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This file contains various control experiments such as siRNA validation, impact on cell toxicity or the effects of HDAC6 knock-down on the expression of other HDAC family members.

Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2α is a potent oncogenic stimulus, but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate KrasG12D and delete Hif2α solely within the pancreas. Surprisingly, loss of Hif2α in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of β-catenin and SMAD4. The relationship among HIF2α, β-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2α resulted in reduced β-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and β-catenin. Cancer Res; 73(15); 4781–90. ©2013 AACR.

Supplementary Table 1 and Figure Legend from Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers

Supplementary Figure 1 from Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers

Supplementry Figure 4 - PDF file 812K, HIF2� promotes B-catenin and Smad4 expression

Supplementary Figure 2 - PDF file 2100K, Normal pancreas development in Ptf1Cre;Hif2�f/f mice

Supplementary Figure 5 - PDF file 5613 K, Loss of Smad4 in PKH2 mPanINs

Supplementary Materials and Methods- PDF file 100K, Additional experimental procedures including Generation of Hif2�-floxed mouse line, Tissue processing and Immunostaining, Western Blot, and Small Interfering RNA transfection

In the context of pancreatic cancer, metastasis remains the most critical determinant of resectability, and hence survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in pancreatic cancer invasion and metastasis because this is likely to have profound clinical implications. In pancreatic cancer cell lines, Hh inhibition with cyclopamine resulted in down-regulation of snail and up-regulation of E-cadherin, consistent with inhibition of epithelial-to-mesenchymal transition, and was mirrored by a striking reduction of in vitro invasive capacity (P < 0.0001). Conversely, Gli1 overexpression in immortalized human pancreatic ductal epithelial cells led to a markedly invasive phenotype (P < 0.0001) and near total down-regulation of E-cadherin. In an orthotopic xenograft model, cyclopamine profoundly inhibited metastatic spread; only one of seven cyclopamine-treated mice developed pulmonary micrometastases versus seven of seven mice with multiple macrometastases in control animals. Combination of gemcitabine and cyclopamine completely abrogated metastases while also significantly reducing the size of “primary” tumors. Gli1 levels were up-regulated in tissue samples of metastatic human pancreatic cancer samples compared with matched primary tumors. Aldehyde dehydrogenase (ALDH) overexpression is characteristic for both hematopoietic progenitors and leukemic stem cells; cyclopamine preferentially reduced “ALDH-high” cells by ∼3-fold (P = 0.048). We confirm pharmacologic Hh pathway inhibition as a valid therapeutic strategy for pancreatic cancer and show for the first time its particular efficacy against metastatic spread. By targeting specific cellular subpopulations likely involved in tumor initiation at metastatic sites, Hh inhibitors may provide a new paradigm for therapy of disseminated malignancies, particularly when used in combination with conventional antimetabolites that reduce “bulk” tumor size. [Cancer Res 2007;67(5):2187–96]

Supplementary Figure 1 - PDF file 2170K, Generation of the Hif2�-floxed strain, and validation of Hif2� inactivation in the pancreas

Supplementary Tables S1-S2 - PDF file 73K, List of primary antibodies, along with the sources and working dilutions (S1); primers used in RT-PCR analyses (S2)

Supplementary Figure and Table Legends�- PDF file 93K, Legend for Supplemental Tables S1-S2 and Supplemental Figures S1-S5

