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Background: The clinical relevance of clearly defined pretherapeutic basal calcitonin (bCt) cut-offs for predicting lymph node metastases (LNMs) and long-term outcomes (LOs) has so far not been tested in a large cohort of patients with medullary thyroid cancer included in a Ct screening program during the initial diagnostic workup of thyroid nodules., Material and Methods: Female (f) patients with a bCt level of ≤23 pg/mL and male (m) patients with a level of ≤43 pg/mL were assigned to Group 1 (minimal oncologic risk), patients with a bCt between 24 and 84 pg/mL (f) and 44-99 pg/mL (m) to Group 2 (low oncologic risk), and those with a bCt of ≥85 pg/mL (f) and ≥100 pg/mL (m) to Group 3 (high oncologic risk). All patients underwent surgery applying a uniform surgical protocol. The median follow-up was 100 months., Results: The study included 306 patients. In 3/115 (2.6%) patients in Group 1 and in 3/50 (6.0%) in Group 2, LNM in the central but not lateral neck and no distant metastases (DMet) were documented. In both groups, the biochemical long-term cure rate was 95.7% and the disease-specific-survival (DSS) rate was 100% at 10, 15 and 20 years. Lateral LNM and DMet were diagnosed only in Group 3. The bCt levels of N0 and N1 patients showed broadly overlapping ranges, thus impeding the differentiation between those patients through bCt. Both the cure rate and DSS were significantly worse in Group 3. The overall biochemical long-term cure rate was 78.2%., Conclusions: Within a Ct screening program, grouping patients upon pretherapeutic bCt provides a simple risk classification system for indicating surgery, predicting LN involvement, and LOs.

Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed "primary hyperplasia". Whether these tumors represent a multi-glandular clonal disease or hyperplasia has not been robustly proven so far. Loss of Menin protein expression is associated with inactivation of both alleles and a good surrogate for a MEN1 gene mutation. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene is mutated in MEN4 and encodes for protein p27 whose expression is poorly studied in the syndromic MEN1 setting.Here, we analyzed histomorphology and protein expression of Menin and p27 in parathyroid adenomas of 25 patients of two independent, well-characterized MEN1 cohorts. The pattern of loss of heterozygosity (LOH) was assessed by fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Further, next-generation sequencing (NGS) was performed on eleven nodules of four MEN1 patients.Morphologically, the majority of MEN1 adenomas consisted of multiple distinct nodules, in which Menin expression was mostly lost and p27 protein expression reduced. FISH analysis revealed that most nodules exhibited MEN1 loss, with or without the loss of centromere 11. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors.Syndromic MEN1 parathyroid adenomas therefore consist of multiple clones with subclones, which supports the current concept of the novel WHO classification of parathyroid tumors (2022). p27 expression was lost in a large fraction of MEN1 parathyroids and must therefore be used with caution in suggesting MEN4., (© 2024. The Author(s).)

The clinical manifestation of multiple endocrine neoplasia type 2 (MEN2) in terms of developing medullary thyroid cancer (MTC), pheochromocytoma (PCC), and/or primary hyperparathyroidism (PHPT) is related to the respective pathogenic variant of the RET proto-oncogene. The aim of this study is to retrospectively analyze the individual, genotype-dependent clinical manifestations of a large cohort of MEN2 patients. By comparing their clinical profile with currently existing evidence-based knowledge, an optimal therapy and prevention strategy in terms of prophylactic thyroidectomy and clinical follow-up could be ensured. This is a retrospective single-center study of 158 MEN2 patients who were diagnosed and/or surgically treated at a tertiary referral care center between 1990 and 2022. All participants were categorized according to their pathogenic variant of the RET proto-oncogene. Subsequently, the clinical manifestation of the disease and its time of occurrence was documented. Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.

Competing Interests: Conflicts of Interest No conflicts of interest.

Introduction: Intraoperative parathyroid hormone (PTH) spikes occur in up to 30% of patients during surgery for primary hyperparathyroidism. This can lead to a prolonged PTH decline and cause difficulties in using current interpretation criteria of intraoperative PTH monitoring. The aim of this study aim was to evaluate an alternative interpretation model in patients with PTH spikes during exploration., Methods: 1035 consecutive patients underwent surgery for primary hyperparathyroidism in a single center. A subgroup of patients with intraoperative PTH spikes of >50 pg/mL were selected (n = 277; 27.0%). The prediction of cure applying the Miami and Vienna criteria was compared with a decay of ≥50% 10 min after excision of the enlarged parathyroid gland using the "visualization value" (VV; =PTH level immediately after visualization of the gland) as basal value. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated., Results: Using the VV, sensitivity was 99.2% (Vienna 71.0%; Miami 97.7%), specificity was 18.2 (Vienna 63.6%; Miami 36.4%), and accuracy was 92.8 (Vienna 70.4%; Miami 92.8%). Of 255 single-gland disease patients, 72 were identified correctly as cured by applying the VV (P < 0.001), yet 10 of 22 patients with multiple-gland disease were missed compared with the Vienna Criterion (P = 0.002). The comparison with the Miami Criterion showed that six more patients were correctly identified as cured (P = 0.219), whereas four patients with multiple-gland disease were missed (P = 0.125)., Conclusions: Using the VV as a baseline in patients with intraoperative PTH spikes may prove to be an alternative and therefore can be recommended. However, if the VV is higher than the preexcision value, it should not be applied., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: When applying intraoperative parathyroid hormone monitoring (IOPTH) to patients with primary hyperparathyroidism (PHPT), there are established criteria predicting biochemical cure in patients with basal parathyroid hormone (PTH) levels in the medium range (100-400 pg/ml); however, there is a challenge concerning patients with low (less than 100 pg/ml) or high (more than 400 pg/ml) basal PTH levels. The aim of this study was to investigate the value of the 'Vienna criterion' applied during IOPTH in patients with PHPT and various basal PTH concentrations., Methods: Consecutive patients between 1999-2009 with a biochemical diagnosis of PHPT who underwent surgical parathyroidectomy were included. Based on preoperative PTH levels they were divided into three groups: group 1 (low) (<100 pg/ml), group 2 (medium) (100-400 pg/ml) and group 3 (high) (>400 pg/ml) basal PTH. PTH was measured at the start of the operation, when the gland was excised and then at 5, 10 and 15 min after. Calcium and PTH levels were measured at 7 days and 12 months postoperatively. Sensitivity, specificity, positive and negative predictive value, as well as accuracy of IOPTH were calculated for the different groups postoperatively., Results: 675 patients with PHPT were analysed. Sensitivity and specificity were 83.7 per cent and 66.7 per cent in group 1 (n = 187), 90.7 per cent and 69.2 per cent in group 2 (n = 433), and 94.4 per cent and 100 per cent in group 3 (n = 55) to predict cure. Preoperative creatinine (p = 0.002) showed significant statistical difference between the groups but was not related to intraoperative PTH decline. At 12 months follow-up normocalcaemia was documented in 98.9 per cent in group 1, 99.0 per cent group 2, and 98.0 per cent of group 3 patients., Conclusion: Normocalcaemia was predicted intraoperatively by applying the 'Vienna criterion' in 98 to 100 per cent and was confirmed after 12 months follow-up in up to 99.0 per cent of patients. Low specificity and a high false-negative rate in patients with low basal PTH show that other criteria might be better suited for this group., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Purpose: Papillary thyroid carcinoma (PTC) spreads early to lymph nodes (LN). However, prophylactic central (CND) and lateral neck dissection (LND) is controversially discussed in patients with clinically negative nodes (cN0). The preoperative prediction of LN metastasis is desirable as re-operation is associated with higher morbidity and poor prognosis. The study aims to analyse possible benefits of a systemic bilateral diagnostic lateral lymphadenectomy (DLL) for intraoperative LN staging., Methods: Preoperative prediction of LN metastasis by conventional ultrasound (US) was correlated with the results of DLL and intra-/postoperative complications in 118 consecutive patients with PTC (cN0) undergoing initial thyroidectomy and bilateral CND and DLL., Results: Lateral LNs (pN1b) were positive in 43/118 (36.4%) patients, including skip lesions (n = 6; 14.0%). Preoperative US and intraoperative DLL suspected lateral LN metastasis in 19/236 (TP: 8.1%) and 54/236 (TP: 22.9%) sides at risk, which were confirmed by histology. Sixty-seven out of 236 (FN: 28.4%) and 32/236 (FN: 13.6%) sides at risk with negative preoperative US and intraoperative DLL lateral LN metastasis were documented. DLL was significantly superior compared to US regarding sensitivity (62.8% vs 22.1%; p < 0.002), positive predictive value (100% vs 76.0%), negative predictive value (82.4% vs 68.2%), and accuracy (86.4% vs 69.1%), but not specificity (100% vs 96.0%; p = 0.039). DLL-related complications (haematoma) occurred in 6/236 [2.5%] sides at risk, including chylous fistula in 2/118 [1.7%] patients., Conclusion: DLL can be recommended for LN staging during initial surgery in patients with PTC to detect occult lateral LN metastasis not suspected by US in order to plan lateral LN dissection., (© 2022. The Author(s).)

