Lessons learned from Jordan's response to the Syria refugee crisis.

The number of refugees across the world has jumped from 15.7 million to 34.6 million in the past 10 years, and their forced displacement situation remain for an average period of 20 years. To ensure sustainable benefits, health system strengthening through development cooperation should be a priority in parallel to humanitarian aid early on in refugee crises.

Changes in diagnosis and operative treatment of insulinoma over two decades.

PURPOSE: Most insulinomas are small solitary, benign neoplasms. Imaging and surgical techniques improved over the last 20 years. Thus, the aim of the present study was to analyze changes in diagnosis and surgery of insulinoma patients in a referral center over two decades. METHODS: Operated patients with a histologically proven insulinoma were retrieved from a prospective database. Clinico-pathological characteristics and outcomes were retrospectively analyzed with regard to the time periods 2000-2010 (group 1) and 2011-2020 (group 2). RESULTS: Sixty-one of 202 operated patients with pNEN had an insulinoma, 37 (61%) in group 1 and 24 (39%) in group 2. Of those 61 insulinomas, 49 (80%) were sporadic benign, 8 (13%) benign MEN1-associated insulinomas, and 4 (7%) sporadic malignant insulinomas. In 35 of 37 (95%) patients of group 1 and all patients of group 2, the insulinoma was preoperatively identified by imaging. The most sensitive imaging modality was endoscopic ultrasound (EUS) with correctly diagnosed and localized insulinomas in 89% of patients in group 1 and 100% in group 2. In group 1, significantly less patients were operated via minimally invasive approach compared to group 2 (19% (7/37) vs. 50% (12/24), p = 0.022). Enucleation was the most frequently performed operation (31 of 61, 51%), followed by distal resection (15 of 61, 25%) without significant differences between groups 1 and 2. The rate of relevant postoperative complications was not different between groups 1 and 2 (24% vs. 21%, p = 0.99). Two patients with benign insulinoma (1 out of each group) experienced disease recurrence and underwent a second resection. After a median follow-up of 134 (1-249) months, however, all 57 (100%) patients with benign insulinoma and 3 out of 4 patients with malignant insulinoma had no evidence of disease. CONCLUSION: Insulinoma can be preoperatively localized in almost all patients, allowing for a minimally invasive, parenchyma-sparing resection in selected patients. The long-term cure rate is excellent.

Mutation-based, short-term "neoadjuvant" treatment allows resectability in stage IVB and C anaplastic thyroid cancer.

INTRODUCTION: Few available data indicate that a mutation-based "neoadjuvant" therapy in advanced anaplastic thyroid carcinoma (ATC) might convert an initially unresectable primary tumor to resectable and optimize local tumor control. We evaluated a preoperative short-term "neoadjuvant" therapy with a BRAF-directed therapy or, in case of BRAF non-mutated tumors, an mKI/checkpoint inhibitor combination in three patients with ATC stage IVB and C. METHODS: In the context of preoperative diagnostics, immunohistochemistry (IHC) assessment and genetic analysis was started as soon as possible. The antiangiogenetic therapy with lenvatinib was immediately after diagnosis of ATC started as bridging therapy. In case of a BRAF-mutated ATC, a combination therapy of dabrafenib and trametinib, in case of BRAF-wildtype ATC a combination of pembrolizumab and lenvatinib was given for 4 weeks. If re-staging has shown a significant therapy response due to a decrease in size of > 50%, surgical resection was reconsidered. A primary tumor resection was performed first. As a second step, limited distant metastasis have been resected approximately 4 weeks after thyroid surgery. After postoperative recovery, the targeted systemic therapy was continued. PATIENTS: Two patients presented with BRAF-wildtype ATC stage IVC, one with BRAF-mutated ATC stage IVB. All patients were evaluated by surgery, nuclear medicine and oncology upon diagnosis of ATC. RESULTS: In all three cases, the "neoadjuvant" therapy induced a dramatic response and led to local resectability in primarily non-resectable ATC stage IVB or C. We have chosen for the first time a short-term "neoadjuvant" treatment period to reduce the risk of bleeding and/or fistula due to potential rapid tumor shrinkage. The results of surgery after only short-term "neoadjuvant" therapy showed two R0 und one R1 resections. Postoperative histopathological findings confirmed an extent of tumor necrosis or regressive fibrotic tissue between 60 and > 95% in our patients. CONCLUSIONS: A short-term mutation-based "neoadjuvant" therapy can achieve local resectability in initially unresectable ATC stage IVB or C. A neoadjuvant treatment period of about 4 weeks seems to show similar response as a treatment duration of at least 3 months.

Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

[Controversy: asymptomatic small pancreatic neuroendocrine neoplasms : Current standards in diagnostics and treatment]. / Kontroverse: asymptomatische kleine pankreatische neuroendokrine Neoplasien : Aktuelle Standards in Diagnostik und Therapie.

BACKGROUND: For the increasingly diagnosed entity of small asymptomatic, sporadic, nonfunctional, pancreatic neuroendocrine neoplasms (pNEN), a negligible or at least unclear prognostic relevance of the disease for patient survival has often been observed. OBJECTIVE: Safety and acceptance of a watch-and-wait strategy versus surgical resection for small, asymptomatic nonfunctional (NF) pNEN. METHODS: Presentation and evaluation of the relevant literature as well as the corresponding national and European guidelines. RESULTS: Surgery of small NF-pNEN shows complication rates of 15-32% (Clavien-Dindo ≥ 3) and a mortality of 3.6%. Even for pNEN < 2 cm the presence of lymph node metastases has been observed in 11% of cases, while their prognostic relevance in G1-pNEN compared with active surveillance remains unclear. On average 14% of patients under active surveillance for small NF-pNEN, underwent a resection. Relevant tumor growth during surveillance was found in < 20% of cases. In all well-selected surveillance cohorts no metachronous lymphatic or distant metastases occurred during active surveillance and especially no cases of a metachronous no longer curable disease. CONCLUSION: Even small asymptomatic NF-pNEN have a certain metastatic potential but the clinical relevance has prospectively not yet been clearly determined. Controlled surveillance of these tumors is at least an alternative to immediate tumor resection. Especially patients above 70 years old do not seem to benefit from resection. The pros and cons of a resection should therefore be individually evaluated with the patient.

[Are there still indications for open adrenalectomy?] / Gibt es noch Indikationen für die offene Adrenalektomie?

Despite the triumph of minimally invasive techniques in adrenal surgery, the indications for open adrenalectomy are indispensable in the canon of treatment options and must remain part of the repertoire of visceral surgery. Open adrenalectomy is indicated for advanced adrenal carcinoma (ENSAT stage III). In addition to the frequent local infiltration of these carcinomas which makes the en bloc resection of adjacent organs necessary, thromboses in the renal vein or the vena cava or multiple lymph node metastases can also necessitate an open procedure; however, open adrenalectomy is justified and must also be discussed for adrenocortical carcinoma ENSAT stages I-II (tumor size ≤ 5 cm or > 5 cm, NO). Furthermore, highly suspicious large adrenal tumors (6-8 cm, Hounsfield units > 20) without preoperative evidence of malignancy and other adrenal pathologies, such as neuroblastomas, large pheochromocytomas and also schwannomas can be an indication for open adrenalectomy.

Radical Resection in Entero-Pancreatic Neuroendocrine Tumors: Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence.

BACKGROUND: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. OBJECTIVE: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. PATIENTS AND METHODS: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. RESULTS: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01). CONCLUSIONS: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

Local lung coagulation post resection: an ex-vivo porcine model.

Following non-anatomical resection of lung parenchyma with a Nd:YAG laser, a coagulated surface remains. As ventilation starts, air leakage may occur in this area. The aim of the present study was to investigate, whether additional coagulation either before or after ventilation has an additional sealing effect. Freshly slaughtered porcine heart-lung blocks were prepared. The trachea was connected to a ventilator. Using a Nd:YAG laser (wavelength: 1320 nm, power: 60 W), round lesions (1.5 cm in diameter) with a depth of 1.5 cm were applied to the lung using an 800-µm laser fiber (5 s per lesion). Group 1 (n = 12) was control. Additional coagulation was performed in group 2 (n = 12) without and in group 3 (n = 12) with ventilation restarted. Air leakage (ml) from the lesions was measured. The thickness of each coagulation layer was determined on histological slices. Differences between individual groups were analyzed by one-way ANOVA (significance p < 0.05). After resection, 26.2 ± 2.7 ml of air emerged from the lesions per single respiration in group 1. Air loss in group 2 was 24.6 ± 2.5 ml (p = 0.07) and in group 3 23.7 ± 1.8 ml (p = 0.0098). In comparison to groups 1 and 2 thickness of the coagulation layers in group 3 was significantly increased. After non-anatomical porcine lung resection with a Nd:YAG laser, additional coagulation of the ventilated resection area can reduce air leakage.

