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Background: Conceptually, thyroid tumor desmoplasia may be better suited for excluding node metastases in sporadic MTC than preoperative serum calcitonin levels. Methods: This analysis included 181 patients with unilateral sporadic MTC graded on the 7‐grade desmoplasia scale after thyroidectomy and neck dissection. Results: When thyroid tumor desmoplasia reached 1% and ≥50%, node metastases increased from 0% to 7% (median of 0 metastases) and 83% (median of 7.5 metastases), microscopic lymphatic invasion from 0% to 3% and 35%, extrathyroid extension from 0% to 5% and 22%, and extranodal growth from 0% to 0% and 44%, whereas biochemical cure declined from 100% to 95% and 25%. Thyroid tumor diameters and basal calcitonin overlapped widely among the seven desmoplasia groups, precluding differentiation by thyroid tumor size or serum calcitonin levels. Conclusions: Thyroid tumor desmoplasia, unlike serum calcitonin levels, discriminates extremely well between node‐negative and node‐positive sporadic MTC, opening new avenues for precision surgery. [ABSTRACT FROM AUTHOR]

This review aimed to describe the inculpation of microRNAs (miRNAs) in thyroid cancer (TC) and its subtypes, mainly medullary thyroid carcinoma (MTC), and to outline web-based tools and databases for bioinformatics analysis of miRNAs in TC. Additionally, the capacity of miRNAs to serve as therapeutic targets and biomarkers in TC management will be discussed. This review is based on a literature search of relevant articles on the role of miRNAs in TC and its subtypes, mainly MTC. Additionally, web-based tools and databases for bioinformatics analysis of miRNAs in TC were identified and described. MiRNAs can perform as oncomiRs or antioncoges, relying on the target mRNAs they regulate. MiRNA replacement therapy using miRNA mimics or antimiRs that aim to suppress the function of certain miRNAs can be applied to correct miRNAs aberrantly expressed in diseases, particularly in cancer. MiRNAs are involved in the modulation of fundamental pathways related to cancer, resembling cell cycle checkpoints and DNA repair pathways. MiRNAs are also rather stable and can reliably be detected in different types of biological materials, rendering them favorable diagnosis and prognosis biomarkers as well. MiRNAs have emerged as promising tools for evaluating medical outcomes in TC and as possible therapeutic targets. The contribution of miRNAs in thyroid cancer, particularly MTC, is an active area of research, and the utility of web applications and databases for the biological data analysis of miRNAs in TC is becoming increasingly important. [ABSTRACT FROM AUTHOR]

Context Medullary thyroid cancer (MTC) has a historic recurrence rate up to 50%, and surgery remains the only cure. Objective This study aims to assess factors related to recurrence and metastatic spread in MTC. Methods Retrospective chart review was performed from 1990 to 2023 at a single specialized tertiary care referral center. Descriptive analysis and regression models were used for analysis. Sixty-eight patients with MTC, who underwent surgery, were included and the main outcome measure was recurrence. Results Mean age at diagnosis was 54.9 years (42.2-64.1), 65% (n = 44) females. Lymph node and distant metastases were found in 24% (n = 16) and 4% (n = 3), respectively. RET mutations were present in 52% (n = 35): MTC risk levels were highest 6%, high 7%, and moderate 39%. Mean tumor size was 1.9 cm (1.2-3.2) and mean preoperative calcitonin was 504.4 pg/mL (133.2-1833.8). Total thyroidectomy (TT) was performed in 10 patients, TT + central neck dissection (CND) in 28, and TT + CND + lateral neck dissection (LND) in 25. On final pathology, 40% had positive central nodes and 25% had positive lateral nodes. Recurrence was 22%, median follow-up 4.7 years (1.2-28.0). Male gender (hazard ratio [HR] 5.81, P =.021), positive lateral neck nodes (HR 8.10, P =.011), and high/highest MTC risk level RET mutations (HR 8.66, P =.004) were significantly associated with recurrence. Preoperative calcitonin >2175 pg/mL was a strong predictor for distant metastasis (area under the curve [AUC] 0.893) and a good predictor for lateral neck disease (AUC 0.706). Extent of surgery was not significantly associated with recurrence (P =.634). Conclusion One of 4 patients undergoing surgery for MTC will recur. Risk factors associated with recurrence are male gender, lateral lymph node metastasis, and high/highest MTC risk level mutations, but not necessarily surgery type. Preoperative calcitonin >2175 pg/mL is suggestive of advanced disease and should prompt further evaluation. [ABSTRACT FROM AUTHOR]

