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.

Medullary thyroid cancer with ectopic Cushing's syndrome: A multicentre case series.

OBJECTIVE: Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. DESIGN: Retrospective cohort study in three German and one Swiss referral centres. PATIENTS: Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. MEASUREMENTS: The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. RESULTS: The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment for ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64-111) than matched controls (190 months, 95% CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. CONCLUSION: This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case.

Procalcitonin measured by three different assays is an excellent tumor marker for the follow-up of patients with medullary thyroid carcinoma.

OBJECTIVES: Procalcitonin (PCT) has been suggested as a tumor marker in patients with medullary thyroid carcinoma (MTC). Clinical application data in long term follow-up are missing. METHODS: 210 serum samples of 169 consecutive patients with MTC (92 sporadic, 77 hereditary, 158 postoperative follow-up, 11 preoperative) were collected between 2018 and 2020. Postoperative patients were stratified into three groups according to their disease status at the end of follow-up: cured (n=51, calcitonin (CT) levels < limit of quantitation), minimal residual disease (n=55, detectable CT and no metastases provable by imaging methods), metastatic disease (n=52). In five patients CT and PCT were measured while on therapy with tyrosine kinase inhibitors (TKI). CT was analyzed by the Roche ECLIA, PCT by three assays from Roche, PES, Abbott. RESULTS: The mean ± SD values seen with the three PCT assays in the MTC response groups, cured: <0.06, 0.016 ± 0.007, 0.014 ± 0.007 ng/mL, minimal residual disease: 0.511 ± 0.800, 0.389 ± 0.687, 0.341 ± 0.614 ng/mL, metastatic disease 109 ± 202, 60.4 ± 110, 63.3 ± 115 ng/mL correlate well with the CT results in these groups: cured <1.0 pg/mL, minimal residual disease 91.3 ± 121.5 pg/mL, metastatic disease 14,489 ± 30,772 pg/mL. There was a significant correlation (p<0.001) between the three PCT assays (Roche/PES r=0.970, Roche/Abbott r=0.976, Abbott/PES r=0.995). In the course of treatment with TKI both CT and PCT reflected clinical state. Preoperative PCT in hereditary MTC has the same diagnostic validity than CT. CONCLUSIONS: PCT measured with three different immunoassays is as good as the standard tumor marker CT in the follow-up of MTC but has a superior analytical stability.

Calcitonin measurement in pediatrics: reference ranges are gender-dependent, validation in medullary thyroid cancer and thyroid diseases.

BACKGROUND: There is only limited information on serum reference ranges of calcitonin (CT) in infants, children and adolescents. This gap hampers valid diagnostics in patients with multiple endocrine neoplasia type 2 (MEN 2) and planned prophylactic thyroidectomy. In addition, age-dependent reference ranges for CT are necessary to define a cure in medullary thyroid carcinoma (MTC). We asked whether the reference ranges for CT levels were age- and gender-dependent in the serum of a pediatric cohort. METHODS: A total of 6090 serum samples of 2639 subjects of the LIFE-Child cohort aged between 1 month and 17.9 years were analyzed by the CT electrochemiluminescence immunoassay (ECLIA). Reference intervals were estimated using the LMS method. For clinical validation the serum of 28 patients (61 samples) with MEN 2 and 106 patients (136 samples) with thyroid diseases were analyzed. RESULTS: CT levels showed a clear age- and gender-dependence with significantly higher values in boys (p<0.01). An accelerated decline of CT levels from newborn to children at the age of 4 and 5 years was observed for both sexes. A cure for MTC was demonstrated in 71% of MEN 2 patients after thyroidectomy, whereas 5 patients remained suspicious for micrometastasis or relapse. Only 1.5% of our patients with thyroid diseases revealed increased CT levels. CONCLUSIONS: This is the largest study to establish novel pediatric reference ranges from the CT values of healthy subjects. It allows a precise laboratory monitoring of CT in pediatric patients with MEN 2. Thyroid diseases did not have a relevant influence on CT levels in our pediatric cohort.