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

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

Serotonin deficiency induced after brain maturation rescues consequences of early life adversity.

Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKO × MS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.

[Nodular goiter]. / Struma nodosa.

The indications for surgery of benign goiter should be balanced and professional as the prevalence of benign nodular goiter in Germany is high and not all goiters must be surgically treated. Thyroid nodules are detected in up to 76% of healthy people using modern high-resolution ultrasound (US) and only a few of these nodules are malignant or symptomatic. Even today a thorough medical history, detailed examination of the neck region, a qualified US of the thyroid gland, a 99m-technetium scintigraphy and fine needle aspiration help to select patients who will benefit from thyroid surgery. In the last 10 years several thyroid imaging reporting and data systems (TI-RADS) classifications have been introduced. The TI-RADS classification is a standardized assessment of thyroid nodules and risk stratification system in thyroid US which helps to select those nodules with a high risk of cancer. Asymptomatic euthyroid nodular goiter without any suspicion of malignancy and scintigraphically cold thyroid nodules without any other evidence of malignancy are not indications for thyroid surgery. The decision to operate should be made on an interdisciplinary basis in conformity with the relevant guidelines and exhaustion of diagnostic tools.

A retrospective comparison of robotic versus laparoscopic distal resection and enucleation for potentially benign pancreatic neoplasms.

PURPOSE: The present study aimed to compare robotic-assisted versus laparoscopic distal pancreatic resection and enucleation for potentially benign pancreatic neoplasms. METHODS: Patients were retrieved from a prospectively maintained database. Demographic data, tumor types, and the perioperative outcomes were retrospectively analyzed. RESULTS: In a 10-year period, 75 patients (female, n = 44; male, n = 31; median age, 53 years [range, 9-84 years]) were identified. The majority of patients had pancreatic neuroendocrine neoplasms (n = 39, 52%) and cystic neoplasms (n = 23, 31%) with a median tumor size of 17 (3-60) mm. Nineteen (25.3%) patients underwent enucleation (robotic, n = 11; laparoscopic, n = 8) and 56 (74.7%) patients underwent distal pancreatic resection (robotic, n = 24; laparoscopic, n = 32), of those 48 (85%) underwent spleen-preserving procedures. Eight (10.7%) procedures had to be converted to open surgery. The rate of vessel preservation in distal pancreatectomy was significantly higher in robotic-assisted procedures (62.5% vs. 12.5%, p = 0.01). Twenty-six (34.6%) patients experienced postoperative complications (Clavien-Dindo grade > 3). Twenty (26.7%) patients developed a pancreatic fistula type B. There was no mortality. After a median follow-up period of 58 months (range 2-120 months), one patient (1.3%) developed local recurrence (glucagonoma) after enucleation, which was treated with a Whipple procedure. CONCLUSION: The robotic approach is comparably safe, but increases the rate of splenic vessel preservation and reduces the risk of conversion to open surgery.

Anaplastic thyroid carcinoma: changing trends of treatment strategies and associated overall survival.

