Search Results (27)

Medullary thyroid carcinoma (MTC) is a thyroid tumor with neuroendocrine properties purportedly derived from C-cells. The biochemical activity of medullary thyroid carcinoma includes the production of calcitonin and carcinoembryonic antigen, which are sensitive tumor markers, facilitating diagnosis, follow-up, and prognostication. Calcitonin-negative medullary thyroid carcinoma is a rare, poorly understood primary neuroendocrine carcinoma of the thyroid characterized by classic medullary thyroid carcinoma morphology without raised serum calcitonin and with or without the expression of calcitonin detected by immunohistochemistry. Previous studies reported that C-cells were derived from the neural crest; however, more recently, C-cells have been indisputably shown to be derived from the pharyngeal endoderm and ultimobranchial bodies. Ultimobranchial body (UBB) remnants can persist in the thyroid and express p63, but their function is poorly understood. Some have postulated that ultimobranchial bodies may be the “stem” cell of the thyroid and may be precursors for thyroid tumors, particularly mixed tumors with follicular and medullary components. We present a unique case of calcitonin-negative MTC in a 58-year-old male arising in an inflamed and fibrotic thyroid with numerous scattered ultimobranchial body remnants and concomitant C-cell hyperplasia/medullary microcarcinoma (CCH/MMC). The ultimobranchial body remnants, C-cell hyperplasia, and medullary thyroid carcinoma were MTC classifier positive according to ThyroSeq^®. The areas representing CCH/MMC expressed calcitonin by IHC while the main MTC tumor was negative. An additional unique feature was an area demonstrating a “mixed” C-cell/thyroid follicular epithelial phenotype. In this review we review the possible etiologies of calcitonin-negative MTC, the possibility of a neoplastic sequential progression from ultimobranchial bodies to CCH/MMC to medullary thyroid carcinoma with the individual elements (UBB, CCH/MMC, MTC) demonstrated in this thyroid, and previous postulations that ultimobranchial bodies may be the source of some follicular thyroid cancers, medullary thyroid cancers, and mixed tumors of medullary and follicular epithelial types. Full article

The neuropeptide calcitonin gene-related peptide (CGRP), especially α-CGRP, is central in migraine pathophysiology. Although CGRP is a therapeutic target and potential biomarker, inconsistencies in measurement procedures need to be further studied for reliable results. This study aims to analyze factors influencing plasma CGRP measurement. Chronic migraine (CM) patients were recruited in our Headache Unit. Blood samples were collected before and during treatment with CGRP monoclonal antibodies, processed and stored. Levels of CGRP were measured with isoform-specific enzyme-linked immunosorbent assay (ELISA) tests. Statistical tests were used to assess concentration changes and group differences. The addition of protease inhibitors (PIs) to plasma samples significantly increased α-CGRP level detection, with a smaller effect on β-CGRP. No correlation was found between the α- and β-CGRP levels in plasma. The plasma-PI samples showed higher CGRP concentrations than in serum. The α-CGRP levels decreased during treatment while the β-CGRP levels remained stable. α-CGRP and age correlated negatively, but no sex-related differences were observed either for α- or β-CGRP. PI improved CGRP detection in plasma. The α-CGRP levels, which were influenced by age, decreased with specific treatment, suggesting its potential role as a biomarker. In contrast, β-CGRP remained stable, suggesting independent regulation of both isoforms. Full article

Stereotactic body radiation therapy (SBRT) for lung tumors near the chest wall often causes significant chest wall pain (CWP), negatively impacting patients’ quality of life. The mechanisms behind SBRT-induced CWP remain unclear and may involve multiple factors. We investigated crosstalk between radiation-activated osteoclasts and sensory neurons, focusing on osteoclast-derived factors in CWP. Using murine pre-osteoclast cell line Raw264.7, we induced differentiation with Receptor Activator of Nuclear Factor kappa-beta Ligand (RANKL), followed by 10 Gy gamma-irradiation. Conditioned media (C.M) from irradiated osteoclasts was used to treat sensory neuronal cultures from mouse dorsal root ganglia. Neuronal cultures were also exposed to 10 Gy radiation, with and without osteoclast co-culture. Osteoclast markers and pain-associated neuropeptides were analyzed using RT-qPCR and histochemical staining. Osteoclasts differentiation and activity were inhibited using osteoprotegerin (OPG) and risedronate. High-dose radiation significantly increased the size of tartrate-resistant-acid-phosphatase (TRAP)-positive osteoclasts (1.36-fold) and activity biomarkers (Ctsk, 1.35-fold, Mmp9, 1.76-fold). Neurons treated with C.M from irradiated osteoclasts showed ~1.5-fold increase in Calca (calcitonin gene-related peptide) and Tac1 (substance P) expression, which was mitigated by osteoclast inhibitors. These findings suggest that radiation enhances osteoclast activity and promotes pain signaling. Osteoclast inhibitors may represent a therapeutic strategy to reduce CWP and improve quality of life. Full article