United States and European Multicenter Prospective Study for the Analytical Performance and Clinical Validation of a Novel Sensitive Fully Automated Immunoassay for Calcitonin.

BACKGROUND: The objective of this study is the validation and proof of clinical relevance of a novel electrochemiluminescence immunoassay (ECLIA) for the determination of serum calcitonin (CT) in patients with medullary thyroid carcinoma (MTC) and in different diseases of the thyroid and of calcium homeostasis. METHODS: This was a multicenter prospective study on basal serum CT concentrations performed in 9 US and European referral institutions. In addition, stimulated CT concentrations were measured in 50 healthy volunteers after intravenous calcium administration (2.5 mg/kg bodyweight). RESULTS: In total, 1929 patients and healthy controls were included. Limits of blank, detection, and quantification for the ECLIA were 0.3, 0.5, and 1 ng/L, respectively. Highest intra- and interassay coefficients of variation were 7.4% (CT concentration, 0.8 ng/L) and 7.0% (1.1 ng/L), respectively. Medians (interval) of serum CT concentrations in 783 healthy controls were 0.8 ng/L (<0.5-12.7) and 3 ng/L (<0.5-18) for females and males, respectively (97.5th percentile, 6.8 and 11.6 ng/L, respectively). Diagnostic sensitivity and specificity were 100%/97.1% and 96.2%/96.4%, for female/males, respectively. Patients (male/female) with primary hyperparathyroidism, renal failure, and neuroendocrine tumors showed CT concentrations >97.5th percentile in 33%/4.7%, 18.5%/10%, and 8.3%/12%, females/males, respectively. Peak serum CT concentrations were reached 2 min after calcium administration (161.7 and 111.8 ng/L in males and females, respectively; P < 0.001). CONCLUSIONS: Excellent analytical performance, low interindividual variability, and low impact of confounders for increased CT concentrations in non-MTC patients indicate that the investigated assay has appropriate clinical utility. Calcium-stimulated CT results suggest good test applicability owing to low interindividual variability.

Is Routine Screening of Young Asymptomatic MEN1 Patients Necessary?

BACKGROUND: Recent clinical practice guidelines recommend that routine screening of MEN1 mutation carriers should start at the age of 5 years. The occurrence of clinically relevant MEN1 organ manifestations in children (≤18 years) was evaluated. METHODS: Two prospective collected databases of MEN1 patients (n = 166) who underwent annual screening were retrospectively analyzed for organ manifestations in MEN1 patients ≤18 years. The follow-up was based on the most recent screening examination until December 2015. RESULTS: Twenty [11 females, 9 males, (12%)] of 166 MEN1 patients were diagnosed with at least one organ manifestation at age ≤18 years. The most frequent manifestation was mild asymptomatic pHPT (n = 9, 45%, age range 8-18 years). Eight (40%) young patients had pNENs (three non-functioning pNENs, five insulinomas, age range 9-18 years). All five insulinomas were diagnosed based on hypoglycemic symptoms. The other organ manifestations were asymptomatic pituitary adenomas in six patients (30%, age range 15-18 years) and a bronchial carcinoid in one 15-year-old patient. Only six (30%) patients ≤18 years had clinically relevant organ manifestations. CONCLUSION: Symptomatic or severe manifestations in MEN1 patients rarely occur below the age of 16 years. With regard to psychological burden and cost-effectiveness, routine screening of asymptomatic MEN1 patients should be postponed at least until the age of 16 years.

Medullary Thyroid Carcinoma: Imaging.