Recurrent laryngeal nerve (RLN) paresis is a rare but serious complication in thyroid surgery. Intermittent intraoperative nerve monitoring (IONM) was thought to prevent paresis of the RLN, but until today data are not conclusive. Our objective was to confirm the hypothesis that IONM can reduce paresis of RLN compared to nerve visualization alone. Therefore, we examined one of the largest cohorts ever evaluated of a tertiary referral center for endocrine surgery undergoing thyroid surgery for benign thyroid disease.Overall, 2097 patients who underwent thyroid surgery for benign thyroid disease in 2016 and 2017 were evaluated. RLN was identified by IONM or visualization only. Preoperative and postoperative laryngoscopic examination was used to evaluate RLN paresis. Patients' characteristics and perioperative data were extracted retrospectively.Overall, 1963 patients (2720 nerves at risk [NAR]) were included in this study: 378 surgeries with IONM (560 NAR) and 1585 without IONM (2160 NAR). Transient and permanent RLN pareses were found in 13 (3.4%; NAR=2.3%) and one (0.3%; NAR=0.2%) nerve treated with IONM vs. 37 (2.3%; NAR=1.7%) and five (0.3%; NAR=0.2%) nerves without IONM (P=0.507; NAR P=0.654), respectively.Using intermittent IONM, our retrospective study could not demonstrate a significant decrease of RLN pareses in patients undergoing thyroid surgery for benign thyroid disease. This is probably explained by the very low overall number of RLN pareses in our department. Nevertheless, because of patients' safety to avoid any bilateral RLN pareses, we recommend IONM in bilateral resections.

Primary hyperparathyroidism (pHPT) is well treatable surgically. Sonography (US) and sestamibi scintigraphy (MIBI) are used routinely, but it is unclear how valuable they are in determining Parathyroid glands' different locations. This study aimed to evaluate the prognostic value of US and MIBI in relation to the different localization of parathyroid adenomas in one of the largest study populations analyzed to date.1089 patients with pHPT who had treatment in one tertiary referral center between 2007 and 2016 were analyzed. Preoperative US and MIBI reports were compared with the parathyroid adenoma's intraoperative localization. All parathyroid glands were confirmed by histological diagnosis.No gland was detectable in 22.5% and 27.7% of all patients, by US or by MIBI, respectively. In relation to the different adenoma locations, the sensitivity of US ranged from 21.3% (upper right) to 68.9% (lower left) and of MIBI ranged from 23.5% (upper right) to 72% (lower left). The specificity for US ranged from 85% (lower right) to 99.2% (upper right) and for MIBI ranged from 86.1% (lower right) to 99.1% (upper right. Positive predictive values for all gland sites were 54% and 59% for MIBI and US, respectively. The value increased for side-only prediction to 73% and 78%, respectively. Neither the parathyroid hormone level nor the calcium value level influenced the sensitivity or specificity of the two test methods.The validity of preoperative US and MIBI depends crucially on the specific localization of adenomas. This should be considered when planning the extent of parathyroid surgery.

Potassium iodide (KI) treatment affects the vascularity of the thyroid gland and therefore may improve intraoperative visualization of essential structures. However, clear evidence for its usage is lacking, and its implementation in patients suffering from Graves' disease is becoming rare. The objective of this retrospective study was to assess the impact of KI treatment on the intraoperative course and the outcome of patients undergoing thyroidectomy for Graves' diseases. The study included 442 patients: 125 patients (28.3%) who received a preoperative treatment with KI (“Group KI”) and 317 patients (71.7%) without a KI therapy (“Group No-KI”). Indication for KI treatment was a thyroid bruit (82.5%), as well as hyperthyroidism refractive to medical treatment with antithyroid drugs (17.4%). All patients underwent total thyroidectomy. Permanent vocal cord paresis and permanent hypoparathyroidism were similar in both groups. KI treatment was associated with a significantly longer operative time (142 vs. 128 min, p

ZusammenfassungFür minimalinvasive Operationsverfahren, die heute den Goldstandard bei Nebennierentumoren darstellen, stehen in spezialisierten Zentren laparoskopische (transperitoneal) und retroperitoneoskopische Techniken zur Verfügung. Diese Übersichtsarbeit vermittelt einen Überblick über die Indikationen zur minimalinvasiven Adrenalektomie, die technische Durchführung, das perioperative Management sowie über typische Verfahrens-assoziierte Komplikationen.