This expert consensus document represents an initiative by the European Neuroendocrine Tumor Society (ENETS) to provide guidance for synoptic reporting of radiological examinations critical to the diagnosis, grading, staging and treatment of neuroendocrine neoplasms (NENs). Template drafts for initial tumor staging and follow-up by computed tomography (CT) and magnetic resonance imaging (MRI) were established, based on existing institutional and organisational reporting templates relevant for NEN imaging, and applying the RadLex lexicon of radiological information (Radiological Society of North America), for consistency regarding the radiological terms. During the ENETS Scientific Advisory Board meeting 2018, the template drafts were subject to iterative interdisciplinary discussions among experts in imaging, surgery, gastroenterology, oncology and pathology. Members of the imaging group stated a strong preference for a combination of limited and standardised options by way of drop-down menus. Separate templates were produced for the initial work-up and for follow-up, respectively. To provide a detailed description of the radiological findings of the primary tumor and its local extension and spread, different templates were developed for bronchial, pancreatic and gastrointestinal NENs for CT and MRI, respectively. Each template was structured in 10 sections: clinical details, comparative imaging modality, acquisition technique, primary tumor findings, regional lymph node metastases, distant metastases, TNM classification, reference lesions according to RECIST 1.1, additional findings and conclusion. Two templates were developed for follow-up, for CT and MRI, respectively, and were specifically focused on assessment of therapy response. These included a qualitative response assessment, such as decrease of vascularisation and presence of necrosis, and a quantitative assessment according to RECIST 1.1 and the modified RECIST (mRECIST) for assessing tumor response following transarterial chemoembolisation., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Purpose of Review: Small intestinal neuroendocrine neoplasms (siNENs) are slowly growing tumours with a low malignant potential. However, more than half of the patients present with distant metastases (stage IV) and nearly all with locoregional lymph node (LN) metastases at the time of surgery. The value of locoregional treatment is discussed controversially., Recent Findings: In stage I to III disease, locoregional surgery was currently shown to be curative prolonging survival. In stage IV disease, surgery may prolong survival in selected patients with the chance to cure locoregional disease besides radical/debulking liver surgery. It may improve the quality of life and may prevent severe local complications resulting in a state of chronic malnutrition and severe intestinal ischaemia or bowel obstruction. Locoregional tumour resection offers the opportunity to be curative or to focus therapeutically on liver metastasis, facilitating various other therapeutic modalities. Risks and benefits of the surgical intervention need to be balanced individually.

Background: Neuroendocrine neoplasia of the small intestine (siNEN) are frequently diagnosed with liver metastases. The impact of the presence of liver metastases on overall survival and the necessity of surgery for liver metastasis is discussed controversially. The aim of this study is to evaluate and compare the overall long-term survival of patients with siNENs with and without liver metastasis at initial diagnosis and the possible benefit of surgical treatment as compared to active surveillance of metastases. 123 consecutive patients with siNENs were treated between 1965 and 2016. All clinical and histological records were reevaluated including analysis of the proliferation rates in all specimens. The 1-, 5-, 10- and 20-year overall survival was estimated by Kaplan-Meier analysis for patients with and without liver metastasis and according to the type of treatment (surgical vs. surveillance) of liver metastases if present., Results: The 1-, 5-, 10- and 20-year overall survival rate was 89.0%, 68.4%, 52.8% and 31.0% in patients without and 89.5%, 69.5%, 33.2% and 3.6% in those with liver metastases. No statistically significant differences were observed comparing the two groups. Within the group of patients with liver metastases, the type of treatment (surgical vs. surveillance) was in favor of patients undergoing surgery. Multivariate analysis showed that the presence of liver metastases upon diagnosis was an individual risk factor associated with worse survival., Conclusion: The presence of liver metastasis at initial diagnosis does not have a statistically significant influence on survival. Surgery for hepatic metastasis seems to show a benefit for overall survival and may be indicated especially in patients symptomatic due to high tumor burden and serotonin hypersecretion to reduce hormone activity.

The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies., (© 2020 S. Karger AG, Basel.)

Background: Measurements of both basal (b) calcitonin (CT) and calcium (Ca)-stimulated CT (Ca-sCT) levels are performed to identify medullary thyroid cancer (MTC) at an early stage when used as part of the diagnostic workup of thyroid nodules (CT screening). Novel immunochemiluminometric assays, which are highly sensitive and specific for monomeric CT and avoid cross-reactivity, have been introduced over the past decade. No prospectively generated data have so far become available to answer the frequently raised question as to whether Ca-sCT in contrast to bCT alone is helpful and, therefore, still indicated for the early detection of MTC. Methods: Ca-stimulation tests were performed in 149 consecutive patients with thyroid nodules and elevated bCT. Regardless of Ca-sCT levels, all patients had an operation applying a uniform surgical protocol, including thyroidectomy and systematic lymph node dissection. Recently published sex-specific cutoff levels for the differentiation of MTC and other C-cell pathologies (C-cell hyperplasia [CCH]) were used to compare the diagnostic performance of bCT or Ca-sCT alone and in combination using receiver-operating characteristic (ROC) analysis. In addition, CT cutoff levels to predict lateral lymph node metastasis were evaluated for bCT compared with Ca-sCT. Follow-up for all patients was documented and correlated with initial CT levels. Results: MTC was identified in 76 (50.1%) patients, in 21/76 (27.6%) with lymph node and in 4 (5.3%) with distant metastasis. Using predefined cutoff levels, patients could effectively be subdivided into a group above the cutoff level with definitive diagnosis of MTC (100%) and below (gray zone) with a significant overlap of CCH and MTC (all classified as pT1a; males: 19/58 [37.5%], females: 7/41 [17.1%]). The areas under the ROC curve (AUC) were excellent for the diagnosis of MTC in all tests. Determination of bCT proved to be superior for both diagnosing MTC in males (AUC for bCT: 0.894; AUC for Ca-sCT: 0.849) and females (bCT: 0.935; Ca-sCT: 0.868) and also for diagnosing lymph node metastasis in the lateral compartment (males: bCT: 0.925; Ca-sCT: 0.810; females: bCT: 0.797; Ca-sCT: 0.674). Combining both tests did not improve diagnostic accuracy. Using a cutoff level of >85 pg/mL for females and >100 pg/mL for males, the sensitivity for diagnosing lateral neck lymph node metastasis was 100%. Below these cutoff levels, no patient showed persistent or recurrent disease (median follow-up: 46 [ ± 27] months). Conclusions: Predefined sex-specific bCT cutoff levels are helpful for the early detection of MTC and for predicting lateral neck lymph node metastasis. Ca-sCT did not improve preoperative diagnostics. bCT levels >43 and >100 pg/mL for males and of >23 and >85 pg/mL for females are relevant for advising patients and planning the extent of surgery.

