typically benign. Mainly based on our recently published contributions, we analyzed the influence of gender on type of tumors, complexity of surgery, and long-term outcome. Cortisol-secreting adrenal tumors are more often diagnosed in female patients, while the incidence of Conn’s syndrome and pheochromocytoma is similar between male and female patients. Adrenalectomy is more difficult in male patients because of longer operating time and higher blood loss. The probability of cure in male patients with Conn’s syndrome is significantly lower. Gender does not influence long-term results in adrenal hypercortisolism and pheochromocytomas.

The morphological differentiation between benign and malignant adrenocortical tumors is an ongoing problem in diagnostic pathology. In recent decades the complex scoring systems have been widely used to calculate the probability of malignancy in adrenocortical tumors on the basis of a variety of histomorphological parameters. We herewith present a substantially simplified method to diagnose adrenocortical carcinoma by a single histomorphological parameter on a consecutive series of more than 800 adrenocortical tumors. Between January 2000 and May 2019, altogether 2305 adrenalectomies for of all types of diseases were removed, approximately 98% by minimally invasive approaches. After exclusion of pheochromocytomas, adrenal ganglioneuromas, adrenal metastases, Cushing’s disease related specimens, and Conn’s adenomas, the present series finally consisted of 837 adrenocortical tumors. All tumors were analyzed by experienced pathologists of a single institution using standard histopathological methods (Hematoxylin-Eosin and Ki67 stained sections). Clinical and histopathologic data were prospectively collected and retrospectively analyzed. Clinically, 385 patients had 420 functioning tumors (FT), and 417 had non-functioning adrenal tumors (NFT). The mean size of FT was 3.8 ± 1.4 cm (range 0.5–16 cm) and for NFT 4.5 ± 1.6 cm (range 1.5–18 cm). Histomorphologically, 32 adrenal tumors were classified as adrenocortical carcinoma (ACC; 3.8%). In all 32 cases (tumor size 9.1 ± 4.0 cm, range 3–18 cm), confluenting tumor necrosis could be demonstrated. The remaining 805 tumors (control group) completely lacked this highly reproducible single morphological feature. Ki67 levels above 10% were found in 31 of 32 ACCs and never in adrenocortical adenomas (ACA). With a mean follow-up of 8.2 years, 24 out of 32 patients primarily diagnosed as ACC developed distant metastases (75.0%), whereas all patients in the control group remained free of local or distant recurrence. We conclude that a single morphological parameter (confluenting tumor necrosis) is sufficient to predict a poor clinical course in adrenocortical tumors. The histomorphological diagnosis of this parameter is straightforward and highly reproducible.

The treatment of hypercortisolism for patients with bilateral adrenal disease (BAD) is controversial. Bilateral total adrenalectomy results in permanent hypocortisolaemia requiring lifelong steroid replacement. A more conservative surgical approach, with less than bilateral total adrenalectomy (leaving functional adrenal tissue either unilaterally or bilaterally), represents an alternative option; however, long-term outcome or recurrence data are limited. We report our experience with the surgical management of hypercortisolism caused by BAD. Between 2004 and 2016, 42 patients (12 male, 30 female; mean age 58 ± 10 years) with clinical or subclinical Cushing’s syndrome (CS/sCS) caused by BAD underwent adrenal surgery via the posterior retroperitoneoscopic approach. Adrenal surgery was defined as “adrenalectomy” when total gland excision was performed or “resection” when a partial or subtotal adrenal resection was performed. Clinical, radiological and biochemical parameters were evaluated preoperatively and postoperatively. Seventy adrenal operations performed in total included unilateral resection (n = 3), unilateral adrenalectomy (n = 15), bilateral resection (n = 9), adrenalectomy and contralateral resection (n = 14) and bilateral total adrenalectomy (n = 3). Median operating time was 47.5 min (30–150) with no difference between unilateral and bilateral (synchronous included) procedures (p = 0.15). Mortality was zero. Clavien–Dindo grade of postoperative complications was I (n = 5) and IV (n = 3). All but one patient with CS and 17/31 patients with sCS received postoperative steroid supplementation for a median duration of 20 (1.5–129) months. After median follow-up of 40 months (3–129), the remission rate was 92%; 11 patients required ongoing steroid supplementation. There were three biochemical recurrences (two underwent contralateral resection); two patients with new/progressive radiological nodularity are biochemically eucortisolaemic. A significant reduction in BMI (p = 0.01) and antihypertensive requirements (p = 0.04) was observed postoperatively. A surgical approach which facilitates the conservation of functional adrenal tissue represents a suitable strategy for hypercortisolism caused by BAD. This approach avoids the necessity for lifelong steroid replacement in the majority of cases with low rates of adrenal insufficiency and recurrence.

The aim of the work was to investigate the effect of early thyroidectomy on the course of active Graves’ orbitopathy (GO) in patients with low probability of remission [high TSH receptor antibody (TRAb) serum levels, severe GO] compared to that of continued therapy with antithyroid drugs. Two cohorts were evaluated retrospectively (total n=92 patients with active GO, CAS≥4). Forty-six patients underwent early thyroidectomy (Tx-group) 6±2 months after initiation of antithyroid drug (ATD) therapy, while ATD was continued for another 6±2 months in the ATD-group (n=46). These controls were consecutively chosen from a database and matched to the Tx-group. GO was evaluated (activity, severity, TRAb) at baseline and at 6 month follow-up. At baseline, both cohorts were virtually identical as to disease severity, activity and duration, as well as prior anti-inflammatory treatment, age, gender, and smoking behavior. At 6 month follow-up, NOSPECS severity score was significantly decreased within each group, but did not differ between both groups. However, significantly more patients of the Tx-group presented with inactive GO (89.1 vs. 67.4%, * p=0.02), and mean CAS score was significantly lower in Tx-group (2.1) than in ADT-group (2.8; * p=0.02) at the end of follow-up. TRAb levels declined in both groups (Tx-group: from 18.6 to 5.2 vs. ATD-group: 12.8–3.2 IU/l, p 0 =0.07, p 6months =0.32). Residual GO activity was lower in Tx-group, associated with a higher rate of inactivation of GO. This allows an earlier initiation of ophthalmosurgical rehabilitation in patients with severe GO, which may positively influence quality of life of the patients.