Long-acting synthetic somatostatin analogues (SSA) are an essential part of the treatment of neuroendocrine neoplasms. We evaluated the chemopreventive effects of a long-acting somatostatin analogue on the development of pancreatic neuroendocrine neoplasms (pNENs) in a genetically engineered MEN1 knockout mouse model. Heterozygote MEN1 knockout mice were injected every 28 days subcutaneously with the somatostatin analogue lanreotide (Somatuline Autogel©; Ipsen Pharma) or a placebo starting at day 35 after birth. Mice were euthanized after 6, 9, 12, 15 and 18 months, and the size and number of pNENs were measured due histological analysis and compared to the placebo group. The median tumor size of pNENs was statistically significantly smaller after 9 (control group vs. SSA group; 706.476 µm2 vs. 195.271 µm2; p = 0.0012), 12 (placebo group vs. SSA group 822.022 vs. 255.482; p ≤ 0.001), 15 (placebo group vs. SSA group 1192.568 vs. 273.533; p ≤ 0.001) and after 18 months (placebo group vs. SSA group 1328.299 vs. 864.587; p ≤ 0.001) in the SSA group. Comparing the amount of tumors in both groups, a significant reduction was achieved in treated Men1(+/−) mice (41%, p = 0.002). Immunostaining showed, however, no significant difference in the expression of the apoptosis marker caspase-3, but a significant difference in Ki67 index as a marker for tumor cell proliferation (p ≤ 0.005). Long-acting somatostatin analogues may be an effective chemopreventive approach to delay the progression of MEN1-associated pNENs. After our preclinical results, we would recommend to evaluate the effects of long-acting SSA in a prospective clinical trial.

Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts (n = 43 and n = 141 tissues) of non-functional treatment-na&iuml, ve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months, p = 0.005). In treatment-na&iuml, ve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months, p = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.

Background Pancreatic ductal adenocarcinoma (PDAC) is among the most dismal of human malignancies. Neuropeptides have shown to be implicated in angiogenesis, tumor growth, and formation of distant metastases in various solid tumors. In the present study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the impact of neuropeptide Y (NPY) and its receptors 1 (Y1) and 2 (Y2) in preneoplastic lesions and pancreatic cancer as a potential target with antiproliferative properties. In addition, human PDAC tissue was analyzed. Materials and methods By interbreeding conditional LsL-Trp53R172H,LsL-KrasG12D and Pdx1-Cre strains, we obtained LsL-KrasG12D;LsL-Trp53R172H;Pdx1-Cre(KPC), LsL-KrasG12D;Pdx1-Cre(KP) and control mice (n = 8 each). Mice were then followed in a longitudinal study for 3 to 6 mo. Pancreata were analyzed in regard to pancreatic intraepithelial neoplasia (PanIN) lesions and invasive carcinoma. Corresponding sections were then assessed by immunohistochemistry and quantitative polymerase chain reaction for NPY, Y1 and Y2 expression in murine and human samples. Results NPY and Y1 expressions were detected in human and murine pancreatic samples, but expression levels were similar in neoplastic and non-neoplastic tissue. Y2 revealed a significant increase of expression in the transgenic mouse model in PanIN lesions and pancreatic cancer compared to control. This holds also true for human samples of pancreatic cancer. Immunohistochemistry of Y2 in murine and human samples of PanINs and pancreatic carcinoma revealed an increased expression in PanIN lesions and pancreatic cancer. Conclusions Y2 is strongly overexpressed in pancreatic cancer and may modulate angiogenesis.