Background: Hemodynamic instability is frequently observed during adrenalectomy for pheochromocytoma (PCC). Guidelines recommend liberal preoperative volume administration. However, it is unclear whether fluid deficiency or vasoplegia causes shifting hemodynamics and whether minimally invasive hemodynamic monitoring with esophageal Doppler (EDM) can help visualize intraoperative changes avoiding volume overload and complications., Methods: Ten patients with biochemically verified PCC and five patients with hormonally inactive adrenal tumors (HIAT; control group) were treated following a strict protocol. During laparoscopic adrenalectomy, goal-directed fluid therapy was performed using EDM. Hemodynamic and biochemical data were documented. The primary outcome variables were fluid requirement and hemodynamic parameters., Results: Applying EDM, total intraoperative fluid administration was slightly higher in PCC patients than in patients with HIAT (2100 ± 516 vs. 1550 ± 622 ml, p = 0.097; 12.9 ± 4.8 vs. 8.3 ± 0.7 ml kg -1 h -1 , p = 0.014). Hemodynamics varied considerably within the PCC group and was associated with type and level of secreted catecholamines. Arterial blood pressure and systemic vascular resistance index reached their minimum in the 10-min period after resection of PCC. Without liberal fluid administration, an increase in cardiac index was observed in both groups comparing baseline measurements to end of surgery. This increase was statistically significant only in PCC patients (PCC: 2.31 vs. 3.15 l min -1 m -2 , p = 0.005; HIAT: 2.08 vs. 2.56 l min -1 m -2 , p = 0.225)., Conclusions: As vasoplegia, but not hypovolemia, was documented after tumor resection, there is no evidence that PCC patients profit from liberal fluid administration during laparoscopic adrenalectomy. To avoid volume overload, noninvasive techniques such as EDM should be routinely used to visualize the variable intraoperative course., Trial Registration: ClinicalTrials.gov, Identifier: NCT01425710.

Purpose: After successful surgery for primary hyperparathyroidism, bone mineral density (BMD) does not improve equally in all patients. As no trial has so far aimed to influence normalization of BMD, it was the goal of this investigation to determine whether pharmacological treatment is effective in improving regain of BMD after successful parathyroidectomy in patients with preoperatively diagnosed osteoporosis or osteopenia and to evaluate when treatment may be indicated., Methods: In this randomized, placebo-controlled, double-blind trial, 52 patients were treated with strontium ranelate 2 g daily + 1000 mg calcium + 800 IU vitamin D (strontium group; SG) or with 1000 mg calcium + 800 IU vitamin D alone (placebo group; PG) for 1 year. The main outcome measures were BMD (lumbar spine, femoral neck, radius) and bone turnover markers., Results: The baseline characteristics were similar in both groups. Absolute BMD (1.007 ± 0.197 vs. 0.897 ± 0.137 g/cm 2 ; p = 0.024) and both relative (9.94 vs. 3.94%; p < 0.001) and absolute (0.09 ± 0.06 vs. 0.03 ± 0.04 g/cm 2 ; p < 0.001) changes in lumbar-spine BMD were significantly higher in the SG than in the PG. Compared to baseline, BMD significantly increased in both groups at the lumbar spine (p < 0.001 and p = 0.001, respectively) and femoral neck (both p < 0.001), whereas radius BMD only changed significantly in the SG. However, the proportion of patients with osteoporosis/osteopenia significantly declined only at the lumbar spine in the SG (from 69.0 to 37.9%; p = 0.034), whereas no decrease was found in the PG. No severe adverse events occurred., Conclusions: Postoperative anti-osteoporotic treatment can positively influence regain of BMD mainly in the lumbar spine and should be considered. Without treatment, most patients and especially those with low preoperative markers of bone turnover remained osteoporotic/osteopenic 1 year after surgery.

The diagnosis of neuroendocrine neoplasia (NEN) is often made at an advanced stage of disease, including hepatic metastasis. At this point, the primary may still be unknown and sometimes cannot even be detected by functional imaging, especially in very small tumors of the pancreas (pan) and small intestinal (si) entities. The site of the primary may be based on biopsy specimens of the liver applying a specific set of markers. Specimens of liver metastases from 87 patients with NENs were studied. In retrospect, 50 patients had si and 37 pan NENs. Tissue samples were evaluated by immunohistochemistry. The markers applied were insulin gene enhancer protein Islet-1 (ISL-1), homeobox protein CDX-2 (CDX2), thyroid transcription factor 1 (TTF-1), and serotonin. Positive stains for CDX2 were documented in 43 (86%) and for serotonin in 45 (90%) of 50 siNENs. Three panNENs were positive for CDX2 and one for serotonin, respectively. ISL-1 was negative throughout in siNENs and also negative in 8 of 50 panNENs (21.6%). TTF-1 was negative in more than 90% of the specimens of either entity. Immunohistochemical markers in liver metastasis can lead the way to the site of the primary NEN. They should always be used in combined clusters.

Background: Patients with multiple endocrine neoplasia type 1 (MEN-1) develop multiple pancreatic neuroendocrine neoplasias (PNENs). Size at diagnosis and growth during follow-up are crucial parameters. According to the WHO 2017, grading is another important parameter. The impact of grading compared to size (WHO 2000) on the clinical course needs to be evaluated., Methods: Sixty PNENs of six patients with MEN-1 were retrospectively evaluated., Results: Fifty-one tumors with a diameter of < 20 mm were graded as G1. Two of 9 tumors with diameters of ≥20 mm were graded as G2. Tumor size of ≥20 mm correlated significantly with higher proliferation (p = 0.000617). Lymph node metastases were documented in two patients with a total of 19 tumors. In one patient, all 13 tumors (diameter: 0.4 to 100 mm) were classified as G1. However, metastases were documented in 9/29 lymph nodes. In the other patient, 5 tumors (3.5 to 20 mm) were classified as G1. The sixth tumor (30 mm) was classified as G2 (Ki-67: 8%). Metastases were revealed in 2/20 lymph nodes., Conclusions: Tumor size of ≥20 mm seems to correlate with more aggressive MEN-1 related pancreatic disease, regardless of individual proliferation. Tumors ≥20 mm and tumors graded as G2 should be treated surgically regardless of their size.

Background: At the time of diagnosis, one-third of medullary thyroid carcinoma (MTC) patients show lymph node (LN) or distant metastasis. A metastasized MTC requires different surgical strategies., Objective: This study aimed to determine the value of ultrasound and [18F]fluoro-dihydroxyphenylalanine positron emission tomography with computed tomography (F-DOPA-PET-CT) in localizing MTC, as well as LN and distant metastasis., Methods: The study included 50 patients (24 males/26 females) with preoperative ultrasound, F-DOPA-PET-CT, and histologically proven MTC. Imaging results were correlated with both preoperative basal calcitonin (bCt) levels and final histology., Results: Tumors were classified as pT1a:17 (diameter, mean ± standard deviation: 5.8 ± 3.0 mm), pT1b:15 (15.0 ± 3.2 mm), pT2:9 (27.3 ± 7.0 mm), and pT3:9 (38.3 ± 24.2 mm). The median bCt level was 202 pg/mL (lower/upper quartile: 82/1074 pg/mL). Ultrasound was positive for tumor in 45/50 (92%) patients (20.0 ± 16.0 mm) and negative in 5 patients (3.2 ± 2.2 mm). Overall, 43/50 (86%) patients had positive F-DOPA local scans (20.0 ± 16.4 mm), while 7 (14%) patients were negative (7.7 ± 8.1 mm). Lastly, 21/50 (42%) patients had LN metastasis; 8/21 (38%) patients had positive LNs suspected with ultrasound, and 12/21 (57%) patients had positive LNs suspected with F-DOPA. Tumor and LN sensitivity of ultrasound was 92% and 43%, respectively, and 86% and 57% of F-DOPA-PET-CT, respectively. In 3/50 (6%) patients and 3/50 (6%) patients, mediastinal LN metastasis and distant metastasis, respectively, were diagnosed only by F-DOPA-PET-CT., Conclusion: Ultrasound and F-DOPA-PET-CT are sensitive for the localization of MTC but not for the presence and location of LN metastasis (limitations: size/number). Only F-DOPA ensures the diagnosis of distant metastasis and influences the extent of LN surgery. Surgical strategy cannot be predicted based on neither ultrasound nor F-DOPA-PET-CT.