The management of hereditary pheochromocytoma has drastically evolved in the last 20 years. Bilateral pheochromocytoma does not increase mortality in MEN2 or von Hippel-Lindau (VHL) mutation carriers who are followed regularly, but these mutations induce major morbidities if total bilateral adrenalectomy is performed. Cortical sparing adrenal surgery may be proposed to avoid definitive adrenal insufficiency. The surgical goal is to leave sufficient cortical tissue to avoid glucocorticoid replacement therapy. This approach was achieved by the progressive experience of minimally invasive surgery via the transperitoneal or retroperitoneal route. Cortical sparing adrenal surgery exhibits

WOS: 000439200100008, PubMed ID: 29794110, Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

Successful localization is mandatory for focused parathyroidectomy. If ultrasound and sestamibi scan are negative, bilateral neck exploration is necessary. We examined the contribution of complementary computed tomography (CT) scan to identify the affected parathyroid gland. Between November 1999 and April 2014, 25 patients (20 females and 5 males; mean age 67 ± 11 years) with negative or dubious standard imaging (ultrasound and sestamibi scan) underwent CT scan prior to parathyroidectomy and were included in this study. Fifteen patients had had previous neck surgery for parathyroidectomy (n = 11) or thyroidectomy (n = 4). Thin-slice CT (n = 9) or four-dimensional (4D) CT imaging (n = 16) was used. Cure was defined as >50 % post-excision fall of intraoperatively measured parathyroid hormone or fall into the normal range, confirmed by normocalcaemia at least 6 months after surgery. Preoperative CT scan provided correct localization in 13 out of 25 patients (52 %) and was false positive once. Parathyroidectomy was performed by a focused approach in 11 of these 13 patients as well as in 1 patient guided by intraoperatively measured parathyroid hormone (ioPTH). Thirteen patients required bilateral neck exploration. The cure rate was 96 % (24/25 patients). One patient has persistent primary hyperparathyroidism (pHPT) and one a recurrent disease. Six patients presented a multiglandular disease. A CT scan identifies about half of abnormal parathyroid glands missed by conventional imaging and allows focused surgery in selected cases.

Visualization and precise dissection of the parathyroid glands are a crucial step of thyroidectomy. Moreover, identification of parathyroid adenoma in patients with primary hyperparathyroidism can be challenging due to the possible abnormal location of the enlarged parathyroid. Near-infrared fluorescence (NIR) can be adopted during video-assisted neck surgery in addition to standard endoscopic magnification to enhance the visualization of the parathyroid tissue. Between July and August 2017, five patients (one male, four females) underwent video-assisted neck surgery at our hospital. One patient suffered from primary hyperparathyroidism. The four remaining patients underwent thyroidectomy for multinodular goiter or Graves’ disease. The parathyroid glands were firstly identified by the video-assisted approach and then confirmed by the NIR visualization of the endogenous autofluorescence of the parathyroid tissue. Low-dose (2.5 mg/ml) indocyanine green was administered to visualize the vascular supply during and/or after the dissection. The standard dose of 2.5 mg (1 ml per injection) was used to allow repeated injection during the same procedure. An endogenous parathyroid autofluorescence could be visualized by the NIR camera in all patients. The right upper parathyroid adenoma could be detected prior to fully dissection of the gland from the surrounding tissue. Twelve out of 16 parathyroid glands have been visually identified during four total thyroidectomies. Eleven glands showed an autofluorescence prior to indocyanine green (ICG) injection. Further, ICG injection has been used for guiding the dissection of the gland in three cases and for confirmation of the vascular supply at the end of the procedure in the remaining cases. There were neither intraoperative nor postoperative complications. The 5-mm 30° NIR camera allows for enhanced visualization of the parathyroid tissue during video-assisted thyroidectomy. This promising tool can become standard for video-assisted neck surgery.

AimsMany studies have previously reported a higher prevalence of papillary thyroid carcinomas (PTC) in patients with Graves' disease (GD). MicroRNAs (miRNAs) are small, non-coding RNAs that are upregulated in PTC compared with benign thyroid tissue. The objective of the study was to examine the miRNA expression of selected miRNAs that are known to be upregulated in PTC in patients with GD.MethodsParaffin embedded thyroid tissue from 159 patients with GD was screened for expression of the miRNAs 146b, 181b, 21, 221 and 222 by RT-PCR. The expression profiles of four normal thyroids, 50 PTCs without concomitant GD and 11 patients with untreated GD served as the controls.ResultsThe expression pattern of these miRNAs in patients with GD is intermediate between that of benign thyroid tissue (pConclusionsIn conclusion, we found an intermediate expression of specific miRNAs in thyroid tissue from patients with GD that fell between the expression levels found in normal thyroid glands and PTC, which suggests a possible influence of certain miRNAs on developing PTC in patients with GD.