Poorly differentiated thyroid malignancy, a rare histological type of aggressive thyroid malignancy with associated difficulties and gaps in its histological and molecular characterization, might lead to challenging clinical presentations that require a prompt multimodal approach. This case study involved a 56-year-old, non-smoking male with a rapidly developing goiter (within 2–3 months) in association with mild, non-specific neck compressive symptoms. His medical history was irrelevant. A voluminous goiter with substernal and posterior extension up to the vertebral bodies was detected using an ultrasound and computed tomography (CT) scan and required emergency thyroidectomy. He had normal thyroid function, as well as negative thyroid autoimmunity and serum calcitonin. The surgery was successful upon “Y” incision, which was used to give better access to the retrosternal component in order to avoid a sternotomy. Post-operatively, the subject developed hypoparathyroidism-related hypocalcemia and showed a very high serum thyroglobulin level (>550 ng/mL). The pathological report confirmed poorly differentiated, multifocal thyroid carcinoma (with an insular, solid, and trabecular pattern) against a background of papillary carcinoma (pT3b, pN0, and pM1; L1; V2; Pn0; R1; and stage IVB). The subject received 200 mCi of radioiodine therapy for 6 weeks following the thoracic surgery. Whole-body scintigraphy was performed before radioiodine therapy and showed increased radiotracer uptake at the thyroid remnants and pre-tracheal levels. Additionally, single-photon emission computed tomography combined with CT (SPECT/CT) was performed, and confirmed the areas of intense uptake, in addition to a moderate uptake in the right and left pulmonary parenchyma, suggesting lung metastasis. To conclude, an overall low level of statistical evidence exists regarding poorly differentiated malignancy in substernal goiters, and the data also remains scarce regarding the impact of genetic and molecular configurations, such as the BRAF-positive profile, in this specific instance. Furthermore, multimodal management includes additional diagnosis methods such as SPECT/CT, while long-term multilayered therapy includes tyrosine kinase inhibitors if the outcome shows an iodine-resistant profile with a poor prognosis. Awareness remains a key factor in cases of a poorly differentiated carcinoma presenting as a rapidly growing goiter with substernal extension in an apparently healthy adult. A surgical approach, while varying with the surgeon’s skills, represents a mandatory step to ensure a better prognosis. In addition to a meticulous histological characterization, genetic/molecular features provide valuable information regarding the outcome and can further help with the decision to use new anti-cancer drugs if tumor response upon radioiodine therapy is no longer achieved; such a development is expected in this disease stage in association with a BRAF-positive configuration. Full article

Background and Objectives: Ultrasound measurement of thyroid volume is not routinely performed in children without suspected thyroid disorders. However, pediatricians must be aware of the normal thyroid volume values in children in order to recognize and treat thyroid disorders in children on time. Therefore, this study aimed to explore factors that influence thyroid volume in children aged 4 to 18 years and to provide descriptive data on thyroid volume across this age range. Materials and Methods: This was a prospective, non-interventional cross-sectional study conducted on a population of children aged 4 to 18 years without confirmed thyroid disorders. We used validated formulas for calculating thyroid volume that integrate the linear dimensions of this organ, such as length, width, and depth, as well as the appropriate correction factor. The Spearman or Pearson correlation coefficient was calculated to assess the relationship between total thyroid volume and various continuous variables, while multiple linear regression analysis was used to evaluate the effect of potential predictors on the total thyroid volume. Results: The study included 100 children, predominantly girls (75.0%). Significant positive correlations with thyroid volume were found for age, height, weight, body mass index (BMI), body surface area, serum creatinine, birthweight, and number of comorbidities, while calcitonin was negatively correlated with children’s thyroid volume. We identified age, BMI, and serum creatinine as significant independent positive predictors of thyroid volume in children. Conclusions: Age, BMI, and serum creatinine emerged as significant independent positive predictors of thyroid volume and should be considered when interpreting pediatric thyroid ultrasound measurements. Full article