Introduction: Pentagastrin (Pg) stimulated calcitonin (sCT) was used to enhance accuracy in medullary thyroid cancer (MTC) diagnosis. As it is now unavailable, calcium (Ca) has been recommended as an alternative. The aim of this study was to define gender-specific cut-off values to predict MTC in patients with elevated basal CT (bCT) following Pg-sCT and Ca-sCT stimulation and to compare the time courses of CT release during stimulation., Materials and Methods: The stimulation tests were applied in 62 consecutive patients with thyroid nodules. Basal calcitonin was measured by chemiluminescent immunometric assay. All patients underwent thyroidectomy and bilateral central neck dissection. C-cell pathology was confirmed by histological and immunohistochemical evaluation., Results: In 39 (0.63) patients MTC was documented while isolated C-cell hyperplasia (CCH) was identified in 23 (0.37) patients. Medullary thyroid cancer was predicted in males with bCT values > 43 pg/mL or sCT concentrations > 470 pg/mL (Pg-sCT) or > 1500 pg/mL (Ca-sCT), and in females with bCT concentrations > 23 pg/mL or sCT concentrations > 200 pg/mL (Pg-sCT) or > 780 pg/mL (Ca-sCT), respectively. Pg-sCT correctly predicted MTC in 16 (0.66) compared to 13 (0.54) after Ca-sCT in males and in 12 (0.80) compared to 11 (0.73) in females; without statistical significance. In patients with CCH or low tumor burden, there was a tendency of faster CT release after Ca stimulation (CT peak after 3min in > 60%) compared to patients with advanced MTC (CT peak after 3min in < 10%)., Conclusions: Using gender-specific cut-off values, Ca could replace Pg to predict MTC with similar diagnostic power., Competing Interests: Potential conflict of interest: None declared.

The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Objective: Prolonged hypocalcemia but normal intact parathyroid hormone (iPTH) levels after surgery for primary hyperparathyroidism (PHPT) are referred to as 'hungry bone syndrome' (HBS). The aim was to evaluate preoperative risk factors for HBS with a focus on the impact of 25-hydroxyvitamin D (25(OH)D) deficiency., Design: Patients having undergone initial successful surgery for sporadic PHPT within 6 years were considered for retrospective analysis., Methods: A total of 385 patients were evaluated, of whom 33 (8.6%) developed HBS influencing negatively the postoperative bone metabolism. All patients underwent biochemical evaluations two days before parathyroid surgery and were followed biochemically on a daily basis in the first postoperative week and thereafter at 8 weeks and 6 months., Conclusions: No relationship was established between preoperative 25(OH)D deficiency and HBS. The only significant risk factor for HBS in multivariable analysis was high levels of preoperative iPTH. As HBS therefore cannot be predicted preoperatively, we recommend a consistent postoperative calcium and vitamin D supplementation to improve the bone metabolism., (© 2018 European Society of Endocrinology.)

Objective: Little is known about the natural changes in parathyroid function after successful parathyroid surgery for primary hyperparathyroidism. The association of intact parathyroid hormone (iPTH) and calcium (Ca) with "temporary hypoparathyroidism" and "hungry bone syndrome" (HBS) was evaluated., Design: Potential risk factors for temporary hypoparathyroidism and HBS were evaluated by taking blood samples before surgery, intra-operatively, at postoperative day (POD) 1, at POD 5 to 7, in postoperative week (POW) 8 and in postoperative month (POM) 6., Patients: Of 425 patients, 43 (10.1%) had temporary hypoparathyroidism and 36 (8.5%) had HBS., Measurements: The discriminative ability of iPTH and Ca on POD 1 for temporary hypoparathyroidism and HBS., Results: Intact parathyroid hormone (IPTH) on POD 1 showed the highest discriminative ability for temporary hypoparathyroidism (C-index = 0.952), but not for HBS. IPTH was helpful in diagnosing HBS between POD 5 and 7 (C-index = 0.708). Extending the model by including Ca resulted in little improvement of the discriminative ability for temporary hypoparathyroidism (C-index = 0.964) and a decreased discriminative ability for HBS (C-index = 0.705). Normal parathyroid metabolism was documented in 139 (32.7%) patients on POD 1 and in 423 (99.5%) 6 months postoperatively, while 2 (0.5%) patients had persistent hyperparathyroidism, one diagnosed between POD 5 and 7 and another at POW 8. No patients suffered from permanent hypoparathyroidism., Conclusions: The necessity for Ca and vitamin D3 substitution cannot be predicted with certainty before POD 5 to 7 without serial laboratory measurements. Based on the results, a routine 8-week course of Ca and vitamin D3 treatment seems reasonable and its necessity should be evaluated in a follow-up study., (© 2017 John Wiley & Sons Ltd.)

Although the majority of neuroendocrine tumors of the small intestine (siNETs) classified as low-grade G1 or G2 show slow local growth, they are frequently diagnosed at an advanced stage of metastatic disease. The surgical treatment is curative in stages I-III or palliative in stage IV in an attempt to avoid local complications of bowel obstruction and ischemia of the small bowel by unremoved lymph node metastases. Individualized surgical procedures performed by experienced surgeons considering tumor multifocality and the primary extent of lymph node metastases along the mesenteric vessels are recommended to remove as much tumor volume as possible, while avoiding major complications intraoperatively and small bowel syndrome postoperatively.

Objective: Normal or elevated 24-hour urinary calcium (Ca) excretion is a diagnostic marker in primary hyperparathyroidism (PHPT). It is used to distinguish familial hypocalciuric hypercalcaemia (FHH) from PHPT by calculating the Ca/creatinine clearance ratio (CCCR). The variance of CCCR in patients with PHPT is considerable. The aim of this study was to analyse the parameters affecting CCCR in patients with PHPT., Design: The data were collected prospectively. Patients with sporadic PHPT undergoing successful surgery were included in a retrospective analysis., Patients: The analysis covered 381 patients with pre-operative workup 2 days before removal of a solitary parathyroid adenoma., Measurements: The impact of serum Ca and 25-hydroxyvitamin D3 (25-OH D3) on CCCR., Results: The coefficient of determination (R 2 ) in the multivariable model for CCCR consisting of age, Ca, 25-OH D3, 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3), testosterone (separately for males and females), intact parathyroid hormone (iPTH) and osteocalcin was 25.8%. The only significant parameters in the multivariable analysis were 1,25-(OH)2 D3 and osteocalcin with a drop in R 2 of 15.4% (P<.001) and 2.4% (P=.006), respectively. Bone mineral densities at the lumbar spine, distal radius and left femoral neck were not associated with CCCR (r=-.08, r=-.10 and r=-0.09)., Conclusions: In multivariable analysis, 1,25-(OH)2 D3 and osteocalcin were the only factors correlating with CCCR. Vitamin D3 replacement may therefore impair the diagnostic value of CCCR and increase the importance of close monitoring of urinary Ca excretion during treatment., (© 2017 John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to demonstrate the high number of kidney stones in primary hyperparathyroidism (PHPT) and the low number of in fact "asymptomatic" patients., Methods: Forty patients with PHPT (28 female, 12 male; median age 58 (range 33-80) years; interquartile range 17 years [51-68]) without known symptoms of kidney stones prospectively underwent multidetector computed tomography (MDCT) and ultrasound (US) examinations of the urinary tract prior to parathyroid surgery. Images were evaluated for the presence and absence of stones, as well as for the number of stones and sizes in the long axis. The MDCT and US examinations were interpreted by two experienced radiologists who were blinded to all clinical and biochemical data. Statistical analysis was performed using the Wilcoxon signed-rank test., Results: US revealed a total of 4 kidney stones in 4 (10 %) of 40 patients (median size 6.5 mm, interquartile range 11.5 mm). MDCT showed a total of 41 stones (median size was 3 mm, interquartile range 2.25 mm) in 15 (38 %) of 40 patients. The number of kidney stones detected with MDCT was significantly higher compared to US (p = 0.00124)., Conclusions: MDCT is a highly sensitive method for the detection of "silent" kidney stones in patients with PHPT. By widely applying this method, the number of asymptomatic courses of PHPT may be substantially reduced. MDCT should be used primarily to detect kidney stones in PHPT and to exclude asymptomatic PHPT.