Imaging plays an important role in early detection and staging of medullary thyroid carcinoma (MTC) as well as in follow-up to localize early recurrence. MTC is a rare, calcitonin-secreting thyroid malignancy often diagnosed by ultrasound and calcitonin screening as part of the routine workup for any thyroid nodule. If calcitonin is elevated, imaging studies are needed for preoperative staging, which dictates surgical management. This can be done by ultrasound of the neck and abdomen. Computed tomography (CT) or magnetic resonance imaging (MRI) studies for more distant disease are done preoperatively if calcitonin levels are higher than 500 pg/ml. Neither FDG-PET/CT nor F-DOPA-PET/CT are used routinely for preoperative staging but may contribute in doubtful individual cases. Postoperative elevated calcitonin is related to persistence or recurrence of MTC. Imaging studies to localize tumor tissue during postoperative follow-up include ultrasound, CT, MRI as well as PET studies. They should be used wisely, however, since treatment consequences are often limited, and even patients with persistent disease may survive long enough to accumulate significant radiation doses. Imaging studies are also useful for diagnosis of associated components of the hereditary MTC such as pheochromocytoma and primary hyperparathyroidism (pHPT).

Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the thyroid C cells producing mainly calcitonin (CTN) used as tumor marker. MTC occurs either sporadic (75%) or in a hereditary form (multiple endocrine neoplasia type 2, MEN2), due to germline mutations in the RET proto-oncogene. The discovery of an MTC in a patient has several diagnostic implications involving a specific strategy: preoperative evaluation of the tumor marker CTN and the extent of the disease, classification of MTC as sporadic or hereditary by DNA testing, and screening for associated endocrinopathies in hereditary MTC. Elevated CTN is a highly sensitive and specific tumor marker for diagnosis and follow-up of MTC. CTN is directly related to the tumor mass. In patients with nodular thyroid disease, diagnosis of MTC could be made by CTN determination as an indicator of tumor burden in conjunction with fine-needle aspiration. Patients with confirmed sporadic or hereditary MTC should have a total thyroidectomy and depending on the preoperative CTN value and the extent of disease additional dissection of the lymph nodes in the central and lateral neck compartment. In MEN 2 patients diagnosed by screening, the time of prophylactic thyroidectomy depends on RET mutation and CTN level.

Hereditary Medullary Thyroid Cancer Genotype-Phenotype Correlation.

During the last two decades, there has been a marked expansion of our knowledge of both the basic and clinical aspects of multiple endocrine neoplasia type 2 (MEN2). There are two clinically distinct types of MEN2 syndrome, termed MEN2A and MEN2B. Within MEN2A, there are four variants: (i) classical MEN2A, represented by the uniform presence of MTC and the less frequent occurrence of pheochromocytoma, or primary hyperparathyroidism, or both; (ii) MEN2A with cutaneous lichen amyloidosis; (iii) MEN2A with Hirschsprung's disease; and (iv) familial medullary thyroid carcinoma (FMTC), i.e., families or individuals with only MTC. MEN2B is associated with MTC, pheochromocytoma, and mucosal neuromas. Hereditary MTC is caused by autosomal dominant gain of function mutations in the RET proto-oncogene. Specific RET mutations may suggest a predilection toward a particular phenotype and clinical course with a strong genotype-phenotype correlation. Based upon these genotype-phenotype correlations, RET mutations are now stratified into three risk levels, i.e., highest, high, and moderate risk, based on the penetrance and aggressiveness of the MTC. Children in the highest risk category should undergo thyroidectomy in their first year of life, and perhaps even in their first months of life. Children in the high-risk category should have ultrasound of the neck and calcitonin (CTN) measurement performed prior to thyroidectomy. Thyroidectomy should typically be performed at the age of 5 or earlier, depending on the presence of elevated serum CTN levels. However, heterogeneity in disease expression and progression within these groups varies considerably. To personalize disease management, the decision regarding the age of prophylactic thyroidectomy is no longer based upon genotype alone but is currently driven by additional clinical data, the most important being serum CTN levels; specifically, the decision to perform thyroidectomy should err on the safe side if the CTN level is elevated but below 30 pg/ml, especially in the moderate risk group. Personalized management also includes decisions about the best age to begin biochemical screening for pheochromocytoma and primary hyperparathyroidism.

Long-Term Follow-up in Medullary Thyroid Carcinoma.

