Calcitonin negative Medullary Thyroid Carcinoma: a challenging diagnosis or a medical dilemma?

BACKGROUND: Medullary thyroid carcinoma is a neuroendocrine tumor belonging form a malignant growth of the thyroid parafollicular C-cells, representing from 1 to 10% of all thyroid cancer. The biochemical activity of medullary thyroid carcinoma includes the production of calcitonin and carcinoembryogenic antigen, which are sensitive tumor markers, facilitating the diagnosis, follow-up and prognostication. The diagnosis is reached through the identification of high basal calcitonin serum level or after pentagastrin stimulation test. Medullary thyroid carcinoma is able to produce other relevant biomarkers as procalcitonin, carcinoembryionic antigen and chromogranin A. In Literature are described few cases of medullary thyroid carcinoma without elevation of serum calcitonin, an extremely rare event. The aim of this study was to analyse the presentation, the main features and therapeutic management of medullary thyroid carcinoma associated with negative serum calcitonin levels. METHODS: Using the PubMed database, a systematic review of the current Literature was carried out, up to February 2018. Finally, nineteen articles met our inclusion criteria and were selected according to the modified Newcastle-Ottawa scale. RESULTS: Fourty-nine patients with definitive pathology confirming medullary thyroid carcinoma and with calcitonin serum level in the normal range were identified (24 female, 24 male and not reported gender in 1 case). Mean age was 51.7 years. Serum calcitonin levels were reported for 20 patients with a mean value of 8.66 pg/mL and a range of 0.8-38 pg/mL. Despite the low or undetectable calcitonin serum level, at immunochemistry in almost the half of the cases reported by the Authors, the tumors presented diffuse or focal positivity for calcitonin and carcinoembryionic antigen, while was reported a chromogranin A positivity in 41 of the 43 tested patients. CONCLUSIONS: Calcitonin negative medullary thyroid carcinoma is an extremely rare pathology. The diagnosis and the surveillance is often challenging and delayed, due to the lack of elevation of serum markers as calcitonin and carcinoembryionic antigen. Further studies are needed, to better define options for management of non secretory medullary thyroid carcinoma and to identify new and reliable biomarkers associated to diagnosis and relapse of this medical dilemma.

Comparing neuronal spike trains with inhomogeneous Poisson distribution: evaluation procedure and experimental application in cases of cyclic activity.

A procedure is proposed to compare single-unit spiking activity elicited in repetitive cycles with an inhomogeneous Poisson process (IPP). Each spike sequence in a cycle is discretized and represented as a point process on a circle. The interspike interval probability density predicted for an IPP is computed on the basis of the experimental firing probability density; differences from the experimental interval distribution are assessed. This procedure was applied to spike trains which were repetitively induced by opening-closing movements of the distal article of a lobster leg. As expected, the density of short interspike intervals, less than 20-40 ms in length, was found to lie greatly below the level predicted for an IPP, reflecting the occurrence of the refractory period. Conversely, longer intervals, ranging from 20-40 to 100-120 ms, were markedly more abundant than expected; this provided evidence for a time window of increased tendency to fire again after a spike. Less consistently, a weak depression of spike generation was observed for longer intervals. A Monte Carlo procedure, implemented for comparison, produced quite similar results, but was slightly less precise and more demanding as concerns computation time.

Fractionated analysis of paired-electrode nerve recordings.

Multi-unit activity recorded from two electrodes positioned at a distance on a nerve may be analysed by cross-correlation, but units similar in direction and velocity of propagation cannot be distinguished and separately evaluated by this method. To overcome this limit, we added two features, represented by the impulse amplitudes of the paired recordings, to the dimension given by the impulse delay. The analysis was fractionated according to the new dimensions. In experimental recordings from the locomotor appendage of the lobster Homarus americanus, the fractionated analysis proved capable of identifying the contributions of single active units, even if these were superimposed and indiscernible in the global cross-correlation histogram. Up to 5 motor and 10 sensory units could be identified. The shape of the paired impulses was evaluated by an averaging procedure. Analogous evaluations on simulated recordings made it possible to estimate the influences exerted on performance by variations in noise level and in the number and firing rate of active units. The global signal could be resolved into single units even under the worst conditions. Accuracy in evaluating the amount of unit activity varied, exceeding 90% in about half of the cases tested; a similar performance was attained by evaluation of the impulse shapes.