Pancreatic neuroendocrine neoplasias (pNEN) are the most common cause of death in adult patients with multiple endocrine neoplasia type 1 (MEN1). So far, only few chemopreventive strategies (e.g., with somatostatin analogues) have been evaluated for MEN1 associated pNENs. In this experimental study on 75 Men1(+/T) knockout mice, the effect of aspirin (n = 25) and an inhibitor of angiotensin-I converting enzyme (enalapril, n = 25) compared to controls (n = 25) were evaluated as single chemopreventive strategies for pNENs after 6, 9, 12, 15, and 18 months. After each study period, mice were sacrificed and the resected pancreata were evaluated by histopathological analysis, immunostaining, and real-time PCR. PNEN size and number was measured. Aspirin and enalapril lead to a pNEN size reduction of 80% (167,518 vs. 838,876 µm2, p < 0.001) and 79% (174,758 vs. 838,876 µm2, p < 0.001) compared to controls. Furthermore, aspirin and enalapril treatment resulted in a significant reduction of the number of pNENs by 33%, (p = 0.04) and 41% (p = 0.002) respectively. The apoptosis marker caspase 3 revealed a higher positive expression in pNEN of treated Men1(+/T) mice. Immunostaining of VEGF in pNEN detected a downregulation of its expression in treated Men1(+/T) mice compared to the control group. REL A transcript was significantly downregulated in 18-months treated enalapril Men1(+/T) mice, but not in aspirin-treated Men1(+/T) mice. There was no significant difference in the Ki-67 index. Using a transgenic mouse model that imitates human MEN1, this study provides first evidence that aspirin and enalapril are effective chemopreventive agents that aid in the progression of pNENs.

Background: Pancreatic neuroendocrine neoplasias (pNENs) are uncommon but fascinating tumors with an annual incidence of 1 per 100,000 people. pNENs present either as functional tumors, causing specific hormonal syndromes like Zollinger-Ellison syndrome (ZES) or organic hyperinsulinism, or as non-functional pancreatic tumors (NF-pNENs). The natural history of pNENs is highly variable. 90% of all insulinomas or small NF- pNENs are readily curable by surgical resection. Most other functional and late detected NF-pNENs have a less favorable chance for cure. Methods: A systematic review of the literature was performed to identify the current state of the art with regard to the key issues of surgery in pNEN G1/G2. Results: This article provides a comprehensive review of the current literature addressing the current challenges in pNEN surgery. Conclusion: Patients with completely resected tumors generally have a good prognosis, and an aggressive surgical approach combined with conservative treatment options in patients with advanced disease rarely provides cure but often results in long-term survival.

Background Goal directed fluid management in major abdominal surgery has shown to reduce perioperative complications. The approach aims to optimize the intravascular fluid volume by use of minimally invasive devices which calculate flow-directed variables such as stroke volume (SV) and stroke volume variation (SVV). Objective We aimed to show the feasibility of routinely implementing this type of hemodynamic monitoring during pancreatic surgery, and to evaluate its effects in terms of perioperative fluid management and postoperative outcomes. Methods All patients undergoing pancreatic surgery at a university hospital during two successive 12 months periods were included in this retrospective cohort analysis. Twelve months after the implementation of a standard operating procedure for a goal directed therapy (GDT, N = 45) using a pulse contour automated hemodynamic device were compared with a similar period before its use (control, N = 31) regarding mortality, length of hospital and ICU stay, postoperative complications and the use of fluids and vasopressors. Results Overall, 76 patients were analysed. Significantly less crystalloids were used in the GDT group. Patients receiving GDT showed significantly fewer severe complications (insufficiency of intestinal anastomosis: 0 vs. 5 (P = 0.0053) and renal failure: 0 vs. 4 (P = 0.0133). Mortality for pancreatic surgery was 1 vs. 3 patients, (P = 0.142), and length of stay (LOS) in the intensive care unit (ICU) was 4.38 ± 3.63 vs. 6.87 ± 10.02 (P= 0.0964) days. Use of blood products was significantly less within the GDT group. Conclusions Implementation of a SOP for a GDT in the daily routine using flow-related parameters is feasible and is associated with better outcomes in pancreatic surgery.

