[Current developments in the treatment of neuroendocrine tumors]. / Aktuelle Entwicklungen in der Behandlung neuroendokriner Tumoren.

BACKGROUND: Well-differentiated neuroendocrine tumors (NET) are rare malignancies that are clinically very heterogeneous. Accordingly, their treatment is also complex and dependent on various factors. With currently available systemic therapies, the prognosis is often favorable. OBJECTIVES: This article aims to provide an overview of current treatment strategies for NET, addressing the most important NET locations. METHODS: The current European guidelines and further relevant literature on the treatment of NET were reviewed for this purpose. RESULTS: The therapeutic spectrum for NET is extremely broad: For NET of the stomach/duodenum, appendix, and rectum, endoscopic or surgical resection is often sufficient, and metastatic tumors are rare. NET of the pancreas, small intestine and lung should also undergo potentially curative resection in the early stages. In the metastatic stage, locoregional treatments such as surgery and liver tumor embolization play a role. Major advances have been made in drug therapy, with somatostatin analogs (octreotide and lanreotide), an mTOR inhibitor (everolimus), and a tyrosine kinase inhibitor (sunitinib) being widely used. Peptide receptor radionuclide therapy (PRRT) is also an invaluable option. In some cases, classic chemotherapy is indicated. CONCLUSIONS: Many effective therapies are now available for NET. It is important to select the right therapy at the right time for each patient through interdisciplinary management.

Does Genotype-Specific Phenotype in Patients with Multiple Endocrine Neoplasia Type 2 Occur as Current Guidelines Predict?

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.

Syndromic MEN1 parathyroid adenomas consist of both subclonal nodules and clonally independent tumors.

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.

Feasibility of Autofluorescence Using Overlay Imaging for the Detection of Parathyroid Glands: Defining Standards.

BACKGROUND: The aim of this study is to define standards for the use of near-infrared autofluorescence (NIRAF)-based overlay imaging via EleVision IR (Medtronic, Dublin, Ireland) and to evaluate its clinical applicability. PATIENTS AND METHODS: This prospective study included 189 patients who had undergone open thyroid and/or parathyroid surgery and in whom EleVision IR was applied to visualize at least one parathyroid gland (PG) between January 2021 and May 2022 in a tertiary referral care center. Whether the PGs were first localized by the surgeon or by overlay imaging was noted. Handling of the device, application time and duration, distance, infrared intensity (IR%), and the angle of each measurement were analyzed. In thyroidectomies, the specimens were subsequently scanned for further PGs. NIRAF patterns and intensities were described. RESULTS: Overall, 543 PGs were analyzed in 158 (83.6%) surgeries of thyroid glands (TGs) and in 49 (25.9%) surgeries for hyperparathyroidism. In 111 (58.7%) patients, identical numbers of PGs were detected by the surgeon and by overlay imaging. While a larger number of PGs was identified by the surgeon in 48 (25.4%) patients, overlay imaging served to detect more PGs in 30 (15.9%) cases. In four (2.1%) patients, PGs were visualized post-thyroidectomy due to their autofluorescence on the specimen. NIRAF-based overlay imaging was applied to depict the PGs early on after exposure by the surgeon. The ideal distance for the measurement ranged between 8 and 12 cm with an angle of 90° and a mean IR% of 34.5% (± 17.6). CONCLUSIONS: Considering the standard operating procedures, NIRAF-based overlay imaging can be used as an adjunct tool for intraoperative localization.

Primary Hyperparathyroidism and Intraoperative Parathyroid Hormone Monitoring: Application of a Modified Interpretation in Patients With "Parathyroid Hormone Spikes".

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.

The value of intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism and varying baseline parathyroid hormone levels.

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.

Papillary thyroid cancer: the value of bilateral diagnostic lymphadenectomy.

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.

Novel mutations of the calcium-sensing receptor impede differential diagnosis of primary hyperparathyroidism and familial hypocalciuric hypercalcemia.