Background: Total extraperitoneal patch plastic (TEP) is one of the most commonly used minimal invasive techniques for inguinal hernia treatment. The recurrent rate is 1-5%. In recurrent cases after TEP, Lichtenstein procedure is the preferable operation. As a new and innovative alternative we [for full text, please go to the a.m. URL], 133. Kongress der Deutschen Gesellschaft für Chirurgie

Adrenal pheochromocytomas are neoplasms characterized by catecholamine excess. Determination of metanephrines by high-pressure liquid chromatography has been well established for the diagnosis of pheochromocytomas, demonstrating high sensitivity and specificity. This study evaluates the diagnostic value of newly available enzyme immunoassays for metanephrines in plasma and urine. Chromogranin A was studied as a potential additional diagnostic tool. Spontaneous blood samples and 24-h urine samples were collected in 149 subjects, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas, 30 nonfunctioning adrenal masses, 15 patients with essential hypertension and 42 healthy normotensive volunteers. Plasma and urinary metanephrine and normetanephrine as well as chromogranin A were determined and putative thresholds were calculated by ROC analysis. Plasma free normetanephrine was found to be the best single parameter with the highest sensitivity (89.5%) and specificity (98.3%) using a threshold of 167 pg/ml. Analysis of the combination of plasma free metanephrines revealed a similar sensitivity with lower specificity of 90.0%. Considering both urinary parameters demonstrated a slightly higher sensitivity (92.9%) with lower specificity (77.6%). ROC analysis revealed a threshold of 215 µg/l for chromogranin A with rather low sensitivity (73.9%) and specificity (74.2%). A weak positive correlation was found between the tumor size of pheochromocytomas and plasma metanephrine (r = 0.53, p ≤ 0.05) as well as chromogranin A (r = 0.60, p ≤ 0.01). In conclusion, plasma free and urinary metanephrines measured by enzyme immunoassays are convenient and reliable parameters for the diagnosis of pheochromocytoma. In contrast, CgA demonstrated poor sensitivity and specificity.

BackgroundSalivary cortisol is increasingly used to assess patients with suspected hypo- and hypercortisolism. This study established disease-specific reference ranges for an automated electrochemiluminescence immunoassay (ECLIA).MethodsUnstimulated saliva from 62 patients with hypothalamic–pituitary disease was collected at 0800 h. A peak serum cortisol level below 500 nmol/l during the insulin tolerance test (ITT) was used to identify hypocortisolism. Receiver-operating characteristic (ROC) analysis allowed establishment of lower and upper cutoffs with at least 95% specificity for adrenal insufficiency and adrenal sufficiency. Saliva from 40 patients with confirmed hypercortisolism, 45 patients with various adrenal masses, and 115 healthy subjects was sampled at 2300 h and after low-dose dexamethasone suppression at 0800 h. ROC analysis was used to calculate thresholds with at least 95% sensitivity for hypercortisolism. Salivary cortisol was measured with an automated ECLIA.ResultsWhen screening for secondary adrenal insufficiency, a lower cutoff of 3.2 nmol/l and an upper cutoff of 13.2 nmol/l for unstimulated salivary cortisol allowed a highly specific diagnosis (i.e. similar to the ITT result) in 26% of patients. For identification of hypercortisolism, cutoffs of 6.1 nmol/l (sensitivity 95%, specificity 91%, area under the curve (AUC) 0.97) and 2.0 nmol/l (sensitivity 97%, specificity 86%, AUC 0.97) were established for salivary cortisol at 2300 h and for dexamethasone-suppressed salivary cortisol at 0800 h.ConclusionsThe newly established thresholds facilitated initial screening for secondary adrenal insufficiency and allowed excellent identification of hypercortisolism. Measurement by an automated immunoassay will allow broader use of salivary cortisol as a diagnostic tool.

Recurrent laryngeal nerve (RLN) palsy is the major concern of reoperative thyroid surgery, and the introduction of neuromonitoring could reduce the rate of this complication. The present study is a retrospective analysis of the experience with completion thyroidectomy with and without neuromonitoring in a referral center.Between October 1999 and April 2011, 246 patients [37 men, 209 women; mean age, 55 ± 12.5 (range, 25-80) years] underwent 250 reoperations for recurrent goiter (n = 203), hyperthyroidism (n = 26), or recurrent thyroid cancer (n = 17). The mean interval between the initial and the reoperative procedure was 17.5 years. According to the availability of the neuromonitoring system and to the surgeon preference, 91 operations were performed with neuromonitoring (NM-group), whereas 159 were performed with direct nerve visualization (NV-group) alone. Patients' characteristics, perioperative data, and postoperative complications were collected in a prospectively maintained database.In the NM-group, 51 unilateral and 40 bilateral resections were performed. The NV-group included 122 unilateral and 37 bilateral procedures. The number of nerves at risk after previous surgery was 128 (NM-group) and 161 (NV-group), respectively. We registered eight RLN palsy in the NM-group (6.2 %) and four in the NV-group (2.5 %; p = 0.1).The routine use of intraoperative neuromonitoring seems not to reduce the incidence of RLN during redo thyroid surgery, at least in the setting of a tertiary referral center.