Context Medullary thyroid cancer (MTC) often exhibits aggressive growth with distant organ metastasis, leading to poor survival. Objective The question of whether primary tumor resection (PTR) is beneficial for patients with metastatic MTC remains a subject of debate. In this study, we evaluated the prognostic significance of organ-specific metastases and the number of metastatic organs in these patients, and we also conducted an analysis to determine the therapeutic value of PTR in managing this rare malignancy. Materials and Methods Patients initially diagnosed with metastatic MTC were identified within the Surveillance, Epidemiology, and End Results database. Univariable and multivariable Cox proportional hazards regression models were performed to identify survival predictors. Survival outcomes were calculated using the Kaplan-Meier method and compared using the log-rank tests. Results A total of 186 patients with metastatic MTC at initial diagnosis from 2010 to 2020 were included. Bone, lung, and liver were the most common metastatic organs. Patients with brain metastasis had significantly worse overall survival (P =.007) and cancer-specific survival (P =.0013). Among all patients, 105 (56.45%) underwent PTR, and this group showed reduced overall mortality and cancer-specific mortality (all P <.05). When analyzing different metastatic patterns, PTR significantly lowered the risk of overall mortality and cancer-specific mortality for patients with bone, lung, liver, or distant lymph node involvement (all P <.05). Additionally, among patients with 1 or 2 metastases, those undergoing surgical resection were significantly associated with favorable overall survival (P =.008) and cancer-specific survival (P =.0247). Conclusion PTR may confer therapeutic benefits for carefully selected individuals with metastatic MTCs. To integrate these insights into clinical decision-making settings, it is imperative to undertake multicenter prospective studies in the future. [ABSTRACT FROM AUTHOR]

Aim: Tumor markers often remain elevated after intended curative resection of medullary thyroid carcinoma (MTC). The aim of this study was to determine the expression of αvβ3, a promising theranostics target, in MTC and its metastases. Materials & methods: Avβ3 expression was analyzed in 104 patients using a tissue microarray and correlated with clinicopathological variables and survival. Results: Cytoplasmic αvβ3 positivity was seen in 70 patients and was associated with lymph node metastases at time of initial surgery. Membranous positivity was considered positive in 30 patients and was associated with sporadic MTC. Conclusion: Avβ3 was expressed in the cytoplasm of 67% of MTC patients. Membranous expression, which is presumably most relevant for the theranostic use of αvβ3, was seen in 29%. Article highlights After intended curative resection of medullary thyroid carcinoma (MTC), calcitonin levels often remain elevated indicating remnant disease or metastasis. There is a demand for new imaging and therapeutic options for patients with MTC. Avβ3, an integrin expressed in many tumors, is a promising target for nuclear imaging and treatment using radiolabeled arginine-glycine-aspartic acid (RGD). Cytoplasmic and membranous αvβ3 expression was analyzed using a tissue microarray including primary tumors and lymph node metastases of 104 and 27 patients, respectively. Cytoplasmic expression was considered positive in 67% of patients and was associated with lymph node metastases at the time of initial surgery. Membranous expression, which is thought to be most relevant for the theranostic use of αvβ, was seen in 29% of patients and was associated with sporadic MTC. Survival analysis showed no prognostic value of αvβ3. The correlation of immunohistochemical αvβ3 expression and uptake of radiolabeled RGD should be further assessed in patients with membranous αvβ3 expression. [ABSTRACT FROM AUTHOR]

Carcinoembryonic antigen (CEA) and calcitonin (Ctn) are pivotal biomarkers in the diagnosis and management of medullary thyroid carcinoma (MTC). However, their diagnostic reliability in perioperative period remains a topic of ongoing debate. This review synthesizes researches on perioperative fluctuations in CEA and Ctn levels, and evaluates the impact of their different combinations on MTC diagnosis, treatment decisions, and prognosis. Our findings highlight it is crucial to understand and interpret the various combinations of CEA and Ctn fluctuations within a clinical context. Furthermore, to reduce diagnostic errors and improve patient outcomes, we recommend follow-up diagnostic and treatment protocols designed to address the potential pitfalls associated with the use of these biomarkers. [ABSTRACT FROM AUTHOR]

Medullary Thyroid Carcinoma (MTC), a neuroendocrine malignancy that arises from the calcitonin-secreting parafollicular C-cells of the thyroid, constitutes a minor yet impactful fraction of thyroid malignancies. Distinguished by its propensity for aggressive growth and a pronounced tendency for metastasis, MTC poses formidable obstacles to the early diagnosis and therapeutic intervention. The molecular genetics of MTC, particularly the role of the RET gene and the RAS gene family, have been extensively studied, offering insights into the pathogenesis of the disease and revealing potential therapeutic targets. This comprehensive review synthesizes the latest advancements in the molecular genetics of MTC, the evolution of precision therapies, and the identification of novel biomarkers. We also discuss the implications of these findings for clinical practice and the future direction of MTC research. [ABSTRACT FROM AUTHOR]