After surgery, patients with medullary thyroid carcinoma (MTC) should be assessed regarding the presence of residual disease, the localization of metastases, and the identification of progressive disease. Postoperatively, patients with MTC are staged to separate those at low risk from those at high risk of recurrence. The TNM staging system is based on tumor size, extra-thyroidal invasion, nodal metastasis, and distant spread of cancer. In addition, the number of lymph-node metastases, the number of compartments involved, and the postoperative calcitonin (CTN) and carcinoembryonic antigen (CEA) levels should be documented. The postoperative normalization of the serum CTN level is associated with a favorable outcome. When patients have basal serum CTN levels less than 150 pg/ml after a thyroidectomy, any persistent or recurrent disease is nearly always confined to lymph nodes in the neck. When the postoperative serum CTN level exceeds 150 pg/ml, patients should be evaluated with imaging procedures, including computed tomography (CT) of the neck and chest, contrast-enhanced magnetic resonance imaging (MRI) and ultrasound (US) of the liver, bone scintigraphy, MRI of the bone, and positron emission tomography (PET)/CT. One can estimate the growth rate of MTC metastases by quantifying increases in tumor size over time from sequential imaging studies analyzed with response evaluation criteria in solid tumors (RECIST), and by determining the tumor marker doubling time from sequential measures of serum CTN or CEA levels over multiple time points. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. Patients with persistent or recurrent MTC localized to the neck following thyroidectomy are candidates for neck operations, depending on the tumor extension. Once metastases appear, the clinician must decide which patients require therapy. This requires a balance between the (often) slow rate of tumor progression, which is associated with a good quality of life, and the limited efficacy and potential toxicities of local and systemic therapies. Considering that metastatic MTC is incurable, the management goals are to provide loco-regional disease control, palliate symptoms of hormonal excess, such as diarrhea, palliate symptomatic metastases, like pain or bone fracture, and control metastases that threaten life, such as bronchial obstruction or spinal cord compression. This can be achieved with palliative surgery, external beam radiation therapy (EBRT), or systemic therapy with tyrosine kinase inhibitor (TKI).

The Long-Term Cure of Patients With Hereditary Medullary Thyroid Carcinoma: 40 Years of Follow-Up in a Single Center.

BACKGROUND: The cure rate of patients with hereditary medullary thyroid carcionoma (MTC) can be decisively improved by screening for elevated calcitonin (Ctn) levels and RET gene mutations in patients from families affected by multiple endocrine neoplasia type 2 (MEN2), followed by prophylactic thyroidectomy in persons with mutated RET genes. In this long-term observational study, we investigated whether postoperative cures are indeed maintained decades after the procedure. METHODS: From 1979 to 2021, 277 patients with MEN2 who underwent thyroidectomy were observed postoperatively for 14.4 ± 10.3 years (mean, standard deviation). They were classified as either cured or not cured depending on the last measured serum Ctn level (cured, Ctn < 10 pg/mL or < 2 pg/mL; not cured, Ctn ≥ 10 pg/mL). Depending on their RET mutation status, they were categorized as moderate, high, or highest risk (121, 130, and 26 patients, respectively). RESULTS: 154 patients (55.6%) obtained a long-term cure (Ctn <10 pg/mL). The median age at surgery was 27, 14, and 4 years in patients at moderate, high, and highest risk. All 52 patients who had undergone prophylactic thyroidectomy before the age of 6 years, 9 years, or 6 months had a Ctn level below 2 pg/mL and were cured at the end of the follow-up period. In a multivariable analysis, prognostic factors for a long-term cure were a lower tumor stage and, by tendency, classification as belonging to the moderate as opposed to the highest-risk group. CONCLUSION: In patients receiving an early diagnosis of MEN2 via family screening, prophylactic thyroidectomy taking into account the RET mutation risk group can achieve a long-term cure of MTC with undetectable serum Ctn levels.

Thyroid Dysfunction in Periand Postmenopausal Women-Cumulative Risks.