Item does not contain fulltext PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

Cortical-sparing adrenalectomy in bilateral pheochromocytomas offers a postoperative corticoid-free course and has to be balanced against the risk of local recurrence. In this study we report our experience with the minimally invasive cortical-sparing adrenalectomy in patients with bilateral pheochromocytomas. From January 1996 to February 2011, 66 patients (45 men, 21 women; mean age 36 ± 16 years) were treated for bilateral pheochromocytomas. Fifty-seven patients (88%) were affected by genetic diseases. In 32 patients surgery was synchronously performed on both side, in 34 cases adrenalectomy followed previous surgery. All in all, 101 operations (47 right, 54 left) were conducted using the retroperitoneoscopic access (n = 97) or the laparoscopic route (n = 4). The mortality in our series was zero. Postoperative complications included one patient with a bleeding requiring reoperation and one patient developing a cerebral stroke on the fifth postoperative day. The mean operative time was 67 ± 26 min for unilateral adrenalectomy and 128 ± 68 min for bilateral surgery (range 25–300 min). A cortical-sparing resection was possible in 89 procedures resulting in a corticoid-free postoperative course in 60 patients (91%). A postoperative corticosteroid substitution therapy was necessary in six patients. During a median follow-up period of 48 months, one patient showed a persistent disease and needed reoperation, none developed a recurrent disease. Cortical-sparing surgery for bilateral pheochromocytomas has a low recurrence rate and avoids lifelong cortisone substitution therapy in the majority of cases.

Hereditary pheochromocytoma is associated with germline mutations of a set of susceptibility genes to which the TMEM127 gene has recently been added. Patients with TMEM127 mutations have been thus far exclusively identified with adrenal tumors.A population-based series of 48 consecutive individuals from the European-American Pheochromocytoma Paraganglioma Registry with multiple paraganglial tumors and, of these, one extraadrenal paraganglial tumor were selected for this study. They all had normal results when screened for germline mutations of the genes RET, VHL, SDHB, SDHC, and SDHD. Germline mutation analysis of the TMEM127 gene included a search for intragenic mutations and large rearrangements.Of the 48 eligible patients with extraadrenal paraganglial tumors, two (4.2%) were found to have TMEM127 mutations. One patient had multiple head and neck paraganglioma and one retroperitoneal extraadrenal and adrenal tumor.TMEM127 germline mutations confer risks of extraadrenal paraganglial tumors in addition to the documented adrenal pheochromocytoma. Thus, surveillance for extraadrenal and adrenal paraganglial tumors is likely warranted in TMEM127 mutation carriers, although the true prevalence should be evaluated in patients with extraadrenal paraganglial tumors.

BackgroundFor the clinical management of adrenocortical neoplasms it is crucial to correctly distinguish between benign and malignant tumours. Even histomorphologically based scoring systems do not allow precise separation in single lesions, thus novel parameters are desired which offer a more accurate differentiation. The tremendous potential of microRNAs (miRNAs) as diagnostic biomarkers in surgical pathology has recently been shown in a broad variety of tumours.MethodsIn order to elucidate the diagnostic impact of miRNA expression in adrenocortical neoplasms, a cohort of 20 adrenocortical specimens including normal adrenal tissue (n=4), adrenocortical adenomas (ACAs) (n=9), adrenocortical carcinomas (ACCs) (n=4) and metastases (n=3) was analysed using TaqMan low density arrays to identify specific miRNA profiles in order to distinguish between benign and malignant adrenocortical lesions. Results were validated in a validation cohort (n=16).ResultsConcerning the differential diagnosis of ACAs and ACCs, 159 out of 667 miRNAs were up- and 89 were down-regulated in ACAs. Using real-time PCR analysis of three of the most significantly expressed single key miRNAs allowed separation of ACAs from ACCs. ACCs exhibited significantly lower levels of miR-139-3p (up to 8.49-fold, pConclusionmiRNA profiling of miR-675 and miR-335 helps in discriminating ACCs from ACAs. miRNA analysis may indicate malignant behaviour in cases with indeterminate malignant potential.

Background Although the safety and advantages of minimally invasive, video-assisted thyroidectomy (MIVAT) are well documented in nodular thyroid disease, its role in Graves’ disease is controversial. We compared the outcomes of patients undergoing MIVAT with those undergoing conventional thyroidectomy for Graves’ disease. Methods Of the 497 patients with Graves’ disease referred for surgery (1999–2009), 157 (31.6%) patients underwent the MIVAT procedure (video-assisted group). As a control group, 340 patients undergoing conventional thyroidectomy (conventional thyroidectomy group) were included in the current analysis. MIVAT was proposed if the thyroid volume was ≤30 mL. The data were obtained through a prospectively maintained surgical database. Results Most patients in both groups underwent total thyroidectomy (98% in the MIVAT group and 96.5% in the conventional group). Three (1.9%) conversions to open surgery occurred in the video-assisted group. Hospital stay was significantly shorter ( P = .008) in the video-assisted group (2.1 ± 0.4 days) compared with the conventional thyroidectomy group (2.4 ± 1.4 days). The mean operative time was shorter (84 ± 29 min; range, 15–240) for the video-assisted group compared with the conventional thyroidectomy group (94 ± 43 min; range, 20–360), although this difference was not statistically significant ( P = .05). Postoperative transient hypocalcemia occurred in 14 (8.9%), transient recurrent laryngeal nerve palsy occurred in 2 (1.3%), and postoperative hematoma occurred in 5 (3.2%) patients in the video-assisted group compared with 23 (6.8%), 11 (3.2%), and 8 (2.3%) patients in the conventional thyroidectomy group, respectively ( P = ns). Conclusion In selected patients with Graves’ disease, MIVAT is feasible and can be performed safely with results comparable with open surgery.