Background The incidence of asymptomatic, sporadic, small non-functioning pancreatic neuroendocrine neoplasms (NF-PNENs) has increased in recent decades. Conservative treatment has been advocated for these tumours. The aim of this study was systematically to evaluate the literature on active surveillance and to compare this with surgical management for asymptomatic sporadic small NF-PNENs. Methods PubMed, Embase and the Cochrane Library were searched systematically for studies that compared the active surveillance of asymptomatic, sporadic, small NF-PNENs with surgical management. PRISMA guidelines for systematic reviews were followed. Results After screening 3915 records, five retrospective studies with a total of 540 patients were included. Of these, 327 patients (60·6 per cent) underwent active surveillance and 213 (39·4 per cent) had surgery. There was wide variation in the tumour diameter threshold considered as inclusion criterion (2 cm to any size). The median length of follow-up ranged from 28 to 45 months. Measurable tumour growth was observed in 0–51·0 per cent of patients. Overall, 46 patients (14·1 per cent) underwent pancreatic resection after initial conservative treatment. In most patients the reason was an increase in tumour size (19 of 46). There were no disease-related deaths in the active surveillance group in any of the studies. Conclusion This systematic review suggests that active surveillance of patients affected by sporadic, small, asymptomatic NF-PNENs may be a good alternative to surgical treatment.

Objective Surveillance programmes are recommended for individuals at risk (IAR) of familial pancreatic cancer (FPC) to detect early pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC). However, the age to begin screening and the optimal screening protocol remain to be determined. Methods IAR from non- CDKN2A FPC families underwent annual screening by MRI with endoscopic ultrasonography (EUS) in board-approved prospective screening programmes at three tertiary referral centres. The diagnostic yield according to age and different screening protocols was analysed. Results 253 IAR with a median age of 48 (25–81) years underwent screening with a median of 3 (1–11) screening visits during a median follow-up of 28 (1–152) months. 134 (53%) IAR revealed pancreatic lesions on imaging, mostly cystic (94%), on baseline or follow-up screening. Lesions were significantly more often identified in IAR above the age of 45 years (p

Gastroduodenale neuroendokrine Neoplasien (NEN) haben in den letzten 35 Jahren an Haufigkeit zugenommen. Zeitgleich hat sich auch die Prognose der Patienten wesentlich verbessert, da die Mehrzahl dieser Tumoren heute in einem fruhen Stadium festgestellt wird. NEN des Magens sind die haufigsten Neoplasien neuroendokrinen Ursprungs im Gastrointestinaltrakt. In der Diagnostik nehmen sie eine Sonderstellung ein, da neben dem Staging und Grading unterschiedliche pathophysiologische Grundlagen (Typen) fur die Einteilung herangezogen werden konnen. Diese unterscheiden sich in ihrem biologischen Verhalten und beeinflussen damit die Therapiekonzepte. Da uber 90 % der duodenalen NEN asymptomatisch sind und in der Regel auch in einem kurativen Stadium entdeckt werden, ist stets die Resektion des Tumors anzustreben. Die Moglichkeiten der Resektion reichen von lokalen endoskopischen Verfahren uber lokale chirurgische Verfahren (Duodenotomie mit Exzision) bis hin zur pankreaserhaltenden Duodenektomie oder pyloruserhaltenden bzw. klassischen Whipple-Operation. In diesem Beitrag werden die verschiedenen chirurgischen Therapieansatze vorgestellt.

