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.

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.

Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement.

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.

How to Manage Small Intestine (Jejunal and Ileal) Neuroendocrine Neoplasms Presenting with Liver Metastases?

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.

MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.

The ß-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 ß-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in ß-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 ß-cell activity.

The determination of real fluid requirements in laparoscopic resection of pheochromocytoma using minimally invasive hemodynamic monitoring: a prospectively designed trial.

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.

Effectiveness of anti-osteoporotic treatment after successful parathyroidectomy for primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial.

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/cm2; 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/cm2; 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.

Medullary Thyroid Carcinoma: Do Ultrasonography and F-DOPA-PET-CT Influence the Initial Surgical Strategy?

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.

Primary hyperparathyroidism: Dynamic postoperative metabolic changes.

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.

Factors influencing pre-operative urinary calcium excretion in primary hyperparathyroidism.

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 (R2 ) 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 R2 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.

"Silent" kidney stones in "asymptomatic" primary hyperparathyroidism-a comparison of multidetector computed tomography and ultrasound.

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.

Prophylactic "First-Step" Central Neck Dissection (Level 6) Does Not Increase Morbidity After (Total) Thyroidectomy.

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.

The influence of thiazide intake on calcium and parathyroid hormone levels in patients with primary hyperparathyroidism.

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.

Morbidity Associated with Concomitant Thyroid Surgery in Patients with Primary Hyperparathyroidism.

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.

Clinical presentation in insulinoma predicts histopathological tumour characteristics.

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.

Timing and extent of thyroid surgery for gene carriers of hereditary C cell disease--a consensus statement of the European Society of Endocrine Surgeons (ESES).

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.

The Value of Pretherapeutic Basal Calcitonin Cut-Offs for the Therapeutic Strategy and Prediction of Long-Term Outcome of Patients with Medullary Thyroid Cancer-A 30-Year Single-Center Experience.

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.

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.

Current trends in surgery for renal hyperparathyroidism (RHPT)--an international survey.

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.