Background: The co‐occurrence of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) is thought to be a rare phenomenon. Here, we present a patient undergoing surgery due to a suspected MTC. Histopathological workup confirmed the suspected diagnosis but also described an incidental PTC in the contralateral lobe with lymph node metastasis in the central cervical compartment. Case Presentation: A 58‐year‐old female presented with thyroid nodules and significantly elevated levels of calcitonin and carcinoembryonic antigen (CEA). She underwent total thyroidectomy along with central and bilateral lymph node dissection. Histology revealed a MTC of 20 mm and a BRAF V600E‐positive PTC of 11 mm with central cervical lymph node metastasis. Postoperatively, ablative radioiodine therapy was performed. Two months later, both calcitonin and CEA were normalized. Conclusion: Simultaneous occurrence of MTC and PTC seems to be rare, but recent literature suggests that simultaneous occurrence is probably more frequent than initially thought. Preoperative calcitonin can be helpful in the diagnostic workup of thyroid nodules. Due to different treatment strategies, precise histological differentiation of potential lymph node metastasis is essential. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid carcinoma (MTC) is a rare but aggressive form of thyroid cancer accounting for over 10% of deaths related to thyroid malignancies. MTC can be either hereditary or sporadic. Although it can be cured if it is detected early and completely removed, most patients with MTC are diagnosed when the cancer has already spread beyond the thyroid gland, making it difficult to treat. Managing MTC is complex, despite the availability of newer treatment options like targeted therapy, which works in less than 30% of cases and can lead to severe side effects in some patients. MTC behaves differently in each patient, making the selection of appropriate treatments challenging, even for multidisciplinary teams of experts. This article aims to describe the challenges faced during the diagnostic workup and management of MTC patients. It highlights how holomics, which is an integrated approach combining various biological data types, and artificial intelligence (AI) can assist in improving patient outcomes. By simultaneously analyzing and integrating findings from biochemical, radiological, and histological investigations, genetic studies, and other sources, along with the personal information of a patient, AI can enhance decision-making processes. This innovative approach has the potential to personalize and optimize treatment strategies, leading to better management and improved outcomes for patients with MTC. Background/Objective: Medullary thyroid carcinoma (MTC) is a rare yet aggressive form of thyroid cancer comprising a disproportionate share of thyroid cancer-related mortalities, despite its low prevalence. MTC differs from other differentiated thyroid malignancies due to its heterogeneous nature, presenting complexities in both hereditary and sporadic cases. Traditional management guidelines, which are designed primarily for papillary thyroid carcinoma (PTC), fall short in providing the individualized care required for patients with MTC. In recent years, the sheer volume of data generated from clinical evaluations, radiological imaging, pathological assessments, genetic mutations, and immunological profiles has made it humanly impossible for clinicians to simultaneously analyze and integrate these diverse data streams effectively. This data deluge necessitates the adoption of advanced technologies to assist in decision-making processes. Holomics, which is an integrated approach that combines various omics technologies, along with artificial intelligence (AI), emerges as a powerful solution to address these challenges. Methods: This article reviews how AI-driven precision oncology can enhance the diagnostic workup, staging, risk stratification, management, and follow-up care of patients with MTC by processing vast amounts of complex data quickly and accurately. Articles published in English language and indexed in Pubmed were searched. Results: AI algorithms can identify patterns and correlations that may not be apparent to human clinicians, thereby improving the precision of personalized treatment plans. Moreover, the implementation of AI in the management of MTC enables the collation and synthesis of clinical experiences from across the globe, facilitating a more comprehensive understanding of the disease and its treatment outcomes. Conclusions: The integration of holomics and AI in the management of patients with MTC represents a significant advancement in precision oncology. This innovative approach not only addresses the complexities of a rare and aggressive disease but also paves the way for global collaboration and equitable healthcare solutions, ultimately transforming the landscape of treatment and care of patients with MTC. By leveraging AI and holomics, we can strive toward making personalized healthcare accessible to every individual, regardless of their economic status, thereby improving overall survival rates and quality of life for MTC patients worldwide. This global approach aligns with the United Nations Sustainable Development Goal 3, which aims to ensure healthy lives and promote well-being at all ages. [ABSTRACT FROM AUTHOR]

Background Aims Study design Results Conclusions Relevance to Clinical Practice Pheochromocytoma can occur in patients with multiple endocrine neoplasia type 2, placing them at increased risk of tumour recurrence after surgical resection. Therefore, management of pheochromocytoma in these patients is a clinical challenge.We aim to present and discuss the nursing management of patient with recurrent pheochromocytoma.Case studies. We reviewed and retrieved the necessary information from the medical records.A 34‐year‐old female with a history of medullary thyroid carcinoma and pheochromocytoma complicated by cardiomyopathy, who had undergone surgical resections 6 years ago, presented with abdominal pain for 1 day and was diagnosed with recurrent bilateral pheochromocytoma, hypertensive crisis, acute heart failure, and acute renal failure. Eight hours after hospital admission, she experienced sudden cardiac arrest and received cardiopulmonary resuscitations. She was then supported under extracorporeal membrane oxygenation and continuous renal replacement therapy (CRRT). The adrenal tumour was successfully treated with absolute ethanol ablation followed by gelatin sponge particle embolization, a management approach which has not been reported previously. She had a satisfactory recovery.A comprehensive nursing management approach, including prone ventilation; safe transportation; close cardiopulmonary monitoring; pre‐, intra‐ and post‐procedure care; individualized early rehabilitation; and psychological supports, should be applied to improve the prognoses in patients with similar medical conditions.Bilateral adrenal pheochromocytoma can be managed by absolute ethanol ablation followed by gelatin sponge particle embolization. Comprehensive nursing management, including a team effort regarding patient positioning, transportation, close monitoring, early rehabilitation and psychological support, should be provided during the peri‐procedure period. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the expression of programmed cell death protein-1 (PD-1) and its ligand (PD-L1) immune checkpoint molecules in thyroid carcinomas and determine their association with the clinicopathological characteristics of patients. Thyroid tissue specimens from 100 patients diagnosed with primary thyroid carcinomas including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC) were collected. Sections were prepared from formalin-fixed paraffin-embedded samples, and PD-1 and PD-L1 expressions were examined using immunohistochemistry. PD-1 was detected in tumor-infiltrating lymphocytes (TILs) in 88% of the patients and tumor cells in 28% of the patients with 10% in PTC, 5% in FTC, 5% in MTC, and 8% in ATC). PD-L1 was found in tumor cells and TILs in 30% and 79% of the patients, respectively. Moreover, a significant difference was observed in PD-1 and PD-L1 expression between tumor cells and TILs across different tumor types. However, their expression in tumor cells and TILs was significantly higher in ATC compared to other tumor types. Additionally, the expression of PD-1 and PD-L1 was significantly associated with an advanced stage, higher tumor size, tumor necrosis, and mitosis. A significant positive correlation was also observed between the expression of PD-1 and PD-L1 in tumor cells and TILs. The higher expression of PD-1 and PD-L1 may contribute to tumor progression. Therefore, combinational immunotherapy by these immune checkpoint inhibitors might be a promising strategy for clinical improvement in patients with thyroid cancer, especially those with ATC. [ABSTRACT FROM AUTHOR]

