Background: Serum calcitonin (sCT) is a useful biomarker for medullary thyroid cancer (MTC). Consensus has not been reached concerning sCT measurements in the evaluation of nodular thyroid disease ...(NTD). Objective and Methods: We developed a new immunofluorometric assay for sCT and have validated it in samples from 794 patients 203 with MTC, 205 with autoimmune thyroid disease (ATD), 248 with NTD, 80 with differentiated thyroid cancer (DTC) ‘free of disease', 58 with chronic renal failure (CRF) and 178 normal individuals, including samples after pentagastrin tests and samples from the washout of 92 FNA procedures in patients with NTD or MTC. We also compared some samples from patients with low or high calcitonin levels using both this assay and the Nichols Institute Diagnostics (NID) assay. Results: The assay's analytical sensitivity was 1.0 pg/ml. Considering MTC patients prior to surgery, the cut-off values for the 95% reference range were 11.1 pg/ml for males and 5.5 pg/ml for females and employing the ROC curve were 18.4 pg/ml for males and 7.8 pg/ml for females. sCT in patients with MTC was strongly correlated with disease status. Patients with NTD and ATD did not present false-positive results. sCT measurements were significantly correlated with age (excluding MTC and CRF). The NID test had a strong correlation with our assay. A hook effect was observed only with concentrations >200,000 pg/ml. Conclusions: We developed a novel sCT assay and validated it in healthy subjects, as well as in a large cohort of patients with MTC, NTD, ATD, DTC, and CRF.
The aim of this study was to prospectively compare the detection rate of
Ga-DOTATATE PET-CT with
In-octreotide SPECT-CT and conventional imaging (CI) in medullary thyroid carcinoma (MTC) patients ...with increased calcitonin (Ctn) levels but negative CI after thyroidectomy.
Fifteen patients with raised Ctn levels and/or CI evidence of recurrence underwent
Ga-DOTATATE PET-CT,
In-octreotide SPECT-CT and CI. Histopathology, CI and biochemical/clinical/imaging follow-up were used as the reference standard. PET/CT, SPECT/CT and CI were compared in a lesion-based and organ-based analysis.
PET/CT evidenced recurrence in 14 of 15 patients. There were 13 true positive (TP), 1 true negative (TN), 1 false positive (FP) and no false negative (FN) cases, resulting in a sensitivity and accuracy of 100% and 93%. SPECT/CT was positive in 6 of 15 cases. There were 6 TP, 2 TN, 7 FN and no FP cases, resulting in a sensitivity of 46% and accuracy of 53%. CI procedures detected tumor lesions in 14 of 15 patients. There were 13 TP, 1TN, 1 FP and no FN cases with a sensitivity of 100% and accuracy of 93%. A significantly higher number of lesions was detected by PET/CT (112 lesions, p = 0.005) and CI (109 lesions, p = 0.005) in comparison to SPECT/CT (16 lesions). There was no significant difference between PET/CT and CI for the total number of detected lesions (p = 0.734). PET/CT detected more lesions than SPECT/CT regardless of the organ. PET/CT detected more bone lesions but missed some neck nodal metastases evidenced by CI. The number of lesions per region demonstrated by PET/CT and CI were similar in the other sites.
Ga-DOTATATE PET/CT is superior to
In-octreotide SPECT/CT for the detection of recurrent MTC demonstrating a significantly higher number of lesions.
Ga-DOTATATE PET/CT showed a superior detection rate compared to CI in demonstrating bone metastases.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Summary
Objective
Reviewing the clinical outcomes of a large kindred with a
RET
p.
G
ly533
C
ys mutation, 10 years after the first description of this kindred, has provided an important set of ...clinical data for healthcare decision‐making.
Design and Patients
We identified 728
RET
533 Brazilian relatives, spread out over 7 generations. We performed clinical examination, biochemical and imaging analyses in the proband and in 103 carriers.