PURPOSE: The prognosis of anaplastic thyroid cancer (ATC) is poor. Despite various attempts to modify common treatment modalities, including surgery, external beam radiation (EBRT) and chemotherapy (CTX), no standardized treatment is yet established. This study aimed to analyze the changing trends of treatment concepts and associated overall survival (OS) over the last two decades. METHODS: A retrospective analysis was conducted on 42 patients with histologically confirmed ATC. The outcome measures included the evaluation of clinical characteristics and treatments performed with regard to OS. RESULTS: Median OS for all tumor stages was 6 (range 1 week-79) months, 6.5 months for stage IVA/B and 4 months for stage IVC carcinoma patients. Twenty-one patients with stage IVA/B carcinomas underwent curative treatment, including thyroidectomy with lymphadenectomy (TTX plus LAD, n = 11) or multimodal treatment with TTX plus LAD and EBRT plus/minus CTX (n = 10). The median OS of patients with stage IVA/B carcinomas was significantly prolonged after multimodal treatment than after surgery alone (25 vs. 3 months, p = 0.04). Fifteen of 18 patients with stage IVC carcinomas received palliative, 3 patients multimodal treatment. The median OS of stage IVC patients after trimodal therapy was not significantly longer than after debulking procedures (6 vs. 7 months, p = 0.25). In the time period 1999-2009, only 4 (21%) patients received multimodal treatment compared to 9 (39%) in the period from 2009 to 2019, but this did not result in a significantly prolonged survival in the latter period (8.5 vs. 15 months, p = 0.61). CONCLUSION: Concurrent radio- and/or chemotherapy in combination with surgery seems to result in improved survival in stage IVA/B ATC, whereas this is not the case in patients with stage IVC tumors. Novel treatment regimens are urgently needed to improve the dismal prognosis of ATC.

[Surgical treatment of parathyroid carcinoma : Does the initial en bloc resection improve the prognosis?] / Chirurgie des Nebenschilddrüsenkarzinoms : Verbessert die initiale En-bloc-Resektion die Prognose?

BACKGROUND: Radical en bloc resection of the tumor with ipsilateral hemithyroidectomy and central lymphadenectomy (PTX+HTX) is currently the generally recommended treatment strategy for parathyroid carcinoma (PC) in Germany; however, it remains unclear whether the en bloc resection leads to a prognostic benefit compared to parathyroidectomy (PTX) alone, especially considering disease-free and overall survival. OBJECTIVE: This study analyzed the survival of patients with PC after PTX+HTX compared to patients with PTX. METHODS: Patients with PC were identified from a prospective database and retrospectively analyzed regarding clinicopathological features, surgical treatment, disease-free interval and overall survival. RESULTS: Out of 1705 patients who were operated on because of primary hyperparathyroidism (pHPT), 18 (1.1%) had histologically confirmed PC. In nine patients PTX+HTX was initially performed and the other nine patients received only PTX. After PTX, all of the nine patients developed a recurrence after a median of 18 months (range 7-84 months), while only one patient had a recurrence after PTX+HTX. After PTX a median three (range 2-18) reoperations were indicated for relapse but after PTX+HTX only one patient had to undergo two relapse surgeries (p < 0.001). The recurrence-free survival after PTX+HTX was significantly longer than after PTX (143 vs. 18 months, p = 0.01), while the overall survival of both groups after a median follow-up of 107.5 months did not significantly differ. DISCUSSION: If there is any clinical suspicion of PC, an en bloc resection should be performed to prolong recurrence-free survival and avoid reoperations.

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

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

[Update of the S2k guidelines : Surgical treatment of benign thyroid diseases]. / Aktualisierung der S2k-Leitlinie : Operative Therapie benigner Schilddrüsenerkrankungen.

Thyroid resections represent one of the most common operations with 76,140 interventions in the year 2016 in Germany (source Destatis). These are predominantly benign thyroid gland diseases. Recommendations for the operative treatment of benign thyroid diseases were last published by the CAEK in 2010 as S2k guidelines (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. [AWMF] 003/002) against the background of increasingly more radical resection procedures. Hemithyroidectomy and thyroidectomy are routinely performed for benign thyroid disease in practice. The operation-specific risks show a clear increase with the extent of the resection. Therefore, weighing-up of the risk-indications ratio between unilateral lobectomy or thyroidectomy necessitates an independent evaluation of the indications for both sides. This principle in particular has been used to update the guidelines. In addition, the previously published recommendations of the CAEK for correct execution and consequences of intraoperative neuromonitoring were included into the guidelines, which in particular serve the aim to avoid bilateral recurrent laryngeal nerve paralysis. Moreover, the recommendations for the treatment of postoperative complications, such as hypoparathyroidism and postoperative infections were revised. The updated guidelines therefore represent the current state of the science as well as the resulting surgical practice.