Simple Summary: Routine measurement of basal calcitonin (bCt) levels is used in the preoperative workup of thyroid nodules ("Ct screening") and has been documented to facilitate the early diagnosis and treatment of patients with medullary thyroid cancer (MTC). Although clear cut-offs have been proposed, the relevance for predicting lymph node metastasis (LNM) and long-term outcomes (LOs) has so far not been tested on a large cohort of patients. In this study, 306 patients with MTC were grouped into three oncologic risk groups by clearly defined gender- and assay-specific bCt cutoffs. The rate of central LNM was 2.6% in risk Group 1 (minimal oncologic risk; recently published MTC incidence: females: 17.1%; males: 37.5%) and 6.0% in Group 2 (low oncologic risk: recently published MTC incidence 100%). Lateral LNM and distant metastasis (DMet) were not found. The overall cure rate for both groups was 95.7% and 20-year disease-specific survival (DSS) was 100%. In risk Group 3 (high oncologic risk) LNMs were found in 51.0% (thereof 88.9% also in the lateral neck compartment) and DMet in 13.5%. The cure rate dropped to 58.3% and DSS to 85.3%. Within a Ct screening program, grouping patients upon pretherapeutic bCt provides a simple risk classification system for indicating surgery and its extent, predicting LNM, and estimating LOs. 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. [ABSTRACT FROM AUTHOR]

In ACTH-dependent Cushing syndrome, identifying the source of ACTH can be challenging. A 23-year-old male presented with Cushingoid symptoms and signs to other clinics. Laboratory tests confirmed ACTH-dependent Cushing's syndrome. Imaging revealed a suspicious adenoma in the pituitary, a hypoechoic nodule in the thyroid, and pathological-appearing lymph nodes in the neck. Following a fine needle aspiration cytological examination, medullary thyroid carcinoma was diagnosed. A total thyroidectomy and lymph node dissection were subsequently performed. The pathology report confirmed medullary thyroid carcinoma. When the patient was admitted to our hospital, disease recurrence was considered, and lymph node ACTH washout was performed as an unusual method to identify the source of ACTH. The washout sample yielded a very high value of 958 pg/mL. We describe a patient who was hospitalized with severe symptoms of Cushing's syndrome resulting from medullary thyroid cancer. We employed a novel method involving lymph node ACTH washout to identify the source of ACTH production. Lymph node ACTH washout can be an effective diagnostic option to determine the origin of ACTH. [ABSTRACT FROM AUTHOR]

Context Multikinase inhibitors (MKIs) improve the treatment of refractory thyroid cancer, including radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and advanced medullary thyroid carcinoma (aMTC). Objective This study aims to compare the efficacy of MKIs in improving survival outcomes and safety. Data Sources Comprehensive database searches of MEDLINE via PubMed, EMBASE, and Cochrane were performed from inception to December 2023. Study Selection Three independent authors selected these studies. Randomized controlled trials that compared the use of a MKI to other MKIs or placebo were included. Data Extraction and Synthesis This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Risk of bias was analyzed using the Cochrane risk of bias 2 tool. Bayesian network meta-analysis was performed. Treatments were grouped into common nodes based on the type of MKI. Main Outcomes and Measures Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate, disease control rate, clinical benefit rate, and adverse events. Results Cabozantinib 60 mg/day (CAB60) was associated with the highest prolonged PFS in RAIR-DTC patients, followed by lentivatinib 18 or 24 mg/day (LEN18 or LEN24), and apatinib. PFS was also improved in aMTC patients who received CAB 140 mg/day (CAB140), CAB60, or anlotinib. A significantly greater improvement on the performance of OS was seen in CAB60, LEN24, anlotinib, and sorafenib in RAIR-DTC patients, but in aMTC patients there were lack of statistical differences. Compared with the low-dose MKIs, high-dose MKIs such as CAB, LEN, and vandetanib increased the incidence of adverse events. Conclusion CAB60, LEN, and apatinib are promising topical MKIs with statistically significant primary outcomes in RAIR-DTC patients, while CAB and anlotinib are effective in prolonging PFS in aMTC patients. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1–2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15–20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10–40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects. [ABSTRACT FROM AUTHOR]