BACKGROUND: Menopausal estrogen depletion increases the risk of cardiovascular disease and of osteoporosis. Both of these risks can be increased by thyroid dysfunction as well. This cumulation of risks will be presented. METHODS: This review is based on publications retrieved by a selective search in PubMed (publications dated January 2000 to October 2022) for clinical trials, meta-analyses, randomized controlled trials, and systematic reviews containing the keywords "menopause and thyroid disorders." RESULTS: Hyperthyroidism and menopause have similar symptoms. Decreased levels of thyroid-stimulating hormone (TSH) are found in 8-10% of women in their fifth and sixth decades. TSH is decreased in 21.6-27.2% of women treated with L-thyroxine; decreased TSH is associated with increased cardiovascular mortality (hazard ratio [HR] 3.3, 95% confidence interval [CI]: [1.3; 8.0]) and increased mortality of all causes (HR 2.1; 95% CI: [1.2; 3.8]). Menopausal estrogen depletion accelerates the risk of cardiovascular disease and causes a disproportionate loss of bone density. In hyperthyroidism, bone density is decreased, and the risk of vertebral fractures is increased (HR 3.57; 95% CI: [1.88; 6.78]). CONCLUSION: The risk of heart diseases and bone diseases accelerates around the time of the menopause. Early detection and treatment of hyperthyroidism, which can further elevate the risk of both of these diseases is therefore required. In perimeno - pausal and postmenopausal women who are being treated for hypothyroidism, TSH suppression must be avoided. Thyroid dysfunction is common in women; its manifestations are less obvious with advancing age, making clinical diagnosis more difficult, yet it can have major deleterious effects. Thus, the indications for measuring TSH in perimenopausal women should be kept broad, rather than restrictive.

Clinical relevance of RET variants G691S, L769L, S836S and S904S to sporadic medullary thyroid cancer.

BACKGROUND: Based on reports of higher frequencies among patients with sporadic medullary thyroid cancer (MTC) relative to external controls, the RET (REarranged during Transfection) variants G691S, L767L, S836S and S904S have been considered disease modifiers, suggesting greater lifetime risks of MTC. Other studies, employing different external controls, failed to confirm this association. Using a complementary approach, this study aimed at exploring differences in clinico-pathological characteristics among patients with sporadic MTC carrying no (wildtype), one (heterozygotes) or both (homozygotes) homologue RET variants in the germline, with wildtype cases acting as internal controls. METHODS: Included in this investigation were 150 patients with complete genetic information on G691S, L769L, S836S and S904S RET alleles operated on for sporadic MTC at a tertiary referral centre. RESULTS: Not one statistically significant dose-response relationship was identified between any RET variant (wildtype vs RET heterozygotes vs homologue RET homozygotes) and patient age at MTC diagnosis, gender, primary tumour size, extrathyroidal extension, numbers of involved and removed lymph nodes, or distant metastasis. L769L and S836S homozygotes, unlike G691S and S904S homozygotes, were either rare or absent, limiting the analyses to comparisons of heterozygosity versus wildtype. On time-to-event analysis, G691S, L769L, S836S or S904S carriers and noncarriers developed MTC at similar rates. CONCLUSIONS: In carriers and noncarriers of the RET variants G691S, L767L, S836S and S904S, sporadic MTC appeared clinically and pathologically indistinguishable. This observation, along with the inconclusive evidence of previous association studies, calls for larger longitudinal association studies with age- and sex-matched external controls and additional functional studies of RET biology.

Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors-A Retrospective Multi-Center Registry Analysis.

BACKGROUND: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. METHODS: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. RESULTS: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32-NR (not reached); n = 36), and the median PFS was 21 months (12-39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13-79; n = 22), and the median PFS was 3.5 months (2-14; n = 22) in RET-positive cases. CONCLUSIONS: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10.

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

Basal and stimulated calcitonin and procalcitonin by various assays in patients with and without medullary thyroid cancer.