Background: In terms of morbidity, prophylactic central neck dissection (CND; level 6) in potentially malignant thyroid disease is discussed controversially. The rates of (transient and permanent) hypoparathyroidism and palsy of the recurrent laryngeal nerve (RLN) after "first-step" (FS-)CND are analyzed in this study., Methods: Bilateral and unilateral FSCND, i.e., lymph node dissection along the RLN before (total) thyroidectomy, was performed bilaterally in 68 (group 1) and unilaterally in 44 patients (group 2), respectively. The rates of hypoparathyroidism and palsy of the RLN were documented prospectively and were compared to 237 patients of group 3 (controls) who underwent (total) thyroidectomy only., Results: Fifteen of 68 patients (22 %) of group 1 developed transient and one patient had permanent hypoparathyroidism. Transient unilateral palsy of the RLN was observed in ten patients (15 %); none were permanent. Transient hypoparathyroidism was monitored in 10 of 44 patients (23 %) of group 2 and permanent hypoparathyroidism in 1 (2 %). Six patients (14 %) developed temporary palsy of the RLN; one remained permanent. Palsy was seen in 3 patients on the contralateral side of unilateral FSCND. Transient and permanent hypoparathyroidism was observed in 50 (21 %) and 2 (1 %) of 237 controls. Transient palsy of the RLN was documented in 22 (9 %) of 237 controls and permanent palsy of the RLN in 4 (2 %)., Conclusions: In this single-center series, the overall permanent morbidity was low (1 %). Therefore, FSCND may be recommended (even prophylactically) for experienced high-volume surgeons in patients with thyroid nodules suspicious for malignancy.

Medullary carcinoma (MTC) is an aggressive tumour that derives from the thyroid parafollicular calcitonin-secreting cells (C cells). Lymph node metastasis may occur early in disease pathogenesis and is one of the most important negative prognostic parameters. Surgery is the only curative therapy while chemotherapeutic options are limited. Neuroendocrine differentiated C cells may express somatostatin receptors (SSTR), which have a wide range of biological actions including inhibitory effects on cell survival and angiogenesis and antiproliferative effects on cancer cell lines. Moreover, they are a potential target for various somatostatin analogues. Aim of this study was to analyse the protein expression of SSTR2A and 5 in MTCs with or without the presence of lymph node metastases in correlation with various clinicopathological parameters. This retrospective immunohistochemical analysis included 97 patients with medullary thyroid carcinomas. Protein expression was detected by immunohistochemistry for somatostatin receptors 2A and 5. Various clinicopathological parameters, such as Ki-67 proliferation index or presence of desmoplasia, were included for statistical analysis. SSTR2A protein expression significantly correlated with the presence of lymph node metastases (p = 0.009), locally advanced MTCs staged according to the TNM (p < 0.001) and degree of desmoplasia (p = 0.029). Although SSTR5 protein expression significantly correlated with advanced stages of MTCs (p = 0.023) and degree of desmoplasia (p = 0.020), no correlation was found with the presence of lymph node metastases. Our results provide additional information concerning the aggressiveness of MTCs and reveal that a high SSTR2A and SSTR5 expression might be a poor prognostic feature., (© 2016 APMIS. Published by John Wiley & Sons Ltd.)

Objective: The effects of thiazide medication in patients with primary hyperparathyroidism (PHPT) have so far not been elucidated. The aim of this study was to analyse the extent to which the administration of thiazides may influence biochemical parameters and therefore the diagnosis of PHPT in a large cohort of patients., Design and Patients: The biochemical parameters of 1066 patients with PHPT were analysed, and drug history was documented. Calcium (Ca)/creatinine clearance ratio (CCCR) was calculated. The results of patients given thiazides (n = 170) and those not given thiazides (n = 896) were analysed and compared., Measurements: Twenty-four-hour urinary calcium excretion (24hU), albumin-corrected serum calcium, PTH, creatinine, 1,25OH- and 25OH-vitamin D were measured, and CCCR was calculated., Results: 24hUC a and CCCR were significantly lower in patients on thiazides (P = 0·02 and P = 0·0068, resp.), and serum creatinine was significantly higher in those subjects (P < 0·0001). Serum Ca levels only proved different in an analysis of covariance among patients younger than 60 years (P = 0·003). Nevertheless, PTH was not different in both groups (P = 0·917)., Conclusions: According to recently published guidelines, 24hUCa measurement is necessary to give indication for surgery in asymptomatic patients and to distinguish between PHPT and familial hypocalciuric hypercalcaemia [FHH]. Thiazides significantly decrease 24hUC a , yet neither increase serum Ca nor influence PTH levels in patients with PHPT. However, discontinuing thiazides is crucial for a correct CCCR calculation to pre-operatively rule out FHH. As a consequence, the withdrawal of thiazide medication must be recommended for the diagnosis of PHPT prior to surgery., (© 2016 John Wiley & Sons Ltd.)

A large majority of the currently diagnosed patients with hyperparathyroidism (PHPT) are mild or asymptomatic, mainly women after menopause. Following the debate held at the 16th European Congress of Endocrinology in Wroclaw (Poland) from May 3-7, 2014, arguments are here presented by a surgeon and a medical practitioner considering these situations rather have to profit from surgery, or simply from survey. For the trained endocrine surgeon, it is evident that parathyroidectomy confirms the diagnosis and undoubtedly reduces the discomfort felt by certain patients, prevents all risks of complications, removes patients and medical teams from the monitoring and represents a real individual financial benefit. On the other hand, the medical practitioner considers that mild or asymptomatic PHPT is commonly stable, and very rare are the subjects at risk of complications, particularly of fractures; prevention of vascular and metabolic disorders, nephrolithiasis and bone rarefaction justify regular physical exercise, a safe alimentation, a sufficient calcium and high water intake, the correction of the frequent deficit in vitamin D; finally has also to be considered the impossibility to refer to specialized (endocrine) surgeons, the enormous cohort of subjects more than 50 years with 'mild' or 'asymptomatic' PHPT. The surgeon and the medical practitioner agree to consider that in patients with 'mild' or 'asymptomatic' disease, there is no place for medical treatments, in particular calcimimetics and bisphophonates. Both agree that further studies are needed to clarify the long-term prognosis of operated and non-operated PHPT in term of fractures, cardiovascular risk and mortality. Individual and collective cost/benefit ratios of surgery or survey are also still imperfectly evaluated., (© 2015 European Society of Endocrinology.)

Background: Recurrent laryngeal nerve (RLN) palsy and hypoparathyroidism are serious complications in thyroid and parathyroid surgery. The extent to which incidentally detected thyroid nodules should be treated concomitantly is a matter of debate., Methods: This analysis was based on 1,065 patients who underwent consecutive surgery for primary hyperparathyroidism at a single institution. Together with the surgical strategy, histologic and follow-up examinations were documented prospectively and analyzed retrospectively regarding the occurrence and course of RLN palsy, hypoparathyroidism, and thyroid carcinoma., Results: Altogether, RLN palsy occurred for 38 patients (3.6 %) and proved to be permanent for 1 patient (0.1 %). Postoperative calcium substitution was necessary for 191 patients (17.9 %), with 3 patients showing permanent hypoparathyroidism (0.3 %). Procedures other than open minimally invasive exploration were accompanied by a significantly increased risk for temporary RLN paresis (odds ratio [OR], 6.136) and temporary hypoparathyroidism (OR 3.306). Concomitant thyroid surgery was performed for 502 patients (47.1 %). Compared with open minimally invasive parathyroid exploration, patients undergoing unilateral exploration and hemithyroidectomy (OR 5.827) or bilateral neck exploration (BNE) and thyroidectomy (OR 8.047) had a significantly increased risk for RLN paresis. Patients administered BNE with hemithyroidectomy (OR 2.380) or thyroidectomy (OR 7.233) had a significantly increased risk for hypoparathyroidism. Thyroid malignancy was incidentally detected in 86 patients (8.1 %)., Conclusion: Patients undergoing concomitant thyroid procedures have a significantly higher risk for temporary RLN palsy and hypoparathyroidism. However, the high rate of incidentally detected thyroid carcinoma in an iodine-replete endemic goiter area indicates hemithyroidectomy in the presence of thyroid nodules incidentally identified in preoperative ultrasounds.