ABSTRACT Medullary thyroid carcinoma (MTC) is an uncommon neuroendocrine tumour that is usually asymptomatic at its onset and therefore may not present clinically until the patient has developed advanced or metastatic disease. Common metastatic sites include cervical lymph nodes, liver, bone and lung. This is the case of a patient who presented with an incidental posterior mediastinal mass. Because the posterior mediastinum is an unusual location for MTC, MTC was not a consideration and preliminary histopathological testing did not include calcitonin, which would have been diagnostic. This case highlights the importance of testing for calcitonin more regularly when encountering a mass of unknown origin with neuroendocrine morphology, which may lead to earlier detection of MTC and thus improved prognosis. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is a major health problem that still causes many deaths worldwide. Neuropeptides, such as substance P and calcitonin gene-related peptide, play the neurotransmitter and neurohormone roles that increase tumor invasiveness and metastasis potential. This study aimed to see whether these neuropeptides and their receptors—neurokinin 1 receptor and calcitonin receptor-like receptor—correlate with the diagnosis stage, tumor differentiation grade, and different patient characteristics in colorectal cancer and also to compare them. Methods: We performed serum analyses of substance P and CGRP levels in patients with colorectal cancer and also the immunohistochemical analysis of their receptors in colorectal tumors and then correlated them with the disease stage and with different tumor characteristics. Results: We demonstrated that both substance P and calcitonin gene-related peptide had increased levels in colorectal cancer and that their levels correlated with the stage of the disease and with the tumor differentiation grade. We also demonstrated the correlation of NK-1R and CRLR higher immunohistochemical scores with advanced and poorly differentiated tumors. Conclusions: This study demonstrates that the neuropeptides SP and CGRP and their receptors NK-1R and CRLR could play a role in the pathogenesis of colorectal cancer, and they could be used as diagnostic and prognostic markers and could represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas. Thus, the inhibition of p90RSK restores p53 expression, which in turn inhibits cell proliferation and promotes apoptosis. In the present study, we demonstrated that the p90RSK/MDM2/p53 pathway proved to be an excellent target in the therapy of tumors with MAPK hyperactivation. For this purpose, we selected p53wt melanoma, lung and medullary thyroid carcinoma cell lines with high activation of p90RSK. In these cell lines, we demonstrated that the p90RSK/MDM2/p53 pathway is implicated in the regulation of the cell cycle and apoptosis through p53-dependent transcriptional control of p21 and Bcl-2. Furthermore, with an immunohistochemical evaluation of primary melanomas and lung tumors, which exhibit highly activated p90RSK compared to corresponding normal tissue, we demonstrated that MDM2 stabilization was associated with p90RSK phosphorylation. The results indicate that p90RSK is able to control the proliferative rate and induction of apoptosis through the regulation of p53wt levels by stabilizing MDM2 in selected tumors with constitutively activated MAPKs, making p90RSK a new attractive target for anticancer therapy. [ABSTRACT FROM AUTHOR]

We aimed to provide an updated narrative review with respect to the RET pathogenic variants and their implications at the clinical and molecular level in the diagnosis of medullary thyroid cancer (MTC)/multiple endocrine neoplasia (MEN) type 2, particularly with respect to the presence of cutaneous lichen amyloidosis (CLA). We searched English-language, in extenso original articles with no timeline nor study design restriction that were published on PubMed. A traditional interplay stands for CLA and MTC in MEN2 (not MEN3) confirmation. While the connection has been reported for more than three decades, there is still a large gap in understanding and addressing it. The majority of patients with MEN2A-CLA have RET pathogenic variants at codon 634; hence, it suggests an involvement of this specific cysteine residue in both disorders (most data agree that one-third of C634-positive subjects have CLA, but the ranges are between 9% and 50%). Females seem more prone to MEN2-CLA than males. Non-C634 germline RET pathogenic variants included (at a low level of statistical evidence) the following: RET V804M mutation in exon 14 for MTC-CLA (CLA at upper back); RET S891A mutation in exon 15 binding OSMR variant G513D (familial MTC and CLA comprising the lower legs to thighs, upper back, shoulders, arms, and forearms); and C611Y (CLA at interscapular region), respectively. Typically, CLA is detected at an early age (from childhood until young adulthood) before the actual MTC identification unless RET screening protocols are already applied. The time frame between CLA diagnosis and the identification of RET pathogenic variants was between 5 and 60 years according to one study. The same RET mutation in one family is not necessarily associated with the same CLA presentation. In MTC/MEN2 subjects, the most affected CLA area was the scapular region of the upper back. Alternatively, another hypothesis highlighted the fact that CLA is secondary to long-term prurit/notalgia paresthetica (NP) in MTC/MEN2. OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases. [ABSTRACT FROM AUTHOR]

Purpose: The survival rate of patients with medullary thyroid carcinoma (MTC) who fail to achieve a biochemical cure after surgery is reduced. This study aimed to investigate the prognostic factors affecting the survival of MTC patients who do not achieve a biochemical cure after surgery. Methods: Cox univariate and multivariate proportional hazard models were used to determine the influence of different variables on overall survival (OS). Pearson's chi-square test was used for categorical variables, and paired t-test was used for continuous variables. Results: In our study of 277 MTC patients treated between 2012 and 2022, there were 96 with raised postoperative 1-month calcitonin (Ct) levels (0–9.52 pg/ml). The overall survival (OS) rates of patients with high postoperative 1-month Ct values at 1, 3, and 5 years were 97.9%, 94.6%, and 86.8%, respectively. The univariate analysis revealed that patients with a postoperative 1-month Ct > 441.9 pg/ml had a greater risk of mortality than patients with postoperative 1-month Ct values ranging from 9.52 to 73.4 pg/ml (p = 0.043). Subsequent analyses revealed that receiving targeted therapy did not improve the OS of patients with distant metastasis among those with high postoperative 1-month Ct values (p = 0.527). Conclusion: This study confirmed that MTC patients who did not achieve biochemical remission after surgery had an increased risk of death when the Ct level was > 441.9 pg/ml 1 month after surgery. Additionally, for MTC patients who have not achieved biochemical remission and have experienced disease progression or distant metastasis after surgery, the use of targeted therapy does not prolong survival. [ABSTRACT FROM AUTHOR]