One of the keystones in surgery of the thyroid gland is accurate hemostasis. This can be achieved by conventional ligations or new instruments as harmonic scissors or bipolar devices. In the present study, we report our experience with a new bipolar thermofusion vessel sealing system (TVS) compared to conventional vessel ligation (CVL). This prospective non-randomized study included 186 patients operated on by two surgeons between April and November 2007. Age, gender, preoperative diagnosis, type of surgery, operative time, and complications were prospectively collected. TVS was used in 93 patients (29 M, 64 F; mean age 50 ± 14 years, range 11–83) and CVL in 93 patients (27 M, 66 F; mean age 49 ± 14 years, range 16–82). Results and postoperative complications were registered. Postoperative complications included two cases of transient hypocalcaemia in both groups 1 (TVS group) and 2 (CVL group) hemorrhages requiring reoperation (p = ns). No recurrent laryngeal nerve palsy was observed in both groups. A drain was used in 25 cases in the TVS group and in 47 patients in the CVL group (p

An undiagnosed pheochromocytoma may result in life-threatening consequences. The diagnosis of pheochromocytoma is based on the overproduction of catecholamines. Highly sensitive biochemical assays are essential to avoid false-negative results. Determinations of 24-h urinary epinephrine and norepinephrine levels are established diagnostic tools. However, they may be falsely negative in patients with a biochemically-silent or periodically-secreting pheochromocytoma. Metanephrines, which are metabolites of catecholamines, have been suggested as an alternative diagnostic tool. Urinary metanephrines are determined by high-pressure liquid chromatography (HPLC) in an increasing number of laboratories, whereas plasma metanephrines measured by HPLC are available in specialised centres only. The different HPLC methods may be cost- and time-intensive. Immunoassays such as radio- or enzyme-immunoassays may be alternative procedures. Measurement of metanephrines instead of catecholamines by either technique improved the diagnostic accuracy for the diagnosis of pheochromocytomas. Determination of plasma free metanephrines demonstrated a higher accuracy than their urinary counterparts. The use of immunoassays may be an alternative to the laborious HPLC, although the method needs to be evaluated in more detail.

Octreotide is a somatostatin analogue binding on two receptor subtypes. In previous trials Octreotide showed inhibitory effects on tumour growth and liver metastasis in experimental pancreatic cancer. Thus we evaluated whether the new somatostatin analogue SOM-230 binding on 4 receptor subtypes has superior effects on carcinogenesis in pancreatic carcinoma. About 120 Syrian hamsters were randomised into six groups (n = 20): Gr.1: Aqua/Aqua, Gr.2: BOP/Aqua, Gr.3: Aqua/Octreotide, Gr.4: BOP/Octreotide, Gr.5: Aqua/SOM-230, Gr.6: BOP/SOM-230. Tumour groups 2,4,6 subcutaneously received 10 mg/kg body weight N-nitrosobis-2-oxopropylamin (BOP) weekly for 10 weeks, healthy control Gr.1,3,5 were given aqua. In the 17th week therapy started with Octreotide and SOM-230 for 16 weeks, after 32 weeks animals were sacrificed. Pancreas and liver were histopathologically analysed. Hepatic lipidperoxidation was determined by activities of antioxidative enzymes gluthation-peroxidase (GSH-Px) and superoxiddismutase (SOD) as well as concentration of thiobarbituric-acid reactive substances (TBARS). Incidence of liver metastases was 88.2% in Gr.2 (BOP/Aqua), it was decreased in Gr.4 (BOP/Octreo: 40%) and Gr.6 (BOP/SOM-230: 50%) (P < 0.05). Mean number/animal and mean-2-dimensional size of liver metastases did not differ between tumour groups. Comparing GSH-Px-activity in intrametastatic and extrametastatic hepatic tissue revealed a significant increase extrametastatically in Gr.2 (BOP/Aqua) and Gr.6 (BOP/SOM-230). SOD-activity in liver metastases was decreased in Gr.2 (1,801) (P < 0.05) versus Gr.4 (8,304) and Gr.6 (7,038). Intrametastatic TBARS concentration was increased in Gr.2 compared to Gr.4 (BOP/Octreotid) and Gr.6 (BOP/SOM-230) (P < 0.05). Octreotide and SOM-230 equally reduced liver metastasis in ductal pancreatic adenocarcinoma probably by a reduction of lipidperoxidation.

One of the best known functions of the zinc-finger transcription factor Snail is to induce epithelial-mesenchymal transition (EMT). Twist, a target genes of Snail, is known to promote the development of distant metastases in mice. Increasing evidence suggests that EMT plays a pivotal role in tumor progression and metastatic spread.Snail, Twist, and E-cadherin expression were assessed by immunohistochemistry and real-time quantitative reverse transcriptase-polymerase chain reaction in 12 malignant and 35 benign pheochromocytomas (PCC). Data were correlated with clinical characteristics and genetics.We found Snail expression in 13 (28%) of 47 primary PCC samples. Twist was expressed in 31 (66%) of 47 cases. Only one of 47 PCC showed E-cadherin expression. We observed Snail expression in 7 (58%) of 12 malignant PCC, whereas only 6 (17%) of 35 apparently benign PCC revealed Snail expression (P = 0.01). Furthermore, 11 (92%) of 12 malignant PCC, but only 20 (57%) of 35 benign PCC, revealed Twist expression (P = 0.03). Interestingly, all five metastases showed Snail and Twist expression. In normal adrenal medulla, Snail, Twist, and E-cadherin expression could not be detected.We describe for the first time that EMT markers Snail and Twist are expressed in PCC and that their expression is associated with malignancy. Our study supports a role for EMT in the malignant transformation of PCC.