Background: Insulinomas are rare neuroendocrine tumours (NETs) of the pancreas, characterized clinically by neuroglycopenic symptoms during periods of substrate deficiency. The gold standard test for diagnosing an insulinoma is a 72-h fast. However, the prognostic value of parameters in the standardized 72-h fast on histopathological tumour criteria and clinical presentation has not been examined., Methods: In thirty-three patients diagnosed with an insulinoma records, and data were investigated retrospectively. Histopathological tumour characteristics, including staging, grading and size, were reviewed. Grading was performed using Ki-67 index. Cut-off values for classical grading (G(clas)) were set at G1(clas) ≤ 2%, G2(clas) 3-20% & G3(clas) >20% and for modified grading (G(mod)) at G1(mod) <5%, G2(mod) 5-20% & G3(mod) >20%., Results: When G(mod) criteria were applied, the initial blood glucose was lower in GII/III(mod) patients compared to GI(mod) (2.8 ± 0.8 vs 3.8 ± 1.3 mmol/l; P = 0.046). Basal and end of fast levels of insulin (basal insulin 71 ± 61 vs 20 ± 16 mU/l; P < 0.001; end of fast insulin 77 ± 51 vs 21 ± 20 mU/l; P < 0.001) and c-peptide (basal c-peptide 5.4 ± 2.4 vs 2.7 ± 1.6 μg/l; P = 0.004; end of fast c-peptide 5.3 ± 2.4 vs 2.5 ± 1.4 μg/l; P = 0.001) were significantly higher in GII/III(mod) than in GI(mod). No differences between the groups were observed when G(clas) criteria were applied. Additionally, close correlations were observed between insulin concentration, Ki-67 index and tumour size., Conclusion: This study shows an impact of histopathological tumour characteristics in patients suffering from an insulinoma on clinical presentation during a standardized 72-h fast. Lower initial blood glucose levels and higher concentrations of insulin and c-peptide are associated with worse tumour grading and larger tumour size., (© 2015 John Wiley & Sons Ltd.)

Background: To describe a standardized, efficient, and cost-effective protocol for the diagnosis of temporary/persisting postoperative hypoparathyroidism after (total) thyroidectomy., Methods: We included 237 consecutive patients who underwent (total) thyroidectomy without central neck dissection for various indications. Serum calcium (sCa) and intact parathyroid hormone (iPTH) levels were measured prospectively on the morning of postoperative day 1 to predict the long-term parathyroid metabolism. On the morning of postoperative day 2, measurements were repeated. Follow-up was performed at 1 and 6 months postoperatively., Results: On the morning of postoperative day 1, patients with iPTH ≥ 15 pg/mL (178/237; 75%) and sCa > 2.0 mmol/L were normocalcemic, and "normal" parathyroid metabolism was predicted. iPTH levels of <10 pg/mL and sCa levels of ≤2.0 mmol/L were present in 33 of the 237 patients ("disturbed" parathyroid metabolism; 14%). A "gray zone" included patients with "uncertain" parathyroid metabolism demonstrating iPTH levels between 10 and 15 pg/mL (26/237; 11%). Patients with "disturbed" and "uncertain" parathyroid metabolism were given oral calcium and vitamin D. On the morning of the second postoperative day, iPTH turned to "normal" in 10 of those 26 (38%) patients, and no further calcium or vitamin D was given. During follow-up, supplemental calcium and vitamin D was able to be stopped in all but 2 patients ("permanent" hypoparathyroidism; 2/237; 0.8%)., Conclusion: Measurement of iPTH on the morning after operation allows accurate prediction of postoperative parathyroid function in ≥99% of cases. This simple recommendation is practicable in all surgical units, and is an efficient and cost-effective way to recognize patients who require calcium and vitamin D supplementation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Context: (99m)Tc-Methoxy-isobutyl-isonitrile (MIBI) scintigraphy is a standard preoperative localization imaging modality in patients with primary hyperparathyroidism (pHPT). Its accuracy in localizing a hyperactive parathyroid gland after previous cervical surgery is limited. Recently, (11)C-methionine has been introduced as a promising radiotracer for pHPT imaging. Yet, few data exist for this technique in patients with persisting or recurrent pHPT before reoperation., Objectives: We aimed to investigate the ability of (11)C-methionine positron emission tomography (PET)/computed tomography (CT) to localize a parathyroid disorder after cervical surgery and negative postsurgical (99m)Tc-MIBI single-photon emission CT (SPECT)/CT., Design, Setting, and Participants: Fifteen patients (6 males, 9 females; age range, 36-85 years) with pHPT and negative (99m)Tc-MIBI SPECT/CT who had undergone earlier neck surgery because of pHPT and/or thyroid disorder were recruited. Twelve of the 15 patients had thyroidectomy for goiter or differentiated thyroid carcinoma. Ten patients had previous parathyroid surgery for pHPT, and 2 patients had a history of parathyroid carcinoma. Thirteen of 15 patients showed elevated levels of intact PTH at the time of PET/CT imaging, whereas all patients had elevated serum calcium values., Main Outcome Measurements: Pathological results of contrast-enhanced (11)C-methionine PET/CT and surgical results were evaluated., Results: In 6 of 15 patients (11)C-methionine PET/CT showed a hypermetabolic focus in the upper mediastinum in 2 patients, in the thoracic outlet in 1 patient, and in the cervical region in 3 patients. In 9 of the 15 patients, no hyperactive parathyroid gland could be visualized. Reoperation was performed in 5 of 6 patients without surgical complications. One patient refused surgery. In 2 of the 5 patients, a transsternal procedure was performed. Correlating with the (11)C-methionine PET/CT results, a single parathyroid adenoma was found in 4 patients and parathyroid carcinoma metastasis in 1 patient., Conclusion: (11)C-Methionine PET/CT is a useful complementary imaging technique to localize parathyroid adenoma or carcinoma in (99m)Tc-MIBI SPECT/CT-negative patients.

Objective: The surgical management of primary hyperparathyroidism (PHPT) has undergone considerable advances over the past two decades. The purpose of this report is to review these advances., Participants: This subgroup was constituted by the Steering Committee of the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism to address key questions related to the surgical management of PHPT., Evidence: Data since the last International Workshop were presented and discussed in detail. The topics included improvements in preoperative imaging, intraoperative adjuncts, refinements in local and regional anesthesia, and rapid intraoperative PTH assays., Consensus Process: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup agreed on what recommendations should be made to the Expert Panel regarding surgical approaches to parathyroidectomy., Conclusions: 1) All patients with PHPT who meet surgical criteria should be referred to an experienced endocrine surgeon to discuss the risks, benefits, and potential complications of surgery. 2) Patients who do not meet surgical criteria and in whom there are no medical contraindications to surgery may request a visit with an experienced endocrine surgeon. Alternatively, a multidisciplinary endocrine conference with surgeon involvement could be employed to address all relevant issues. 3) Imaging is not a diagnostic procedure; it is a localization procedure to help the surgeon optimize the operative plan. 4) The frequency of hereditary forms of PHPT may be underappreciated and needs to be assessed with increased vigilance. And 5) surgery is likely to benefit patients due to high cure rates, low complication rates, and the likelihood of reversing skeletal manifestations.