Background: Medullary thyroid carcinoma (MTC) is a rare malignancy derived from parafollicular C-cells, with calcitonin (Ct) as its key biomarker. While basal Ct (bCt) levels above 100 pg/mL strongly suggest MTC, intermediate elevations (10–100 pg/mL) may reflect C-cell hyperplasia (CCH) or other benign conditions, making diagnostics challenging. Although calcium stimulation testing enhances sensitivity, the optimal cut-off values and comparative efficacy of calcium gluconate (CG) versus calcium chloride (CC) remain insufficiently researched. Methods: Data on 176 patients who underwent total thyroidectomy between 2009 and 2025 were retrospectively analyzed. BCt values ranged from 10 to 100 pg/mL, and stimulated Ct (sCt) values were above 100 pg/mL. CG was used from 2009 to 2019, and CC was used from 2020 to 2025. Definitive pathohistological findings divided patients into those with MTC, CCH, or no C-cell pathology. Receiver operating characteristic (ROC) analysis identified optimal Ct thresholds for predicting MTC for each stimulatory agent. Results: Of the 176 patients, 36 (20.5%) had confirmed MTC. A bCt threshold of 31.1 pg/mL yielded 69.4% sensitivity and 87.1% specificity. For sCt, optimal cut-offs were 810.8 pg/mL for CG and 1076 pg/mL for CC. Lower thresholds (388.4 pg/mL for CG and 431.5 pg/mL for CC) improved sensitivity (≥76.9%) and negative predictive value (>91%). Conclusions: Calcium stimulation testing improves MTC detection in patients with moderate bCt elevation. Although CG showed marginally better diagnostic performance, CC remains a practical and reliable alternative, especially when higher cut-off values are considered. Early surgical intervention should be considered when sensitivity-driven thresholds are met. Full article

Transient receptor potential melastatin-3 (TRPM3) channels are cation channels activated by heat and chemical ligands. TRPM3 regulates heat sensation, secretion, neurotransmitter release, iris constriction, and tumor promotion. Stimulation of TRPM3 triggers an influx of Ca²⁺ ions into the cells and the initiation of an intracellular signaling cascade. TRPM3 channels are regulated by phosphatidylinositol 4,5-bisphosphate, the βγ subunit of G-protein-coupled receptors, phospholipase C, and calmodulin. Extracellular signal-regulated protein kinase ERK1/2 and c-Jun N-terminal protein kinase (JNK) function as signal transducers. The signaling cascade is negatively regulated by the protein phosphatases MKP-1 and calcineurin and increased concentrations of Zn²⁺. Stimulation of TRPM3 leads to the activation of stimulus-responsive transcription factors controlled by epigenetic regulators. Potential delayed response genes encoding the pro-inflammatory regulators interleukin-8, calcitonin gene-related peptide, and the prostaglandin-synthesizing enzyme prostaglandin endoperoxide synthase-2 have been identified. Elucidating the TRPM3-induced signaling cascade provides insights into how TRPM3 stimulation alters numerous biochemical and physiological parameters within the cell and throughout the organism and offers intervention points for manipulating TRPM3 signaling and function. Full article

Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the use of onabotulinumtoxin A (ONA) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the treatment of PTH. A comprehensive literature search was conducted on PubMed, including studies published up to September 2024, focusing on the efficacy, safety, and mechanisms of onabotulinumtoxin A and anti-CGRP mAbs in PTH. Both clinical trials and observational studies were reviewed. ONA, widely recognized for its efficacy in chronic migraine, has shown limited benefits in PTH with only one trial involving abobotulinumtoxin A in a cohort of 40 subjects. A phase 2 trial with fremanezumab, an anti-CGRP monoclonal antibody, failed to demonstrate significant efficacy in PTH, raising questions about the utility of targeting CGRP in this condition. ONA may offer advantages over anti-CGRP mAbs, not only in terms of its broader mechanism of action but also in cost-effectiveness and higher patient adherence. Both ONA and anti-CGRP mAbs are potential options for the management of PTH, but the current evidence is insufficient to establish clear guidelines. The negative results from the fremanezumab trial suggest that CGRP inhibition may not be sufficient for treating PTH, whereas onabotulinumtoxin A’s ability to target multiple pain pathways may make it a more promising candidate. Full article