Purpose Preoperative chemotherapy is an accepted standard in the treatment of localized esophagogastric adenocarcinoma. Adding radiation therapy to preoperative chemotherapy appears promising, but its definitive value remains unknown. Patients and Methods Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia were randomly allocated to one of two treatment groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed by surgery (arm B). Primary outcome was overall survival time. A total of 354 patients were needed to detect a 10% increase in 3-year survival from 25% to 35% by addition of radiation therapy. The study was prematurely closed due to low accrual. Results The median observation time was 46 months. A total of 126 patients were randomly assigned and 119 eligible patients were evaluated. The number of patients undergoing complete tumor resection was not different between treatment groups (69.5% v 71.5%). Patients in arm B had a significant higher probability of showing pathologic complete response (15.6% v 2.0%) or tumor-free lymph nodes (64.4% v 37.7%) at resection. Preoperative radiation therapy improved 3-year survival rate from 27.7% to 47.4% (log-rank P = .07, hazard ratio adjusted for randomization strata variables 0.67, 95% CI, 0.41 to 1.07). Postoperative mortality was nonsignificantly increased in the chemoradiotherapy group (10.2% v 3.8%; P = .26). Conclusion Although the study was closed early and statistical significance was not achieved, results point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the esophagogastric junction.

Most of the thyroidal nodules are of benign origin. Compared to palpation 10 times more nodules can be seen by sonography. The evaluation by clinical work-up, sonography, scintigraphy and fine needle aspiration biopsy (FNAB) determines the surgical approach. In benign diseases and small papillary cancer (≤ 1 cm) an unilateral resection is sufficient, otherwise a thyroidectomy is indicated. Minimal invasive videoassisted thyroidectomy (MIVAT) offers improved cosmetic results.

OBJECTIVE To assess retrospectively duration of functioning and rate of complications of a totally implantable venous access system used for long-term chemotherapy. PATIENTS AND METHODS Between 1985 and 1993, a central venous access system (Port-a-Cath) had been implanted subcutaneously for long-term chemotherapy in 1000 patients (479 males, 521 females; mean age 49 [15-86] years). Follow-up observations lasted until the end of the chemotherapy or the removal of the system. RESULTS Mean time of functioning of the catheter system was 284 (2-1563) days. The complication rate was 12.8%: catheter infection in 4.9% and catheter thrombosis in 3.2%. A further 4.7% of patients had less common complications (malfunction, catheter dislocation, skin necrosis, catheter break or disconnection, pneumothorax). A total of 119 (11.9%) systems had to be removed because of complications. The rates of infection and of other complications were significantly lower in patients with solid tumours (2 and 4%, respectively) than in those with haematological disease (6 and 8%) (P < 0.05 for each). CONCLUSION Totally implantable venous access systems are suitable for long-term chemotherapy and cause few complications.

Thirty new malignant tumours were found in 1080 patients (634 men, 446 women; mean age 37.6 +/- 13.6 years) after a median follow-up period of 5 years following 1245 cadaveric kidney transplantations performed between 1972 and 1990. The mean dialysis period before transplantation had been 4.0 +/- 3.1 years. Regarding the type of tumour, carcinomas were by far the most frequent, while there was only one lymphoma. The annual malignancy incidence for renal transplant patients was 0.5%. This is 3.5 times higher for men and 4.2 times for women than in the normal population. Immunosuppression with azathioprine and/or antithymocytic globulin (n = 395) produced the same malignancy incidence (0.54%) as with cyclosporin (n = 685; 0.60%). On the other hand, malignant tumours occurred much earlier under cyclosporin than under azathioprine/antithymocytic globulin (27 and 68 months, respectively).

Over a 10-year period, nine patients (four men, five women, mean age 27 years) underwent surgery for splenic cysts (six epidermoid cysts, two mesothelial cysts and one pseudocyst). Six patients had had suggestive clinical symptoms, but, in the other three, the cysts were only discovered by chance on ultrasound scan. Three of the patients with epidermoid cysts had raised serum concentrations of the tumour markers carcinoembryonic antigen (CEA) or carbohydrate antigen (CA 19-9. All six benign epidermoid cysts contained immunohistochemically demonstrable CEA and/or CA 19-9 in the inner epithelial layer, implying a mesothelial origin for these cysts. In five cases the splenic cysts were completely extirpated (splenectomy in two, hemisplenectomy in one, enucleation in two); in four cases cyst resection was performed, leaving part of the cyst adherent to the spleen. In one of these four patients, a 4 cm cyst persisted postoperatively in the hilus of the spleen, but has remained unchanged over an 8-year period. Splenic cysts are usually benign, despite the presence of tumour markers in the cyst wall, and do not require removal. The only indications for surgical intervention are complications (e.g. rupture), symptomatic cysts or asymptomatic cysts with an increased risk of rupture (diameter greater than 5 cm). The very rare parasitic and infective forms must always be surgically sterilized.

Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitute a large proportion of PA cases and represent a surgically correctable form of the disease. The WNT signaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling is mutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutations in a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. All of the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3. The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression and direct measurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. This report provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occur in APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway may be important in APA formation.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma. MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed. RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype. CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.