The aim of this study was to compare the side effects of the pentagastrin test and the calcium stimulation test in patients with increased basal calcitonin concentration, especially the gender-specific differences of side effects. A total of 256 patients (123 females and 133 males, mean age of 56 ± 27 years, range 21-83 years) had both pentagastrin and calcium stimulation tests. All patients filled in a questionnaire regarding the side effects within 30 min after completion of the stimulation tests. The differences of side effects between female and male patients as well as between the pentagastrin stimulation test and the calcium stimulation test were evaluated. Warmth feeling was the most frequent occurring side effect in all patients who had both pentagastrin and calcium stimulation tests, followed by nausea, altered gustatory sensation, and dizziness. The incidences of urgency to micturate (p < 0.05) and dizziness (p < 0.05) were significantly increased in the female patients as compared to male patients by calcium stimulation test. Significant higher incidences of urgency to micturate (p < 0.05) and warmth feeling (p < 0.05) were found by calcium stimulation test as compared with those by pentagastrin test in female patients. The incidences of nausea (p < 0.05) and abdominal cramping (p < 0.05) in male patients were significantly higher by pentagastrin stimulation test than by calcium stimulation test. There is a significant gender-specific difference in side effects induced by calcium stimulation test. Female patients have fewer side effects by pentagastrin test than by calcium stimulation test. Male patients may tolerate the calcium stimulation test better than the pentagastrin test.

Purpose: This "consensus statement" aims to summarise the current evidence-based knowledge as to "timing" and planning the "extent" of thyroid surgery in terms of an optimal balance between the prevention of thyroid malignancy (involving metastasis) and the risks associated with more extended surgery (permanent hypoparathyroidism, permanent paralysis of the recurrent laryngeal nerve). Surgery "in time" is influenced by genetic findings and age. Basal (and stimulated) calcitonin levels may individualise the timing and extent of surgery., Materials and Methods: The review of English-language studies addressing the management of REarranged during Transfection proto-oncogene mutation carriers including the time, extent of thyroid surgery and results. Evidence is mostly obtained from well-designed, non-experimental descriptive investigations, such as comparative, correlation and case-control studies (level III) with a grading of recommendation B, or from expert committee reports or opinions and/or the clinical experience of respected authorities (level IV) with a grading of recommendation C, respectively., Results: "Risk level D" includes multiple endocrine neoplasia 2B cases. Thyroidectomy is recommended within the first year of life, preferably as soon as possible, due to the very early transformation of C cell hyperplasia to more aggressive tumours. Calcitonin levels may be less helpful. In patients with codon 634 mutations (risk level C), thyroidectomy between ages 2 and 4 years has been proposed based upon evidence of age-dependent and codon-specific progression of early medullary thyroid cancer. In "risk level B" (codons 609, 611, 618, 620, 630 and 804), tandem mutation (804-778) patients should undergo thyroidectomy before the age of 6 years. "Risk level A" includes patients with mutations in codons 321, 515, 533, 600, 603, 606, 635, 649, 666, 768, 776, 790, 791, 804 (single mutation), 833, 844, 861, 891 or 912. Surgery may be postponed until the age of 10 years. However, postponing surgery and avoiding central (level VI) neck dissection in patients with risk levels A to C are only justified in families with a less aggressive MTC history and in combination with the results of basal (and calcium- or pentagastrin-stimulated) serum calcitonin levels. The moment of transition from C cell hyperplasia to MTC seems to occur when calcitonin levels rise. In patients with normal basal and stimulated calcitonin levels, the chance of micro-MTC increases significantly., Conclusions: Hereditary C cell disease acts as a model to apply the results of bedside genetic testing, age and calcitonin levels (genotype-age-calcitonin-concept) for the individual timing of thyroid surgery and its extent.

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer, and it early metastasizes into regional lymph nodes. We evaluated immunohistochemically the expression of the hypoxia marker hypoxia-inducible factor 1α (HIF-1α) as well as extracellular matrix protein tenascin C as a marker of stroma remodelling in a cohort of 160 PTCs. Expression of HIF-1α was seen focally accentuated in 100 of the 160 tumours (62.5 %) including 16 cases with equivocal staining (faint staining or only single-cell staining) and 84 cases with unequivocal staining. HIF-1α expression correlated with the degree of desmoplastic stromal reaction as well as with the expression of tenascin C (p < 0.001, Kruskal-Wallis test, respectively). Moreover, expression of HIF-1α was significantly associated with the presence of lymph node metastases (p < 0.001, Mann-Whitney test) as well as signs of invasion, namely, peritumoural and extrathyroidal invasion as well as angioinvasion (p = 0.024, p < 0.001, p = 0.017, Mann-Whitney test, respectively). Additionally, PTC with unequivocal HIF-1α nuclear staining was a larger tumour than PTC with negative (-) or equivocal HIF-1α expression (p < 0.001, Kruskal-Wallis test). Interestingly, the expression of HIF-1α was not significantly associated with BRAF V600E status (p > 0.05, Mann-Whitney test). Our data show that the expression of HIF-1α is associated with stroma remodelling processes within the tumour and, thus, may play an important role in an invasive behaviour of these tumours independent of BRAF mutation status.

Purpose: Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I., Patients and Methods: We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety., Results: The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients., Conclusion: Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

Purpose: Increased intraoperative parathyroid hormone excretion ("PTH spikes") due to unintended manipulation of parathyroid adenoma can be observed frequently during surgery for primary hyperparathyroidism. This may lead to difficulties in interpreting intraoperative PTH curves. The aim of this study was to elucidate possible risk factors for PTH spikes and to evaluate the impact on different interpretation criteria of intraoperative PTH curves., Methods: Eight hundred forty-seven patients with primary hyperparathyroidism were included. The probability of PTH spikes was analyzed regarding preoperative PTH- and creatinine levels, and size of adenoma and their impact on the Vienna, Miami, and Halle criteria was evaluated., Results: PTH spikes occurred in 102 patients (12 %) and revealed to be independent of PTH- and creatinine levels (p = 0.13) preoperatively. There was a significant negative correlation between "manipulation PTH" and "baseline PTH" values and the gland volume, respectively. Patients presenting with smaller adenomas and those with low-baseline PTH values show significantly higher manipulation values. No risk factor for manipulation was exposed and no significantly higher risk of misclassification as "false positive" in case of PTH spikes was detected for any interpretation criterion. For the "Vienna Criterion," however, a significant increase in the risk of "false negative" misclassification was observed with increasing manipulation values., Conclusions: In patients with PTH spikes, none of the analyzed criteria show a significant increase in missed adenomas. Nevertheless, the Vienna criterion shows a higher rate of potentially unnecessary explorations with increasing manipulation values. Thus, caution is warranted in detecting PTH spikes and in individual interpretations of specific PTH curves is recommended. The Miami criterion seems to be favorable in this group of patients.

Introduction: Over the past years, the incidence of thyroid cancer has surged not only in Germany but also in other countries of the Western hemisphere. This surge was first and foremost due to an increase of prognostically favorable ("low risk") papillary thyroid microcarcinomas, for which limited surgical procedures are often sufficient without loss of oncological benefit. These developments called for an update of the previous practice guideline to detail the surgical treatment options that are available for the various disease entities and tumor stages., Methods: The present German Association of Endocrine Surgeons practice guideline was developed on the basis of clinical evidence considering current national and international treatment recommendations through a formal expert consensus process in collaboration with the German Societies of General and Visceral Surgery, Endocrinology, Nuclear Medicine, Pathology, Radiooncology, Oncological Hematology, and a German thyroid cancer patient support organization., Results: The practice guideline for the surgical management of malignant thyroid tumors includes recommendations regarding preoperative workup; classification of locoregional nodes and terminology of surgical procedures; frequency, clinical, and histopathological features of occult and clinically apparent papillary, follicular, poorly differentiated, undifferentiated, and sporadic and hereditary medullary thyroid cancers, thyroid lymphoma and thyroid metastases from primaries outside the thyroid gland; extent of thyroidectomy; extent of lymph node dissection; aerodigestive tract resection; postoperative follow-up and surgery for recurrence and distant metastases., Conclusion: These evidence-based recommendations for surgical therapy reflect various "treatment corridors" that are best discussed within multidisciplinary teams and the patient considering tumor type, stage, progression, and inherent surgical risk.