BACKGROUND: Calcitonin (CT) is a sensitive marker for evaluation of medullary thyroid cancer (MTC). However, CT measurement can vary with assay- and nonassay-dependent factors, and procalcitonin (PCT) measurement has been proposed for evaluating questionable increases in CT. METHODS: We tested 2 fully automated CT assays (Immulite [IL] and Liaison [LIA]) and 1 nonautomated CT assay (IRMA, Medipan) and compared these results with PCT (Brahms Kryptor). We evaluated preanalytical conditions and PCT cross-reactivity in sera of 437 patients with clinical conditions associated with hypercalcitoninemia. Additionally, we determined the true "nil" CT concentration in 60 thyroidectomized patients and defined CT cutoff concentrations for pentagastrin stimulation testing in 13 chronic kidney disease (CKD) patients and 10 MTC patients. RESULTS: Markedly decreased CT concentrations were found after storage of sera for >2 h at room temperature and >6 h at 4 °C. Cutoff concentrations for basal and stimulated CT were disease and assay dependent. Proton pump inhibitor therapy was the most frequent reason for increased CT. PCT concentrations were higher in patients with MTC than in patients with CKD without infections (P<0.001). Whereas IL and LIA demonstrated comparable analytical quality, the IRMA gave increased CT concentrations in nil sera and showed cross-reactivity with PCT in patients with concomitant bacterial infection. CONCLUSIONS: IL, LIA, and IRMA detected increased CT concentrations in non-MTC patients and discriminated MTC from CKD patients in pentagastrin tests. PCT assessment may be helpful in the diagnostic work-up of increased CT concentrations in questionable clinical circumstances.

Inactivating calcium-sensing receptor mutations in patients with primary hyperparathyroidism.

OBJECTIVE: Primary hyperparathyroidism (HPT) is characterised by autonomous secretion of PTH from enlarged parathyroid glands leading, in most patients, to asymptomatic hypercalcaemia. Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene; it is characterised by lifelong and usually asymptomatic hypercalcaemia. Establishing the correct diagnosis is important because surgery can be curative in HPT, but ineffective in FHH. There is overlap in the diagnostic criteria for the two disorders and some patients carrying inactivating mutations in the CaSR gene, which is suggestive of FHH, also have HPT with hyperplastic parathyroid glands or adenomas. DESIGN AND PATIENTS CaSR gene mutations were analysed and clinical and biochemical parameters evaluated in 139 consecutive outpatients presenting with hypercalcaemia and suspected of having HPT. RESULTS: Six different mutations of the CaSR gene were found in eight patients. In four patients, classical FHH was suspected based on clinical and biochemical results and was confirmed by the CaSR mutations. In the other four patients, HPT was diagnosed based on the biochemical profile or symptoms; in these four patients, the parathyroids were operated on and single adenomas were histologically confirmed. In all four patients, serum calcium decreased postoperatively; and in three patients, serum calcium normalised postoperatively. The CaSR mutations in these patients were R25X, E250K and Q926R. CONCLUSION: The coexistence of HPT and FHH in four of 139 patients suggests a pathogenetic role of CaSR mutations in HPT. Despite also having a CaSR mutation, these patients benefited from parathyroid surgery.

Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey.

OBJECTIVE: Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium-sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long-term treatment. DESIGN: Nationwide retrospective collaborative study. PATIENTS: We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases. MEASUREMENTS: Activating CaSR mutations and clinical and biochemical findings were evaluated. RESULTS: Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 µg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%). CONCLUSION: This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.

Similar Stage-dependent Survival and Outcome in Sporadic and Hereditary Medullary Thyroid Carcinoma.