BACKGROUND: Familial hypocalciuric hypercalcemia 1 (FHH1) is an autosomal dominant disorder caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene, commonly leading-in contrast to primary hyperparathyroidism (PHPT)-to asymptomatic hypercalcemia. It is important to establish the correct diagnosis, as surgery may be curative in PHPT, but most likely ineffective in FHH. The study aims to evaluate patients with FHH1, initially misinterpreted as PHPT and some even undergone surgery. METHODS: CaSR-genotyping was conducted, various biochemical parameters including twenty-four-hour urinary Ca excretion (24hU CE) and the calculated relation of urinary Ca clearance to creatinine clearance (CCCR), type of surgery and 1-year follow-up data of fourteen patients with proven FHH1 were evaluated retrospectively. RESULTS: Genetic analysis revealed a total of nine novel heterozygous variants in the CaSR gene in our study population. Six of fourteen patients (42.9%) underwent surgery for initially suspected PHPT, showing normalized biochemical parameters immediately after surgery. In 1-year follow-up, however, five of six operated patients (83.3%) showed normal parathyroid hormone (PTH), but elevated serum calcium levels. In contrast, only one of the operated patients (16.7%) presented both PTH and serum calcium in the normal range. Histology showed adenoma in three (50%), hyperplasia in two (33.3%), and normal parathyroid tissue in one (16.7%) of the patients. CONCLUSIONS: We discovered novel heterozygous variants in the CaSR gene, which considerably impede differential diagnosis of PHPT and FHH1. Furthermore, our results indicate that parathyroid surgery fails to provide long-term benefits for patients with FHH1 and suspected PHPT, even though this coincidence seems to exist.

Accessing the influence of 99mTc-Sesta-MIBI-positive thyroid nodules on preoperative localisation studies in patients with primary hyperparathyroidism.

PURPOSE: Curative treatment for primary hyperparathyroidism (PHPT) is parathyroidectomy (PTX) with removal of the hyperfunctioning gland(s). In an endemic goitre region, 35-78% of PHPT patients show concomitant thyroid disease. This study aimed to evaluate if 99mTc-sestamibi (MIBI)-positive thyroid nodules decrease sensitivity in regard to localising the hyperfunctioning parathyroid gland(s) in PHPT patients. METHODS: Within 5 years, 497 consecutive patients with biochemically proven PHPT were included in this study. The data was analysed retrospectively. RESULTS: In total, 198 patients underwent PTX with thyroid surgery and 299 patients underwent sole PTX. Sensitivity of MIBI scan for PTX with and without thyroid surgery was 72.1% and 73.6%, respectively. A statistically significant difference in sensitivity of ultrasound for PTX with and without thyroid surgery (57.0% and 70.9%, respectively) was observed (p = 0.029). Thyroid nodule histology did not have a significant effect on the MIBI scan. Unilateral neck exploration (UNE) was performed in 110 patients and bilateral neck exploration (BNE) in 177 patients. The probability of surgical conversion from UNE to BNE due to incorrect localisation was 1.733 times higher in patients with thyroid nodules. CONCLUSIONS: Concomitant benign thyroid nodules did not influence MIBI sensitivity. No correlation between thyroid carcinoma and MIBI uptake was determined. However, MIBI detection of thyroid malignancy is important in patients initially being considered for minimal invasive parathyroidectomy. Sensitivity and positive predictive value of ultrasound were significantly lower in patients with thyroid nodules. The probability of conversion from UNE to BNE due to incorrect localisation was 1.733 times higher in patients with thyroid nodules.

Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

Management of adrenocortical carcinoma: are we making progress?

Adrenocortical carcinoma (ACC) is a rare malignancy characterized by aggressive biology and potential endocrine activity. Surgery can offer cure for localized disease but more than half of patients relapse and primary unresectable or metastasized disease is frequent. Prognosis of metastatic ACC is still limited, with less than 15% of patients alive at 5 years. Recent advances in understanding the molecular profile of ACC underline the high complexity of this disease, which is characterized by limited drugable molecular targets as well as by a complex interplay between a yet scarcely understood microenvironment and potential endocrine activity. Particularly steroid-excess further complicates therapeutic concepts such as immunotherapy, which have markedly improved outcome in other disease entities. To date, mitotane remains the only approved drug for adjuvant and palliative care in ACC. Standard chemotherapy-based protocols with cisplatin, doxorubicin and etoposide offer only marginal improvement in long-term outcome and the number of clinical trials conducted is low due to the rarity of the disease. In the current review, we summarize principles of oncological management for ACC from localized to advanced disease and discuss novel therapeutic strategies, including targeted therapies such as tyrosine kinase inhibitors and antibodies, immunotherapy with a focus on checkpoint inhibitors, individualized treatment concepts based on molecular characterization by next generation sequencing methods, the role of theranostics and evolvement of adjuvant therapy.