Background: The necessity and therapeutic value of lymph node dissection (LND) in early stage T1 MTC patients remain controversial. Methods: Patients with T1MTC were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Poisson regression analysis was utilized to investigate promotive factors for lymph node metastasis in T1MTC patients. Fisher's exact test was employed to calculate baseline differences between non-LND and LND groups. Propensity score match (PSM) was used to control baseline bias. Survival outcomes were calculated by KaplanMeier method and log-rank test. Multivariable Cox regression assessed the prognostic impact of LND across subgroups. Results: Of 3298 MTC cases, 50.4% were T1MTC. The lymph node metastasis rate increased along with the T stage (from 22.2% to 90.5%). Among 1231 T1MTC patients included after exclusion criteria, 72.0% underwent LND and 22.0% had lymph node metastasis. Patients aged younger than 44 years (RR=1.700, p<0.001), male (RR=1.832, p<0.001), and with tumor larger than 10mm (RR=2.361, p<0.001) were more likely to have lymph node metastasis, while elderly patients (p<0.001) and those with microcarcinoma (p<0.001) were more likely to undergo non-LND procedures. LND provided no OS or DSS benefit over non-LND before and after propensity score match (matched 10-year OS/DSS: LND 83.8/96.2% vs non-LND 81.9/99.3%, p>0.05). Subgroup analyses revealed no prognostic gain with LND in any subgroup (p>0.05). Conclusion: Nearly half of MTC patients were diagnosed at T1 stage and had low lymph node risk. Different from ATA guidelines, avoiding routine LND conferred similar prognosis to standard procedures while potentially improving quality of life. Large-scale prospective multi-center studies should be conducted to further validate these findings. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor of the journal Thyroid discussing the prevalence of erectile dysfunction (ED) in patients with RET-altered thyroid cancer who are treated with selpercatinib. The authors conducted a retrospective cohort study of 25 male patients and found that 92% of them reported ED. The study suggests that ED may be a common side effect of selpercatinib treatment and that phosphodiesterase-5 inhibitors (PDE-5i) may be effective in managing this adverse event. Further research is needed to confirm these findings and explore optimal management strategies. The authors acknowledge the support of Eli Lilly and Company in reviewing the study. [Extracted from the article]

Selective RET inhibitors, such as selpercatinib and pralsetinib, have revolutionized the treatment of cancers with RET gene alterations. These inhibitors have shown remarkable clinical efficacy, particularly in RET-driven lung cancer, medullary thyroid cancer, and other solid tumors driven by RET gene fusions. The assessment of treatment response in oncology has been greatly enhanced by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), a valuable tool that measures tumor metabolism and provides early indicators of treatment effectiveness. This work explores the effectiveness of selective RET inhibitors in targeting RET-positive cancers and investigates the utility of FDG-PET in assessing treatment response. The paper includes insightful case studies that highlight the successful application of RET inhibitors in the treatment of RET-positive cancers. The findings suggest that FDG-PET has the potential to serve as a non-invasive biomarker for monitoring treatment response in patients with RET-positive cancers. However, further research is required to establish standardized criteria for interpreting FDG-PET scans in the context of selective RET inhibitors and to uncover the broader applications of FDG-PET in precision oncology. [ABSTRACT FROM AUTHOR]

The aim of the work was to systematically evaluate the efficacy and safety of Vandetanib in the treatment of advanced medullary thyroid carcinoma (MTC). MeSH entries to search for randomized controlled trials and clinical research literature on the application of Vandetanib in the treatment of medullary thyroid cancer from PubMed, Chinese national knowledge infrastructure (CNKI), and Web of Science databases since their establishment until March 2023 were used. In terms of efficacy, the analysis results showed that Vandetanib had a significantly higher objective response rate compared to the control group using placebo (OR=2.13, 95% CI: 1.38, 3.29). In terms of side effects, Vandetanib significantly increases the incidence of hypertension, rash, and diarrhea, and has statistical significance (p+<+0.05). Vandetanib has a better therapeutic effect on MTC, but it also increases the incidence of hypertension, rash, and diarrhea. Attention should be paid to the relief of side effects when using it. [ABSTRACT FROM AUTHOR]