Measurement and Results
The proband has been followed without evidence of structural disease in the last 10 years but with elevated calcitonin. The clinical and surgical features of 60 thyroidectomized
RET
533 relatives were also described. Forty‐six patients had
MTC
(21–72 years), and 11 patients had
C
‐cell hyperplasia (
CCH
) (5–42 years). Twelve
MTC
patients with lymph node metastases had a tumour size of 0·7–2·8 cm. Calcitonin level and
CEA
were correlated with disease stage, and none of the patients presented with an altered
PTH
or metanephrine. A 63‐year‐old woman developed pheochromocytoma and breast cancer. Two other
RET
533 relatives developed lung squamous cell carcinoma and melanoma.
Conclusions
A vast clinical variability in
RET
533 presentation was observed, ranging from only an elevated calcitonin level (3%) to local metastatic disease (25%). Many individuals were cured (42%) and the majority had controlled chronic disease (56%), reinforcing the need for individualized ongoing risk stratification assessment. The importance of this update relies on the fact that it allows us to delineate the natural history of
RET
533
MEN
2
A
10 years after its first description.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The hereditary form of medullary thyroid carcinoma may occur isolated as a familial medullary thyroid carcinoma (FMTC) or as part of Multiple Endocrine Neoplasia 2A (MEN2A) and 2B (MEN2B). MEN2B is a ...rare syndrome, its phenotype may usually, but not always, be noted by the physician. In the infant none of the MEN2B characteristics are present, except by early gastrointestinal dysfunction caused by intestinal neuromas. When available, genetic analysis confirms the diagnosis and guides pre-operative evaluation and extent of surgery. Here we report four cases of MEN2B in which the late diagnosis had a significant impact in clinical evolution and, potentially, in overall survival.
We report four cases, 2 men and 2 women, with differences in their phenotypes and with a late diagnosis. The first case has a history of severe gastrointestinal obstruction requiring a surgery intervention two days after his birth. The second told had nodules in the oral mucosa and constipation since childhood. The third case referred a history of constipation from birth until 5 months of life. The fourth has had a history of chronic constipation since childhood.
New concepts have emerged since the RET oncogene was identified in 1993 as the responsible gene for hereditary medullary thyroid carcinoma. The majority of MEN2B individuals have M918T mutation in the exon 16 of RET, with a few cases having a mutation A883F or the association of V804M with E805K, Y806C or S904C mutations. The consensus classifies the RET mutation in codon 918 as of highest risk and recommends total thyroidectomy and central lymph node dissection until 6 months after birth. A fast and precise diagnosis is essential to reach these goals. The identification of early manifestations such as intestinal ganglioneuromatosis and oral mucosal neuromas should prompt the physician to initiate an investigation for multiple endocrine neoplasia type 2B.
The diagnosis of MEN2B is very important to allow appropriate investigation of associated diseases and to allow counseling and appropriate screening of relatives for a RET mutation. Even patients with MEN2B, which often have typical physical features, may not be properly recognized and be followed as a sporadic case. Based on this, all suspicious cases of multiple endocrine neoplasia should undergo a molecular genetic test.
Calcitonin and carcinoembryonic antigen (CEA) doubling times are established prognostic markers in medullary thyroid cancer (MTC). On the other hand,
F-fluorodeoxyglucose (FDG) positron emission ...tomography/computed tomography (PET/CT) shows an increased rate of detection with high blood tumor marker levels in several cancers. This study aimed to analyze the ability of
F-FDG PET/CT to determine prognosis in the follow-up of patients with MTC.
Medical records of 17 patients with MTC who underwent
F-FDG PET/CT were analyzed retrospectively. All patients were classified into two groups: stable disease or progressive disease.
Eight patients presented with progressive disease, and all of them showed
F-FDG uptake (100%), compared to only 3 of 9 patients who presented in stable condition (33%).