Neuroendocrine liver metastasis from the small intestine: Is surgery beneficial for survival?

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.

Discovery of melanin-concentrating hormone receptor 1 in brown adipose tissue.

Although extensive research on brown adipose tissue (BAT) has stimulated optimism in the battle against obesity and diabetes, BAT physiology and organ crosstalk are not fully understood. Besides BAT, melanin-concentrating hormone (MCH) and its receptor (MCHR1) play an important role in energy homeostasis. Because of the link between hypothalamic MCH neurons and sympathetic BAT activation via ß-adrenoceptors, we investigated the expression and physiological role of the MCHR1 in BAT. MCHR1 was detected in rodent and human BAT with RT-qPCR and western blot analyses. In vivo imaging in rats used the glucose analog [18 F]FDG and the MCHR1-tracer [11 C]SNAP-7941. We found that the ß3-adrenoceptor (ADRB3) agonist CL316,243 increased [11 C]SNAP-7941 uptake in BAT. Additionally, a pharmacological concentration of SNAP-7941-a low-affinity ADRB3 ligand-stimulated [18 F]FDG uptake, reflecting BAT activation. In cultured human adipocytes, CL316,243 induced MCHR1 expression, further supporting a direct interaction between MCHR1 and ADRB3. These findings characterized MCHR1 expression in rodent and human BAT for the first time, including in vitro and in vivo data demonstrating a link between MCHR1 and the ß3-adrenergic system. The presence of MCHR1 in BAT emphasizes the role of BAT in energy homeostasis and may help uncover treatment approaches for obesity.

Acute and Life-threatening Complications in Cushing Syndrome: Prevalence, Predictors, and Mortality.

CONTEXT: Cushing syndrome (CS) results in significant morbidity and mortality. OBJECTIVE: To study acute and life-threatening complications in patients with active CS. METHODS: We performed a retrospective cohort study using inpatient and outpatient records of patients with CS in a tertiary center. A total of 242 patients with CS were included, including 213 with benign CS (pituitary n = 101, adrenal n = 99, ectopic n = 13), and 29 with malignant disease. We collected acute complications necessitating hospitalization, from appearance of first symptoms of hypercortisolism until 1 year after biochemical remission. Mortality data were obtained from the national registry. Baseline factors relating to and predicting acute complications were tested using uni- and multivariate analysis. RESULTS: The prevalence of acute complications was 62% in patients with benign pituitary CS, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Complications observed in patients with benign CS included infections (25%), thromboembolic events (17%), hypokalemia (13%), hypertensive crises (9%), cardiac arrhythmias (5%), and acute coronary events (3%). Among these patients, 23% had already been hospitalized for acute complications before CS was suspected, and half of complications occurred after the first surgery. Glycated hemoglobin (HbA1c) and 24-hour urinary free cortisol positively correlated with the number of acute complications per patient. Patients with malignant disease had significantly higher rates of acute complications. Mortality during the observation period was 2.8% and 59% in benign and malignant CS, respectively. CONCLUSIONS: This analysis highlights the whole spectrum of acute and life-threatening complications in CS, and their high prevalence even before disease diagnosis and after successful surgery.

Measurements of Plasma-Free Metanephrines by Immunoassay Versus Urinary Metanephrines and Catecholamines by Liquid Chromatography with Amperometric Detection for the Diagnosis of Pheochromocytoma/Paraganglioma.

Studies conflict concerning the use of enzyme immunoassays (EIA) for plasma free metanephrines (P-MNs) vs. other methods for pheochromocytoma/paraganglioma (PPGL) diagnosis. We compared commercially available EIAs for P-MNs with high-pressure liquid chromatography (HPLC) for 24 h-urinary MNs (U-MNs) and -catecholamines (U-CATs). 943 (565 female, 378 male) patients (54 PPGL, 889 Non-PPGL) were studied. Simultaneous measurements of all parameters analyzed at the central lab of our university hospital was mandatory for inclusion. Sensitivity of P-MNs (94.4%) was similar to that of U-MNs (100%), and both were higher than of U-CATs (77.8%), specificity of P-MNs (100%) higher than of U-MNs (73.6%), and similar to U-CATs (99.8%). With the recently proposed downward adjusted ULN of P-MNs to correct for the reported negative bias of the EIAs sensitivity (98.1%) raised non-significantly, but specificity decreased significantly (94.8%). Areas under receiver-operating characteristic curves indicated comparable diagnostic performance of P-MNs (0.989) vs. U-MNs (0.995), both better than U-CATs (0.956). In summary, the EIAs to measure P-MNs performed similarly to U-MNs by HPLC, and both better than U-CATs by HPLC. The post-test probability of PPGL given a positive test result was best for P-MNs, and higher than for the other pairs of analytes. Downward corrections of ULN of P-MNs did not improve test performances.