Background Matrix metalloproteinases (MMP) are proteolytic enzymes which degrade the extracellular matrix and therefore play an important role in metastasis. However, the impact of MMP inhibitors (MMPI) on pancreatic cancer is still unclear. Thus we evaluated the influence of selective MMPI Ro 28-2653 on the incidence of liver metastases and the concentration of MMP-2 and MMP-9 in ductal pancreatic adenocarcinoma in Syrian hamster. Material and methods One hundred and thirty male Syrian hamsters were randomised into 8 groups (Gr.1–3: n = 15 , Gr.4–8: n = 17 ). Pancreatic cancer was induced by weekly subcutaneous injection of 10 mg N-nitrosobis-2-oxopropylamin (BOP)/kg body weight (Gr.4–8) while healthy control Gr. 1–3 received 0.5 ml sodium chloride 0.9%. Gr.1 and 4 had free access to a standard diet, Gr. 2, 3 and 5–8 received a diet rich in polyunsaturated fatty acids, which increases liver metastasis in this model. In week 17 oral therapy started: Gr.3 and 6: 60 mg Eudragit/kg body weight/d (vehicle of MMPI), Gr.7 and 8: 40 mg, respectively, 120 mg RO 28-2653/kg body weight/d; Gr.1, 2, 4, 5: no therapy. After 30 weeks all hamsters were sacrificed and histopathologically examined. Additionally concentrations of MMP-2 and MMP-9 were measured in non-metastatic liver and liver metastases. Results Concentrations of MMP-2 and MMP-9 in liver metastases were decreased by high- and low-dose therapy with MMPI. Furthermore, the incidence of liver metastases was significantly reduced by low-dose therapy with Ro 28-2653. Conclusion Low-dose therapy with Ro 28-2653 decreased liver metastasis due to an inhibition of MMP-2 and MMP-9 concentration in ductal pancreatic cancer.

In patients with an adrenal mass, hormonally active tumors including pheochromocytomas as well as aldosterone- and cortisol-secreting adenomas need to be considered. Several studies have demonstrated that metanephrines, which are the metabolites of catecholamines, are reliable parameters for the diagnosis of pheochromocytoma. In patients with an adrenal mass, we found plasma metanephrines, measured by a newly available radioimmunoassay, to be highly sensitive and specific for pheochromocytomas, with a better accuracy than any other biochemical parameter. The plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio is an established screening tool for primary hyperaldosteronism. However, determination of active renin concentration (ARC) in contrast to PRA may offer advantages in regard to processing and standardization. We found a PAC to ARC ratio of >62 in patients with PAC levels>200 ng/L to be a reliable screening method for primary hyperaldosteronism in patients with adrenal masses. The screening for hypercortisolism relies on excess urinary cortisol secretion, loss of the physiological feedback during dexamethasone challenge, and loss of the circadian rhythm. Because urinary-free cortisol may not identify subclinical Cushing's syndrome, in which hypercortisolism is still mild, the 1-mg dexamethasone suppression test has been recommended in all patients with incidentally detected masses. Alternatively, late-night cortisol levels in saliva have been found to have a high sensitivity and specificity for the diagnosis of Cushing's syndrome. In summary, in patients with an adrenal mass, hormonally active adrenal tumors can be excluded with high certainty using a few highly reliable biochemical parameters.

Although deceptively simple, the etio-pathogenesis of pheochromocytoma represents a clinical and molecular genetic investigative challenge. Here, we summarize, from a historical point of view, the 22-year-long studies initiated at the University of Freiburg, which developed from a local experience to a national and finally an international effort. All research activities are translational and clinical and hence, registry based and intended to improve the outcome of the patients, whether by improved detection, prevention, or treatment. Major clinical steps are the prospective study on hormone tests and imaging techniques for adrenal and extra-adrenal abdominal tumors as well as the concept of organ sparing and endoscopic tumor resection. Further, we introduced 18-fluoro-dopa positron emission tomography. Population-based registries were used in order to identify germline mutations in the susceptibility genes VHL, RET, SDHB, and SDHD in non-syndromic pheochromocytoma. We differentiated distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Finally, we identified predictors and prevalence of paraganglioma syndromes associated with mutations of the SDHC gene.

Effects of polyunsaturated fatty acids (PUFA) on carcinogenesis are discussed controversially. Thus, tumor growth seems to be influenced by type and composition of fat dietary; however, the pathomechanism is still unknown. Therefore, we investigated the impact of different PUFAs on liver metastasis and hepatic lipid peroxidation in a solid model of ductal pancreatic cancer in Syrian hamsters.90 male hamsters were randomized into 6 groups (n = 15). Accordingly groups 2, 4 and 6 received 10 mg N-nitrosobis-2-oxopropylamine (BOP)/kg body weight weekly by subcutaneous injection for 12 weeks in order to induce ductal pancreatic cancer, while groups 1, 3 and 5 were treated with 0.5 ml 0.9% sodium chloride. All hamsters received a standard fat diet (SFD) rich in n-6 PUFA for 16 weeks (2.9% fat). Afterwards, groups 1 and 2 had free access to SFD, while groups 3 and 4 were given a diet enriched with n-3, n-6 and n-9 PUFA (SMOF) and groups 5 and 6 were fed a diet high in n-3 PUFA (FISH-OIL). After 32 weeks all hamsters were sacrificed in order to determine incidence of pancreatic carcinoma and liver metastasis. Furthermore hepatic activities of glutathionperoxidase (GSH-Px) and superoxiddismutase (SOD) as well as levels of lipidperoxidation were analyzed intra- and extrametastatically.The incidence of liver metastasis was decreased in the FISH-OIL tumor group compared to the SFD and SMOF groups. However, GSH-Px activity was not influenced by different diets. Extrametastatic hepatic SOD activity did not differ between all groups, while intrametastatic hepatic SOD activity in the SFD-BOP group was increased. In the FISH-OIL-BOP and the SMOF-BOP group intrametastatic SOD activity was lower than in non-metastatic hepatic tissue. Furthermore levels of hepatic lipid peroxidation were decreased in the tumor groups treated with fish oil and SMOF compared to the SFD group. Comparing intra- and extrametastatic TBARS concentration there was no difference in the SFD-BOP and the SMOF-BOP groups, while in the FISH-OIL-BOP group intrametastatic TBARS concentration was increased.Conclusively, fish oil reduced the incidence of liver metastasis in experimental ductal pancreatic cancer. Maybe this effect is caused by an increase of intrametastatic hepatic lipid peroxidation.