Background: Vessel-preserving spleen preservation (SP) during distal pancreatectomy (DP) is supposed to be beneficial for patients with benign and borderline tumors. This study evaluated the first experiences with robotic-assisted laparoscopic DP (RA-LDP) and its rate of vessel preservation and SP compared to conventional laparoscopic DP (C-LDP). Methods: Patients scheduled for spleen-preserving DP for benign or borderline tumors by either C-LDP or RA-LDP were retrieved from a prospective database and retrospectively analyzed regarding vessel-preservation and SP, conversion rate, blood loss, operating time, complications, perioperative blood transfusion, postoperative hospital stay (PHS) and mortality. Results: Twenty-nine patients underwent C-LDP and 12 patients underwent RA-LDP between September 2009 and May 2015. SP rates were 79% (23 of 29) in the C-LDP and 92% (11 of 12) in the RA-LDP group (p = 0.32). Splenic vessels could be preserved in 17% (5 of 29) of the C-LDP and 50% (6 of 12) of the RA-LDP group (p = 0.052). Operating time, intraoperative blood loss, the number of perioperative red blood cell transfusions, overall morbidity and the rate of postoperative pancreatic fistulas were not different between the groups. PHS was shorter in the RA-LDP group (10.5 vs. 13 days; p = 0.02). Conclusion: RA-LDP for benign or borderline tumors of the pancreas is a safe procedure and tended to be associated with a better vessel-preservation rate, thereby making it a good alternative to C-LDP.

Minimal invasive surgical methods are gold standard at the resection of adrenal tumors. Special medical care units provide laparoscopical and retroperitoneoscopical techniques. This review gives an overview about indication of minimal invasive adrenalectomy, technical implementation, perioperative management and generic surgery-associated complications.

Familial pancreatic cancer accounts for 10% of all patients with pancreatic cancer. Because the 5-year survival rate of pancreatic cancer is only 7%, screening programs for high-risk individuals are essential and might be advantageous. Pancreatic ductal adenocarcinoma mostly shows symptoms at an advanced state and treatment is not efficient enough to cure most patients. People with hereditary tumor syndromes or their affected relatives can also be included in such screening programs. Besides the collection of data to investigate the background of the disease, these screening programs aim to diagnose and treat precursor lesions so that more dangerous, invasive lesions are prevented. These precursor lesions can be pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. This review summarizes the latest knowledge of pancreatic screening programs, shows the procedure of pancreatic cancer screening, and gives an overview of current guidelines.

Objective: The prevalence and clinical behavior of bronchopulmonary neuroendocrine tumors (bNET) associated with multiple endocrine neoplasia type 1 (MEN1) are not well defined. This study aimed to determine the prevalence, potential precursor lesions and prognosis of bNET in patients with MEN1. Methods: A database of 75 prospectively collected MEN1 cases was retrospectively analyzed for bNET. Patient characteristics, imaging and treatment were evaluated. Resection specimens of operated patients were reassessed by two specialized pathologists. Available CT scans of the whole cohort were reviewed to determine the prevalence of bronchopulmonary nodules. Results: Five of the 75 MEN1 patients (6.6%; 2 male, 3 female) developed histologically confirmed bNET after a median follow-up of 134 months. The median age at diagnosis of bNET was 47 years (range 31-67), and all patients were asymptomatic. Four patients underwent anatomic lung resections with lymphadenectomy; the remaining patient with multiple lesions had only a wedge resection of the largest bNET. Tumor sizes ranged from 7 to 32 mm in diameter, and all bNET were well differentiated. Two patients had lymph node metastases. Two of 4 reevaluated resection specimens revealed multifocal bNET, and 3 specimens showed tumorlets (up to 3) associated with multifocal areas of a neuroendocrine cell hyperplasia within the subsegmental bronchi. One bNET-related death (1.3%) occurred during long-term follow-up. Review of the available CT scans of the patients without proven bNET revealed small bronchopulmonary lesions (≥3 mm) in 16 of 53 cases (30.2%). Conclusions: bNET in MEN1 might be more common than previously recognized. Their natural course seems to be rather benign. Multifocal tumorlets and multifocal neuroendocrine cell hyperplasia might represent their precursor lesions.