Positive central lymph-nodes are underdiagnosed in patients with Bethesda V cytology in an endemic goiter region.

BACKGROUND: Fine needle aspiration (FNA) is a significant diagnostic procedure for detecting malignancy in patients with nodular thyroid disease. A high proportion of patients with cytological diagnosed follicular neoplasia (Bethesda IV and V) ultimately have thyroid cancer. The aim of this study was to evaluate the incidence of preoperatively undiagnosed central lymph node metastasis in patients with multinodular goiter (MNG). METHODS: Patients who underwent FNA and were classified as Bethesda IV/V were included. Applying a radical approach, all patients underwent (hemi)thyroidectomy and prophylactic unilateral central neck dissection. RESULTS: During our study period 2009-2013, 60 patients (19.7%) were classified as Bethesda IV and 21 (6.9%) Bethesda V. Final histopathological results revealed malignancy in 35 (43.2%) of 81 Bethesda IV/V nodules. Of the nodules classified as Bethesda IV, 20 (33.3%) showed malignancy in the final histology. Ten patients (16.7%) had papillary micro-carcinoma (mPTC, <10 mm), 4 (6.6%) PTC and 6 (10%) follicular thyroid cancer. Fifteen of 21 (71.4%) Bethesda V nodules were revealed as PTC of whom seven (33.3%) patients also had lymph-node metastases. CONCLUSIONS: While 33.3% of the patients with PTC, preoperatively classified as Bethesda V, had previously undetected positive lymph-nodes, only one patient with Bethesda IV had lymph-node metastasis.

Early Diagnosis of Medullary Thyroid Cancer: Are Calcitonin Stimulation Tests Still Indicated in the Era of Highly Sensitive Calcitonin Immunoassays?

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.

PET/MRI versus PET/CT in oncology: a prospective single-center study of 330 examinations focusing on implications for patient management and cost considerations.

PURPOSE: PET/MRI has recently been introduced into clinical practice. We prospectively investigated the clinical impact of PET/MRI compared with PET/CT, in a mixed population of cancer patients, and performed an economic evaluation of PET/MRI. METHODS: Cancer patients referred for routine staging or follow-up by PET/CT underwent consecutive PET/CT and PET/MRI, using single applications of [18F]FDG, [68Ga]Ga-DOTANOC, or [18F]FDOPA, depending on tumor histology. PET/MRI and PET/CT were rated separately, and lesions were assessed per anatomic region; based on regions, per-examination and per-patient accuracies were determined. A simulated, multidisciplinary team meeting served as reference standard and determined whether differences between PET/CT and PET/MRI affected patient management. The McNemar tests were used to compare accuracies, and incremental cost-effectiveness ratios (ICERs) for PET/MRI were calculated. RESULTS: Two hundred sixty-three patients (330 same-day PET/CT and PET/MRI examinations) were included. PET/MRI was accurate in 319/330 examinations and PET/CT in 277/330 examinations; the respective accuracies of 97.3% and 83.9% differed significantly (P < 0.001). The additional findings on PET/MRI-mainly liver and brain metastases-had implications for patient management in 21/263 patients (8.0%). The per-examination cost was 596.97 EUR for PET/MRI and 405.95 EUR for PET/CT. ICERs for PET/MRI were 14.26 EUR per percent of diagnostic accuracy and 23.88 EUR per percent of correctly managed patients. CONCLUSIONS: PET/MRI enables more appropriate management than PET/CT in a nonnegligible fraction of cancer patients. Since the per-examination cost is about 50% higher for PET/MRI than for PET/CT, a histology-based triage of patients to either PET/MRI or PET/CT may be meaningful.