Type and composition of polyunsaturated fatty acids (PUFAs) are suspected to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 PUFAs on tumour growth, liver metastasis and concentration of prostaglandins (PG) and leukotrienes (LT) in experimental ductal pancreatic adenocarcinoma. Ninety male hamsters were randomised into six groups (Gr.) (n=15). While Gr. 1-3 were healthy control groups, Gr. 4-6 weekly received subcutaneous injections of 10mg N-nitrosobis-2-oxypropylamine (BOP)/kg body weight for 12 weeks in order to induce ductal pancreatic adenocarcinoma. Between week 1 and 16 all animals were fed with a standard diet with a raw fat content of 2.9%. In week 17 Gr. 1-6 were allocated to three types of diets: Gr. 1: standard high fat (=SHF diet, rich in n-6 PUFAs)/Gr. 2: FISH-OIL (rich in n-3 PUFAs)/Gr. 3: SMOF (=mixture of n-3, n-6 and n-9 PUFAs)/Gr. 4: BOP+SHF/Gr. 5: BOP+SMOF/Gr. 6: BOP+FISH-OIL. After 32 weeks all animals were sacrificed and pancreas as well as liver were analysed histologically. Furthermore pancreatic and hepatic concentrations of prostaglandins (PGF1alpha, PGE(2)) and LT were measured. FISH-OIL decreased number of macroscopically visible pancreatic tumours (Gr. 4-6: 54.5% vs. 45.5% vs. 9.1%, P

Background Type and composition of dietary fat intake is supposed to play an important role in carcinogenesis. Thus we investigated the effects of n-3, n-6 and n-9 polyunsaturated fatty acids (PUFA) on oxidative stress (lipidperoxidation) and tumour growth in ductal pancreatic cancer. Methods Ninety male hamsters were randomized into 6 groups (gr.) ( n = 15 ) and allocated to 3 main dietary categories: gr. 1 and 2 received a standard high fat diet (SHF, rich in n-6 PUFA), while gr. 3 and 4 were fed with a diet containing a mixture of n-3, n-6 and n-9 PUFA (SMOF) and gr. 5 and 6 had free access to a diet rich in n-3 PUFA (FISH-OIL). Gr. 1, 3 and 5 received weekly subcutaneous (s.c.) injections of 10mg N -nitrosobis-2-oxypropylamine (BOP)/kg body weight in order to induce ductal pancreatic adenocarcinoma. Healthy control gr. 2, 4 and 6 were treated with 0.5ml 0.9% sodium chloride s.c. After 32 weeks all animals were sacrificed. Removed pancreata were weighed and analysed histologically and biochemically. Activities of glutathionperoxidase (GSH-Px), superoxiddismutase (SOD) and levels of lipidperoxidation were measured in samples of pancreatic carcinoma as well as in tumour-free pancreatic tissue. Results While different diets did not significantly alter the overall incidence of histologically proven pancreatic adenocarcinoma, the number of macroscopically visible tumours was decreased in the FISH-OIL-gr. Conclusion Different diets did not significantly influence the incidence of histologically proven pancreatic adenocarcinoma. However, administration of a diet rich in n-3 PUFA (FISH-OIL) resulted in a decrease of macroscopically visible tumours, thus indicating its beneficial effects in respect to attenuation of tumour growth.

Acute pancreatitis often requires parenteral nutrition. Thus, we analyzed, using a randomized trial, whether different fatty acids in parenteral nutrition influence lipidperoxidation and histopathology in acute pancreatitis in rats. Seventy-five male Sprague–Dawley rats were randomized into five groups (gr.) (n=15). Gr. 1 underwent a laparotomy followed by saline infusion, gr. 2–5 received intraductal glycodeoxycholic acid (GDOC) followed by intravenous cerulein. Six hours after induction of pancreatitis (IOP), gr. 2 received saline infusion, while gr. 3 was infused with standard lipovenous (rich in [n−6] polyunsaturated fatty acids (PUFA)), gr. 4 received ClinOleic (rich in [n−9] PUFA), while gr. 5 was infused with Omegaven (rich in [n−3] PUFA) for 18 h. After 24 h, all animals were sacrificed and the pancreas was determined histopathologically according to the severity of pancreatitis. Furthermore, pancreatic lipidperoxidation (TBARS) and activity of lipid production protective enzymes superoxide dismutase (SOD) and gluthationperoxidase (GSHPx) were analyzed. Omegaven infusion reduced the severity of histopathologic changes in acute pancreatitis and decreased lipidperoxidation (TBARS) in pancreatic tissue samples. Furthermore, pancreatic activity of SOD was increased. However, standard PUFA and ClinOleic infusion did not influence the severity of pancreatitis and lipidperoxidation. Parenteral nutrition high in n−3 PUFA seems to be superior to compositions of n−6 or n−9 PUFA in the treatment of acute hemorrhagic pancreatitis in rats.