Medullary thyroid cancer (MTC) shows a relatively poor prognosis among thyroid cancers. Though calcitonin has been used as a diagnostic marker for MTC, it has disadvantages including poor sample stability and discrepancies among results by assay. This study aimed to compare the usefulness of preoperative calcitonin and procalcitonin (PCT) in the diagnosis of MTC. Serum calcitonin and PCT levels were measured before thyroidectomy from MTC (n = 23) and other types of thyroid cancers in patients (n = 1308). Diagnostic performances of calcitonin and PCT for discerning MTC were estimated. In a multivariate analysis, preoperative calcitonin level was independently associated with the diagnosis of MTC, whereas PCT was not. Calcitonin and PCT, respectively, exhibited area under the curve values of 0.997 and 0.979 for the diagnosis of MTC, without significant differences. For calcitonin, the sensitivity, specificity, and positive and negative predictive values were 0.957, 0.992, 0.688, and 0.999, respectively, at a cut-off of 7.2 pg/mL. The corresponding values for PCT were 0.913, 0.995, 0.778, and 0.998 at a cut-off of 0.19 ng/mL. Preoperative calcitonin and PCT showed similar diagnostic utility for MTC. Depending on the patient’s clinical status and laboratory environment, these tests can be used as complementary methods for detecting MTC. Full article

Subarachnoid hemorrhage (SAH) remains a major cause of cerebrovascular morbidity, eliciting severe headaches and vasospasms that have been shown to inversely correlate with vasodilator calcitonin gene-related peptide (CGRP) levels. Although dura mater trigeminal afferents are an important source of intracranial CGRP, little is known about the effects of SAH on these neurons in preclinical models. The present study evaluated changes in CGRP levels and expression in trigeminal primary afferents innervating the dura mater 72 h after experimentally induced SAH in adult rats. SAH, eliciting marked damage revealed by neurological examination, significantly reduced the density of CGRP-immunoreactive nerve fibers both in the dura mater and the trigeminal caudal nucleus in the medulla but did not affect the total dural nerve fiber density. SAH attenuated ex vivo dural CGRP release by ~40% and in the trigeminal ganglion, reduced both CGRP mRNA levels and the number of highly CGRP-immunoreactive cell bodies. In summary, we provide novel complementary evidence that SAH negatively affects the integrity of the CGRP-expressing rat trigeminal neurons. Reduced CGRP levels suggest likely impaired meningeal neurovascular functions contributing to SAH complications. Further studies are to be performed to reveal the importance of impaired CGRP synthesis and its consequences in central sensory processing. Full article

(1) Background: The wider adoption of a preoperative ultrasound and calcitonin screening complemented by an intraoperative frozen section has increased the number of patients with occult sporadic medullary thyroid cancer (MTC). These advances offer new opportunities to reduce the extent of the initial operations, minimizing operative morbidity and the risk of postoperative thyroxin supplementation without compromising the cure. (2) Methods: This systematic review of the international literature published in the English language provides a comprehensive update on the latest progress made in the risk-adapted surgery for sporadic and hereditary MTC guided by an intraoperative frozen section. (3) Results: The current evidence confirms the viability of a hemithyroidectomy for desmoplasia-negative sporadic MTC. To add an extra safety margin, the hemithyroidectomy may be complemented by a diagnostic ipsilateral central node dissection. Despite the limited extent of the surgery, all the patients with desmoplasia-negative sporadic tumors achieved a biochemical cure with excellent clinical outcomes. A hemithyroidectomy decreases the need for postoperative thyroxine substitution, but a total thyroidectomy may be required for bilateral nodular thyroid disease. Hereditary MTC is a different issue. Because each residual thyroid C cell carries its own risk of malignant progression, a total thyroidectomy remains mandatory for hereditary MTC. (4) Conclusion: In experienced hands, a hemithyroidectomy, which minimizes morbidity without compromising the cure, is an adequate therapy for desmoplasia-negative sporadic MTC. Full article

Hypercalcitoninaemia has been described in patients with pseudohypoparathyroidism (PHP) type 1A and 1B. Elevated calcitonin levels are thought to result from impaired Gsα receptor signaling, leading to multiple hormone resistance. Evidence on the risk of medullary thyroid carcinoma (MTC) or C-cell hyperplasia in PHP patients with hypercalcitoninaemia is lacking. A 43-year-old Caucasian man was referred to our endocrinology clinic for chronic hypocalcemia associated with elevated serum parathormone levels and a single cystic thyroid nodule. The patient did not show skeletal deformities, and screening for concomitant hormone resistances was negative, except for the presence of elevated serum calcitonin levels. The workup led to a molecular diagnosis of sporadic PHP1B. Fine needle aspiration of the thyroid nodule was not diagnostic. The calcium stimulation test yielded an abnormal calcitonin response. Given the scarcity of data on the risk of thyroid malignancy in PHP and calcium stimulation test results, total thyroidectomy was performed. Histological examination revealed cystic papillary thyroid cancer in a background of diffuse C-cell hyperplasia. To our knowledge, we are the first to describe a rare form of thyroid cancer combined with C-cell hyperplasia in a patient with PHP and hypercalcitoninaemia. In the present case, a mere receptor resistance might not fully explain the elevated calcitonin levels, suggesting that hypercalcitoninaemia should be carefully evaluated in PHP patients, especially in the case of concomitant thyroid nodules. Further studies on larger cohorts are needed to elucidate this topic. Full article