CONTEXT: Long-term data are scarce on large cohorts with sporadic (sMTC) and hereditary medullary thyroid carcinoma (hMTC). OBJECTIVES: To compare long-term disease-specific survival (DSS) and outcomes between sMTC and hMTC groups. DESIGN: Retrospective analysis. SETTING: German tertiary referral center. PATIENTS: A total of 673 patients with MTC that underwent surgery from January 1974 to July 2019. INTERVENTION: None (observational study). MAIN OUTCOME MEASURE: Differences between sMTC and hMTC in long-term, stage-dependent survival and outcomes. RESULTS: Surgery was performed at median ages of 49 years for sMTC (n = 477, 44% male) and 29 years for hMTC (n = 196, 43% male; P < 0.0001). The mean follow-up times were 9.2 ± 8.0 (sMTC) and 14.6 ± 10.3 years (hMTC). Age and tumor stage at diagnosis were significantly different between the 2 groups (P < 0.0001). The sMTC and hMTC groups had different overall DSS (log rank, P = 0.0183), but similar stage-dependent DSS (log rank, P = 0.1242-0.8981). In a multivariate analysis, sMTC and hMTC did not differ in DSS (hazard ratio [HR] = 1.56; 95% CI, 0.94-2.57), but in both groups, a worse DSS was significantly associated with age at diagnosis (HR = 1.04; 95% CI, 1.02-1.05), male sex (HR = 0.49; 95% CI, 0.32-0.76), and stages III and IV at diagnosis (HR = 20.00; 95% CI, 2.74-145.91 and HR = 97.47; 95% CI, 13.07-726.67, respectively). The groups had significantly different (P < 0.0001) outcomes (i.e., cured, minimal residual disease, structural detectable disease, and death), but similar stage-dependent outcomes (P = 0.9449-0.0511), except for stage III (P = 0.0489). CONCLUSION: Patients with sMTC and hMTC had different ages of onset, but similar stage-dependent DSS and outcomes after the MTC diagnosis. This finding suggested that tumor behavior was similar in sMTC and hMTC.

Real-World Efficacy and Safety of Cabozantinib and Vandetanib in Advanced Medullary Thyroid Cancer.

Background: Management of patients with advanced medullary thyroid cancer (MTC) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib have been approved for the treatment of progressive MTC based on prolonged progression-free survival (PFS) in phase 3 clinical trials. Patients and Methods: To evaluate clinical characteristics, treatment regimens, efficacy, and treatment emergent adverse events (TEAEs) of vandetanib and cabozantinib in MTC patients outside clinical trials at four German tertiary care centers. Forty-eight patients diagnosed between 1990 and 2018 were included. PFS and overall survival (OS) probabilities were estimated using the Kaplan-Meier method and compared by log-rank test. Results: The median age at diagnosis was 46 years (15-80 years); a germ line RET (rearranged during transfection) mutation was known in 6 (13%) patients. Thirty-two (67%) patients showed progressive disease before TKI initiation. Forty-seven (98%) patients were treated with vandetanib and 23 (48%) patients with cabozantinib. Vandetanib was first-line treatment in 41 (85%) patients and cabozantinib in 7 (15%) patients. Partial response was the best response in 12 (26%) patients treated with vandetanib and in 5 (22%) patients treated with cabozantinib. Sixteen (34%) patients treated with vandetanib and 3 (13%) patients treated with cabozantinib had stable disease ≥24 weeks. The median PFS for vandetanib and cabozantinib was 17 months [95% confidence interval, CI, 9.3-24.6 months] and 4 months [CI 3.1-4.9 months], respectively. The 6- and 12-month survival rates were 98% and 86% for vandetanib and 78% and 70% for cabozantinib, respectively. The median OS for vandetanib and cabozantinib was 53 months [CI 43.7-62.3 months] and 24 months [CI 5.9-42.1 months], respectively. In vandetanib-treated patients, the PFS and OS were significantly longer in patients aged ≤60 years at TKI initiation and in patients with ≥5 TEAEs. Additionally, the PFS was longer in the absence of bone metastases. In cabozantinib-treated patients, the PFS was significantly longer in patients experiencing TEAEs and in patients aged ≤60 years, and the OS was significantly longer in patients who had TEAEs and in patients with ≥5 TEAEs. Conclusions: Vandetanib and cabozantinib are effective treatment options in the majority of MTC patients. We hypothesize that the poorer prognosis of cabozantinib-treated patients in our retrospective analysis is most likely due to its use as second-line treatment after treatment failure on vandetanib. However, different degrees of efficacy of the two drugs are possible.