Introduction: Medullary thyroid carcinoma constitutes 5% to 10% of all thyroid cancers. Metastatic adenopathies may pose challenges in intricate anatomical locations, such as the parapharyngeal space. A rare case of metastatic medullary thyroid carcinoma in the parapharyngeal space has been treated in our unit using combined trans-cervical trans-oral robotic surgery. Our objective was to provide a detailed description of the surgery performed on this patient. Method: We reported a singular case report worth of interest. Result: A 42-year-old woman was addressed in our unit for the management of a medullary thyroid carcinoma adenopathy located in the right parapharyngeal space. A parapharyngeal 40.0 mm × 25.0 mm × 12.0 mm adenopathy was removed using a combined trans-cervical and trans-oral robotic approach without sacrifice or injury of vascular or nervous structure. Neither the tracheostomy nor the feeding tube was implemented. Feeding was resumed on postoperative day 1 and hospitalization spanned 7 days. Conclusion: An innovative combined trans-cervical and trans-oral robotic surgery approach was conducted to address a metastatic medullary thyroid carcinoma in the parapharyngeal space. This surgical technique allowed us to circumvent the need for a trans-mandibular approach, tracheostomy, and feeding tube and enabling successful tumor removal without fragmentation. Postoperative care was significantly eased. The sole complication observed was dysphonia, likely resulting from intra-operative stretching of the vagus nerve during the dissection of the carotid artery. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare cancer derived from neuroendocrine C-cells of the thyroid. In contrast to other neuroendocrine tumors, a histological grading system was lacking until recently. A novel two-tier grading system based on the presence of high proliferation or necrosis is associated with prognosis. Transcriptomic analysis was conducted on 21 MTCs, including 9 high-grade tumors, with known mutational status, using the NanoString Tumor Signaling 360 Panel. This analysis, covering 760 genes, revealed upregulation of the genes EGLN3, EXO1, UBE2T, UBE2C, FOXM1, CENPA, DLL3, CCNA2, SOX2, KIF23, and CDCA5 in high-grade MTCs. Major pathways differentially expressed between high-grade and low-grade MTCs were DNA damage repair, p53 signaling, cell cycle, apoptosis, and Myc signaling. Validation through qRT-PCR in 30 MTCs demonstrated upregulation of ASCL1, DLL3, and SOX2 in high-grade MTCs, a gene signature akin to small-cell lung carcinoma, molecular subgroup A. Subsequently, DLL3 expression was validated by immunohistochemistry. MTCs with DLL3 overexpression (defined as ≥ 50% of positive tumor cells) were associated with significantly lower disease-free survival (p = 0.041) and overall survival (p = 0.01). Moreover, MTCs with desmoplasia had a significantly increased expression of DLL3. Our data supports the idea that DLL3 should be further explored as a predictor of aggressive disease and poor outcomes in MTC. [ABSTRACT FROM AUTHOR]

Purpose: Despite several factors that may have been associated with poor disease-free survival (DFS) in patients with medullary thyroid carcinoma (MTC), only a few studies have evaluated the prognostic factors affecting DFS in MTC patients. Therefore, this study evaluated the prognostic factors affecting DFS, in a large number of patients with MTC. Methods: Patients treated for MTC were retrospectively analyzed. Patients were stratified as having persistent/recurrent disease and no evidence of disease (NOD) at the last follow-up. The factors affecting DFS after the initial therapy and during the follow-up period were investigated. Results: This study comprised 257 patients [females 160 (62.3%), hereditary disease 48 (18.7%), with a mean follow-up time of 66.8 ± 48.5 months]. Persistent/recurrent disease and NOD were observed in 131 (51%) and 126 (49%) patients, respectively. In multivariate analysis, age > 55 (HR: 1.65, p = 0.033), distant metastasis (HR: 2.41, p = 0.035), CTN doubling time (HR: 2.7, p = 0.031), and stage III vs. stage II disease (HR 3.02, p = 0.048) were independent predictors of persistent/recurrent disease. Although 9 (8%) patients with an excellent response after the initial therapy experienced a structural recurrence, the absence of an excellent response was the strongest predictor of persistent/recurrent disease (HR: 5.74, p < 0.001). Conclusions: The absence of an excellent response after initial therapy is the strongest predictor of a worse DFS. However, a significant proportion of patients who achieve an excellent response could experience a structural recurrence. Therefore, careful follow-up of patients, including those achieving an excellent response is essential. [ABSTRACT FROM AUTHOR]

Papillary thyroid and medullary thyroid cancers are two distinct types of thyroid neoplasms. Co-occurrence of these cancers is rare, especially in mixed tumours with lymph node metastases. A 66-year-old man presented with a thyroid tumour. Thyroid ultrasonography revealed three separate nodules in the thyroid, suspected to be associated with lymph node metastasis. Although preoperative thyroid function was normal, calcitonin and carcinoembryonic antigen levels were elevated. The patient underwent a total cervical thyroidectomy with bilateral radical dissection. Histological and immunohistochemical analyses identified mixed medullary and papillary thyroid carcinoma (MMPTC) in the nodules in the left lobe of the thyroid and the isthmus. Mixed metastatic spread was observed in several lymph nodes from the neck dissection specimen. Accurate diagnosis of the rare co-occurrences of papillary and medullary thyroid carcinomas is crucial. TSH suppression can be effective for treating papillary thyroid carcinoma, whereas radical surgery is the preferred treatment for medullary thyroid carcinoma. Identifying lymph node metastasis before surgery is a key surgical strategy. [ABSTRACT FROM AUTHOR]