Tumor markers (TM) are crucial in the monitoring of cancer treatment. However, inappropriate requests for screening reasons have a high risk of false positive and negative findings, which can lead to patient anxiety and unnecessary follow-up examinations. We aimed to assess the appropriateness of TM testing in outpatient practice in Switzerland. We conducted a retrospective cohort study based on healthcare claims data. Patients who had received at least one out of seven TM tests (CEA, CA19-9, CA125, CA15-3, CA72-4, Calcitonin, or NSE) between 2018 and 2021 were analyzed. Appropriate determinations were defined as a request with a corresponding cancer-related diagnosis or intervention. Appropriateness of TM determination by patient characteristics and prescriber specialty was estimated by using multivariate analyses. A total of 51,395 TM determinations in 36,537 patients were included. An amount of 41.6% of all TM were determined appropriately. General practitioners most often determined TM (44.3%) and had the lowest number of appropriate requests (27.8%). A strong predictor for appropriate determinations were requests by medical oncologists. A remarkable proportion of TM testing was performed inappropriately, particularly in the primary care setting. Our results suggest that a considerable proportion of the population is at risk for various harms associated with misinterpretations of TM test results. Full article

Medullary thyroid cancer (MTC) is a rare neuroendocrine neoplasm, and calcitonin is its main biomarker. An elevated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune–inflammation index (SII) have been considered as negative prognostic factors in several neoplasms. The aim of this study is to evaluate the potential role of NLR, PLR and SII as biomarkers in MTC. Clinical data and tumor histological characteristics of patients with sporadic MTC, referred to the NET Unit of Federico II University of Naples (ENETS CoE) from 2012 to 2022, were retrospectively evaluated by analyzing preoperative and postoperative calcitonin, NLR, PLR and SII. We included 35 MTC patients undergoing total thyroidectomy. The mean preoperative NLR was 2.70 (±1.41, 0.93–7.98), the PLR was 121.05 (±41.9, 40.98–227.23) and SII was 597.92 (±345.58, 186.59–1628). We identified a statistically significant difference between pre- and post-thyroidectomy NLR (p = 0.02), SII (p = 0.02) and calcitonin (p = 0.0) values. No association with prognosis or tumor characteristics emerged. Elevated preoperative NLR and SII suggest a possible disease-associated inflammatory response, and their reduction after surgery may be related to debulking effects. Further studies are needed to define the role of NLR, PLR and SII as prognostic markers in MTC. Full article

An inflammatory response following dental pulp injury and/or infection often leads to neurogenic inflammation via the axon reflex. However, the detailed mechanism underlying the occurrence of the axon reflex in the dental pulp remains unclear. We sought to examine the intracellular cyclic adenosine monophosphate (cAMP) signaling pathway in odontoblasts via the activation of G_s protein-coupled receptors and intercellular trigeminal ganglion (TG) neuron–odontoblast communication following direct mechanical stimulation of TG neurons. Odontoblasts express heterotrimeric G-protein α-subunit Gα_s and calcitonin receptor-like receptors. The application of an adenylyl cyclase (AC) activator and a calcitonin gene-related peptide (CGRP) receptor agonist increased the intracellular cAMP levels ([cAMP]_i) in odontoblasts, which were significantly inhibited by the selective CGRP receptor antagonist and AC inhibitor. Mechanical stimulation of the small-sized CGRP-positive but neurofilament heavy chain-negative TG neurons increased [cAMP]_i in odontoblasts localized near the stimulated neuron. This increase was inhibited by the CGRP receptor antagonist. In the mineralization assay, CGRP impaired the mineralization ability of the odontoblasts, which was reversed by treatment with a CGRP receptor antagonist and AC inhibitor. CGRP establishes an axon reflex in the dental pulp via intercellular communication between TG neurons and odontoblasts. Overall, CGRP and cAMP signaling negatively regulate dentinogenesis as defensive mechanisms. Full article