Targeted overexpression of CRH receptor subtype 1 in central amygdala neurons: effect on alcohol-seeking behavior.

RATIONALE: The corticotropin-releasing hormone (CRH) system is a key mediator of stress-induced responses in alcohol-seeking behavior. Recent research has identified the central nucleus of the amygdala (CeA), a brain region involved in the regulation of fear and stress-induced responses that is especially rich in CRH-positive neurons, as a key player in mediating excessive alcohol seeking. However, detailed characterization of the specific influences that local neuronal populations exert in mediating alcohol responses is hampered by current limitations in pharmacological and immunohistochemical tools for targeting CRH receptor subtype 1 (CRHR1). OBJECTIVE: In this study, we investigated the effect of cell- and region-specific overexpression of CRHR1 in the CeA using a novel transgenic tool. METHODS: Co-expression of CRHR1 in calcium-calmodulin-dependent kinase II (αCaMKII) neurons of the amygdala was demonstrated by double immunohistochemistry using a Crhr1-GFP reporter mouse line. A Cre-inducible Crhr1-expressing adeno-associated virus (AAV) was site-specifically injected into the CeA of αCaMKII-CreERT2 transgenic rats to analyze the role of CRHR1 in αCaMKII neurons on alcohol self-administration and reinstatement behavior. RESULTS: Forty-eight percent of CRHR1-containing cells showed co-expression of αCaMKII in the CeA. AAV-mediated gene transfer in αCaMKII neurons induced a 24-fold increase of Crhr1 mRNA in the CeA which had no effect on locomotor activity, alcohol self-administration, or cue-induced reinstatement. However, rats overexpressing Crhr1 in the CeA increased responding in the stress-induced reinstatement task with yohimbine serving as a pharmacological stressor. CONCLUSION: We demonstrate that CRHR1 overexpression in CeA-αCaMKII neurons is sufficient to mediate increased vulnerability to stress-triggered relapse into alcohol seeking.

Preoperative Imaging Overestimates the Tumor Size in Pancreatic Neuroendocrine Neoplasms Associated with Multiple Endocrine Neoplasia Type 1.

BACKGROUND: Radiological tumor size of non-functioning pancreatic neuroendocrine neoplasms (Nf-pNENs) associated with multiple endocrine neoplasia type 1 (MEN1) is a crucial parameter to indicate surgery. The aim of this study was to compare radiological size (RS) and pathologic size (PS) of MEN1 associated with pNENs. METHODS: Prospectively collected data of MEN1 patients who underwent pancreatic resections for pNENs were retrospectively analyzed. RS was defined as the largest tumor diameter measured on endoscopic ultrasound (EUS), magnetic resonance imaging (MRI) or computed tomography (CT). PS was defined as the largest tumor diameter on pathological analysis. Student's t test and linear regression analysis were used to compare the median RS and PS. p < 0.05 was considered significant. RESULTS: Forty-four patients with a median age of 37 (range 10-68) years underwent primary pancreatic resections for pNENs. Overall, the median RS (20 mm, range 3-100 mm) was significantly larger than the PS (13 mm, range 4-110 mm) (p = 0.001). In patients with pNENs < 20 mm (n = 27), the size difference (median RS 15 mm vs PS 12 mm) was also significant (p = 0.003). However, the only modality that significantly overestimated the PS was EUS (median RS 14 mm vs 11 mm; p = 0.0002). RS overestimated the PS in 21 patients (21 of 27 patients, 78%). Five of 11 patients (12%) with a Nf-pNEN and a RS > 20 mm had in reality a PS < 20 mm. MRI was the imaging technique that best correlated with PS in the total cohort (r = 0.8; p < 0.0001), whereas EUS was the best correlating imaging tool in pNENs < 20 mm (r = 0.5; p = 0.0001). CONCLUSION: Preoperative imaging, especially EUS, frequently overestimates the size of MEN1-pNENs, especially those with a PS < 20 mm. This should be considered when indicating surgery in MEN1 patients with small Nf-pNENs.