Hauptvorteil der transaxillaren roboterassistierten Schilddrusenresektion (TRAT) ist die Vermeidung einer Narbe am Hals. In Deutschland wird die TRAT bisher nur sehr selten durchgefuhrt, sodass bisher keine Berichte uber Akzeptanz, Operationszeiten und Komplikationen aus Deutschland vorliegen. Im Rahmen einer Pilotstudie wurde allen Patienten mit einer Indikation zur Hemithyreoidektomie ohne praoperativen Malignomnachweis mit einer Lappengrose 18 Jahre nach ausfuhrlicher Aufklarung eine transaxillare roboterassistierte Hemithyroidektomie (TRAHT) angeboten. Die Akzeptanz dieser neuen Technik, Operationszeiten, Komplikationen sowie die Patientenzufriedenheit wurden prospektiv erfasst und ausgewertet. Zwischen Januar 2013 und Oktober 2014 wurde 65 Patienten eine TRAHT angeboten, von denen sich 21 (32 %) fur diese Operationstechnik entschieden. Keine der 21 Operationen musste konvertiert werden und intraoperativ traten keine Komplikationen auf. Die mediane Operationszeit betrug 190 min (106–300 min), wobei eine deutliche Lernkurve zu erkennen war (erste 5 TRAHT 219 min, letzte 5 TRAHT 163 min). Zehn (48 %) der TRAHT-Patienten hatten postoperativ leichte passagere Hautdysasthesien im Bereich des Zugangsweges, 4 (19 %) PatientInnen eine passagere Parese des Nervus laryngeus recurrens und 2 (9 %) PatientInnen eine passagere Parese des oberen Armplexus. Nach den ersten 21 TRAHT wurden dann auch 2 Dunhill-Operationen bei Morbus Basedow uber einen transaxillaren Zugang durchgefuhrt. Die Operationszeiten betrugen 260 und 320 min, Komplikationen traten nicht auf. 21 der 23 (91 %) der PatientInnen waren mit dem kosmetischen Ergebnis sehr zufrieden und wurden sich erneut fur eine TRAT entscheiden. Die TRAT hat bei PatientInnen in Deutschland noch keine grose Akzeptanz. Die Zufriedenheit der Patienten nach dem Eingriff ist aufgrund des kosmetischen Ergebnisses hoch. Kritisch betrachtet werden mussen die lange Operationszeit, neue Komplikationen (z. B. passagere Plexusparese) sowie eine potenziell erhohte passagere Rekurrenspareserate.

Background: Neuroendocrine tumors (NETs) of the ileum are sporadic tumors derived from submucosal gastrointestinal stem cells. They often show clinical symptoms only after hepatic metastasation when curative therapy is limited or impossible. In this study, we analyzed the expression of the candidate genes mammalian target of rapamycin (mTOR), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and death domainassociated protein (DAXX) to investigate the specific oncogenetics and potential therapeutic options for ileal NETs. Methods: In a prospective database, all patients who underwent surgical removal of a NET of the ileum between 2001 and 2011 were specified. Expression analysis was performed for mTOR, ATRX, and DAXX by immunohistochemistry of paraffin-embedded tumor samples. To evaluate the results the immunoreactive score was applied. Normal tissue and tumor tissue were analyzed for the comparison of gene expression levels using quantitative-realtime polymerase chain reaction for ATRX and mTOR genes. Results were correlated under pathologic and clinical aspects. Results: A total of 69 patients were admitted to the study. Positive cytosolic expression of the potential oncogene mTOR was immunohistochemically detected in 76.2% of the human probes. A loss of nuclear ATRX expression was detected in 13.0% of the samples. A nonexpression of the DAXX-protein in cell nuclei was not found (0%). Gene transcript levels did not show a significant alteration in ileal NETs in comparison with normal tissue. Conclusions: mTOR is overexpressed in ileal NETs. Additionally, the loss of ATRX expression was registered, thus underlying a tumorigenic role in a subgroup of these tumors. To enable potential therapeutic application of mTOR inhibitors, further trials with larger study groups are needed.