Purpose: The indications and results of preoperative localization, surgical strategy, indication for thymectomy, the application of intraoperative parathyroid hormone (PTH) monitoring, cryopreservation, and replantation of cryopreserved parathyroid tissue are not well documented in renal hyperparathyroidism (RHPT). The current trends in surgery for RHPT are to be evaluated in an international online survey., Methods: Thirty-three questions regarding preoperative localization, surgical management of RHPT, intraoperative PTH monitoring, immediate/delayed autotransplantation (AT), and parathyroid cryopreservation were sent to members of various societies of endocrine surgeons., Results: The data from 86 responses were analyzed, 61.6 % reported more than 50 parathyroid surgeries per year, and 62.7 % operated on less than 16 patients with RHPT per year. Subtotal or total parathyroidectomy (with/without AT) was the standard procedure in 98.8 % of the cases. Immediate AT was performed in 40.7 % (72.7 % in the forearm). In most patients, the onset of graft function was documented later than 1 week after AT. Cryopreservation was routinely performed in 27.4 %. In 10.7 %, replantation was performed in more than five patients (hypo- or aparathyroidism: n = 41; fresh graft failure: n = 13; reoperations: n = 9). Intraoperative PTH monitoring (in RHPT) was routinely used in 46.2 %. Its influence on surgical strategy was confirmed in 40 %., Conclusions: The survey reflects the divergent strategies applied for AT, cryopreservation, and PTH monitoring in RHPT.

Hereditary and sporadic medullary thyroid carcinoma (MTC) are closely associated with RET proto-oncogene mutations. However, the role of additional changes in the tumor genomes remains unclear. Our objective was the identification of chromosomal regions involved in MTC tumorigenesis and to assess their significance by using MTC-derived cell lines. We used array-CGH (comparative genomic hybridization) to map chromosomal imbalances in 52 primary tumors and ten metastases. Eleven tumors (11/52, 21%) were hereditary and 41 (41/52, 79%) were sporadic. Among the latter, 15 tumors (15/41, 37%) harbored RET mutations. Furthermore, we characterized five MTC cell lines in detail and evaluated the tumorigenicity by severe combined immunodeficiency (SCID)-mouse experiments. Most MTCs had only few copy number changes, and losses of chromosomes 1p, 4q, 19p and 22q were observed most frequently. The number of chromosomal aberrations increased in metastases. Twenty-three percent (12/52) of the primary tumors did not even show any chromosomal gains and losses. We injected three cell lines (two of these were without chromosomal changes and pathogenic RET mutations) into immune deficient SCID mice, and in each case, we observed rapid tumor growth at the injection sites. Our data suggest that MTCs--in contrast to most other tumor entities--do not acquire a multitude of genomic imbalances. SCID mouse experiments performed with chromosomally normal cell lines and without RET mutations suggest that presently unknown submicroscopic genomic changes are sufficient in MTC tumorigenesis., (Copyright © 2011 UICC.)

Background: The purpose of this study was to evaluate the frequency of malignancy, oncologic outcome and perioperative morbidity between small (≤60 mm) and large (>60 mm) adrenal tumors treated by endoscopic adrenalectomy (EA)., Methods: EA was performed in 289 consecutive patients with a mean follow-up of 87.7 ± 45.1 months. Patients were divided in those with tumor size ≤60 mm (group 1; n = 252) and >60 mm (group 2; n = 37). Data on patient's age, gender, hormone function, tumor side, operation time, postoperative complications, conversion to open approach, and rate of malignancy were analyzed. Furthermore, disease-free survival in malignant tumors was estimated and compared between both groups., Results: Patient age (P = .43), gender (P = .09), tumor side (P = .17), and operative time (P = .33) showed no difference in both groups. Functioning tumors were observed in 85% of patients in group 1 compared with 46% in group 2 (P = .0001). Seven (2.8%) patients in group 1 and 7 (18.9%) in group 2 had malignant tumors (P = .0001). Neither rate of conversion (P = .71) and postoperative complication (P = .27) nor recurrence of malignancy (P = .48) differed between both groups. Estimated disease-free survival after 5 years in malignant lesions was 87.5 ± 11.7% for group 1 and 62.5 ± 21.3% for group 2 (P = .49)., Conclusion: EA is a safe and feasible procedure in the majority of large adrenal tumors. Tumor size does not affect the outcome of surgery. In case of malignancy, it does not increase the rate of local recurrence. In experienced hands, tumor size should not influence the decision of surgical access (endoscopic versus open)., (Copyright © 2012 Mosby, Inc. All rights reserved.)

The V600E mutation of the B-type Raf kinase (BRAF) gene is a common event in papillary thyroid carcinoma (PTC) and seems to play a key role in the development and progression of this disease. We evaluated the expression of the mutated BRAF V600E protein in 144 cases of PTC using a novel mutation-specific antibody. Seventy-six PTCs (52.8%) showed unequivocal diffuse cytoplasmic expression of the mutated BRAF protein, and the T1799A point mutation was confirmed by sequencing analysis in selected cases. No statistical difference in V600E BRAF protein expression was seen between microcarcinomas and macrocarcinomas. Further, no significant correlation of V600E expression with clinicopathologic parameters of aggressiveness such as lymph node metastasis, peritumoral infiltration, or perithyroidal infiltration was found. BRAF V600E protein expression was significantly more common in tumors with tall cell or oncocytic features but was less common in tumors with follicular growth pattern. Diffuse sclerosing, solid and follicular variants did not show the mutated BRAF protein. Immunohistochemical detection of the mutated V600E BRAF protein in PTC may facilitate mutational analysis in the clinical setting. Our data show that the expression of the mutated BRAF V600 protein and thus the corresponding BRAF mutation seems not to be per se a marker of aggressiveness but is already seen in clinically indolent microcarcinomas. Nevertheless, the investigation of BRAF V600E protein expression might be of clinical interest especially in therapy-resistant disease, as new therapeutics inhibiting the mutated protein are clinically available.

Background: Most patients with adrenocortical cancer (ACC) continue to present with advanced disease. Invasion into the inferior vena cava (IVC) defines stage III disease and the management of such patients raises additional difficulties., Method: A multicentre survey was organized by emailing a standardized proforma to members of the European Society of Endocrine Surgery (ESES). Anonymised retrospective clinical data were collected., Results: Replies were received from 18 centres in nine countries. ACC with IVC invasion was encountered in 38 patients (18F:20M, age 15-84 years, median 54 years). There were 16 nonfunctioning tumours and 22 functioning tumours predominantly right-sided (26R:12L) and measuring 18-255 mm (median 115 mm). Fourteen patients had metastatic disease at presentation. Tumour thrombus extended in the prehepatic IVC (n = 21), subdiaphragmatic IVC (n = 6) or into the SVC/right atrium (n = 3). Open adrenalectomy was associated with resection of surrounding viscera in 24 patients (nephrectomy n = 16, liver resection n = 14, splenectomy n = 3, Whipple procedure n = 2). IVC was controlled locally (n = 27), at suprahepatic levels (n = 6) or necessitated cardiac bypass (n = 5). Complete resection (R0, n = 20) was achieved in the majority of patients, with a minority having microscopic persistent disease (R1, n = 7) or macroscopic residual disease (R2, n = 4). Perioperative 30-day mortality was 13% (n = 5). Postoperative Mitotane was used in 23 patients and chemotherapy in eight patients. Twenty-five patients died 2-61 months after their operation (median 5 months). Currently, 13 patients are alive at 2-58 months (median 16 months) with known metastatic disease (n = 7) or with no signs of distant disease (n = 6)., Conclusion: This dataset is limited by the lack of a denominator as it remains unknown how many other patients with ACC presenting with IVC invasion did not undergo surgery. The relatively low perioperative mortality and the long disease-free survival achieved by some patients should encourage surgeons with adequate experience to offer surgical treatment to patients presenting with advanced adrenocortical cancers.