F-FDG PET/CT results were able to distinguish progressive from stable disease (P = .009). Calcitonin levels >4,020 pg/mL (P = .0004), CEA levels >26.8 ng/mL (P = .04), and a calcitonin doubling time <24.1 months (P = .015) were associated with progressive disease in our cohort. The proportion of variance explained that predicted progressive disease was 32% for
F-FDG uptake, 27.1% for a calcitonin doubling time of 24.1 months, and 41.2% for doubling time plus
F-FDG PET/CT.
F-FDG uptake was able to distinguish progressive from stable disease. However, this tool should not replace the validated calcitonin doubling time, but rather the combination of information could improve the clinical re-assessment and better identify high-risk patients who require more careful surveillance.
CEA = carcinoembryonic antigen CT = computed tomography
F-FDG =
F-fluorodeoxyglucose MTC = medullary thyroid cancer PET = positron emission tomography PVE = proportion of variance explained sCT = serum calcitonin SUV = standard uptake value US = ultrasound.
RET
sequencing has become an important tool in medullary thyroid cancer (MTC) evaluation and should be performed even in the absence of family history of MTC. The most commonly studied exons in index ...cases are 8, 10, 11, and 13–16. To address the ATA guidelines regarding the sequencing of the entire coding region of
RET
, we selected 50 patients with sporadic MTC (sMTC) without mutations in the hot spot regions of
RET
for extended investigation of exons 1–7, 9, 12, 17, 18, and 19. Twenty-seven of 50 patients presented with one or more features suggesting familial disease. We found only a new
RET
variant (p.Gly550Glu) in one patient with MTC. Several polymorphisms were observed, and their frequency was histogram scaled by exons and introns. Eight patients were also included for somatic mutation search. We estimated the sequencing cost by stratifying into four investigation approaches: (1) hot spot exons in a new patient, (2) the remaining exons if the hot spots are negative in a patient with suspected familial disease, (3) a relative of a carrier for a known
RET
mutation, and (4) tumor sequencing. In spite of the increasing number of variants being described in MTC, it appears that there is no direct clinical benefit in extending
RET
germ line analysis beyond the hot spot regions in sMTC. The cost evaluation in apparent sMTC using a tiered approach may help clinicians make more suitable decisions regarding the benefits of investigating only the hot spots against the entire coding region of
RET
.
The widespread use of neck ultrasonography (US) during the follow-up of patients with papillary thyroid carcinoma (PTC) has led to the discovery of small cervical lymph nodes (LN). Although US has a ...high sensitivity for diagnosing LN, fine needle aspiration biopsy (FNA) and measurement of thyroglobulin in fine needle aspirates (FNA-Tg) have proven to be invaluable tools. The aim of this study is to determine the sensitivity of the combined use of neck US, FNA biopsy and FNA-Tg for diagnosis of cervical lymph nodes. We have studied 32 patients with 44 LN detected by US, 19 classified as inflammatory and 25 as suspicious. 15 of those 25 suspicious LN had high FNA-Tg (13 of the 15 had positive cytology and 2 indeterminate). All of these 15 LN (11 patients) were proven to be PTC metastasis by histopathology. All 19 inflammatory LN and those 10/25 suspicious LN, had cytology negative for malignancy and undetectable FNA-Tg. We conclude that fine needle aspiration biopsy and FNA-Tg combined with neck US are essential for detecting positive cervical lymph nodes due to its high sensitivity and specificity and it should be considered the standard for investigating locally recurrent disease in patients with PTC.
The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic ...regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS.
The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (
= 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment.
Galantamine treatment significantly increased antioxidant enzyme activities, including SOD +1.65 USOD/mg protein, 95% CI 0.39-2.92,
= 0.004 and CAT +0.93 nmol/mg, 95% CI 0.34-1.51,
= 0.01, decreased lipid peroxidation thiobarbituric acid reactive substances log scale 0.72 pmol/mg, 95% CI 0.46-1.07,
= 0.05, and systemic nitrite levels log scale 0.83 μmol/mg protein, 95% CI 0.57-1.20,
= 0.04 compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment.
Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.
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