Context Sporadic medullary thyroid carcinoma (sMTC) rarely occurs in childhood and no studies have specifically focused on this entity. Objective To describe the clinical presentations and long-term outcomes of a large cohort of children and young adults with sMTC compared with hereditary MTC (hMTC). Methods Retrospective study of 144 patients diagnosed with MTC between 1961 and 2019 at an age ≤ 21 years and evaluated at a tertiary referral center. Results In contrast to hMTC (n = 124/144, 86%), patients with sMTC (n = 20/144, 14%) are older (P <.0001), have larger tumors (P <.0001), a higher initial stage grouping (P =.001) and have more structural disease (P =.0045) and distant metastases (DM) (P =.00084) at last follow-up, but are not more likely to die from MTC (P =.42). Among 77 patients diagnosed clinically, not by family history (20/20 sMTC and 57/124 hMTC), there was no difference in the initial stage (P =.27), presence of DM at diagnosis (P = 1.0), disease status at last follow-up (P =.13), overall survival (P =.57), or disease-specific survival (P =.87). Of the 12 sMTC tumors that underwent somatic testing, 11 (91%) had an identifiable alteration: 10 RET gene alterations and 1 ALK fusion. Conclusion sMTC is primarily a RET-driven disease that represents 14% of childhood-onset MTC in this cohort. Pediatric sMTC patients are older, present with clinical disease at a more advanced TNM classification, and have more persistent disease at last follow-up compared with hMTC, but these differences disappear when comparing those presenting clinically. Somatic molecular testing should be considered in sMTC patients who would benefit from systemic therapy. [ABSTRACT FROM AUTHOR]

Abstract Purpose The survival rate of patients with medullary thyroid carcinoma (MTC) who fail to achieve a biochemical cure after surgery is reduced. This study aimed to investigate the prognostic factors affecting the survival of MTC patients who do not achieve a biochemical cure after surgery. Methods Cox univariate and multivariate proportional hazard models were used to determine the influence of different variables on overall survival (OS). Pearson’s chi-square test was used for categorical variables, and paired t-test was used for continuous variables. Results In our study of 277 MTC patients treated between 2012 and 2022, there were 96 with raised postoperative 1-month calcitonin (Ct) levels (0–9.52 pg/ml). The overall survival (OS) rates of patients with high postoperative 1-month Ct values at 1, 3, and 5 years were 97.9%, 94.6%, and 86.8%, respectively. The univariate analysis revealed that patients with a postoperative 1-month Ct > 441.9 pg/ml had a greater risk of mortality than patients with postoperative 1-month Ct values ranging from 9.52 to 73.4 pg/ml (p = 0.043). Subsequent analyses revealed that receiving targeted therapy did not improve the OS of patients with distant metastasis among those with high postoperative 1-month Ct values (p = 0.527). Conclusion This study confirmed that MTC patients who did not achieve biochemical remission after surgery had an increased risk of death when the Ct level was > 441.9 pg/ml 1 month after surgery. Additionally, for MTC patients who have not achieved biochemical remission and have experienced disease progression or distant metastasis after surgery, the use of targeted therapy does not prolong survival.

Background: Calcitonin is a sensitive marker for medullary thyroid carcinoma (MTC) diagnosis and postsurgical follow-up. This study aimed to define the gender and tumor size-specific calcitonin cutoff values for diagnosing MTC. Methods: This retrospective study recruited 95 MTC patients and 10,523 non-MTC patients who underwent thyroid nodule surgery at Zhongshan Hospital between January 2015 and June 2023. Receiver operating characteristic (ROC) curves were used to assess calcitonin cutoff values for diagnosing MTC. Results: Calcitonin levels in non-MTC patients were influenced by gender, CKD stage and age, with gender being the highest ranked predictor. In MTC patients, calcitonin levels were associated with tumor diameter, lymph node metastasis, and TNM stage. In the entire study population, calcitonin cutoff values to diagnose MTC were 17.75 pg/mL for males (sensitivity: 97.60%, specificity: 99.40%) and 7.15 pg/mL for females (sensitivity: 94.34%, specificity: 99.22%). In patients with a thyroid nodule diameter ≤10 mm, the calcitonin cutoff values to diagnose MTC were 17.50 pg/mL for males (sensitivity: 95.00%, specificity: 99.27%) and 7.15 pg/mL for females (sensitivity: 90.91%, specificity: 99.04%). In patients with a thyroid nodule diameter >10 mm, the calcitonin cutoff values to diagnose MTC were 104.80 pg/mL for males (sensitivity: 100.00%, specificity: 100.00%) and 32.60 pg/mL for females (sensitivity: 96.77%, specificity: 100.00%). Conclusion: We have identified the gender and tumor size-specific cutoff values for the diagnosis of MTC. Cutoff values based on gender and tumor diameter may help to improve the accuracy of preoperative diagnosis of MTC, which is worth to be verified by future studies. [ABSTRACT FROM AUTHOR]

Abstract Few studies have investigated the impact of primary tumor resection (PTR) on patients with distant metastasis medullary thyroid carcinoma (DMMTC). This population-based study aims to assess the application of PTR in DMMTC patients, ascertain its benefits, and identify optimal surgical indications. DMMTC Patients diagnosed between 2010 and 2020 were included through the Surveillance, Epidemiology, and End Results (SEER) program. Logistic regression analysis identified driving factors of surgical decision-making. Propensity score matching (PSM), Kaplan–Meier method, and Cox regression were utilized to compare overall survival (OS) and disease-specific survival (DSS) between surgical and non-surgical groups. Subgroup analyses were performed to determine optimal surgical indications. Of 238 DMMTC patients included, 122 (51.3%) patients underwent PTR. Extrathyroidal extension and N1 stage emerged as independent factors promoting the surgical decision. PSM-adjusted survival analyses revealed significant advantages in both OS and DSS for the surgical group. Moreover, subgroup analyses indicated that except for patients aged ≥ 65 years, tumors ≤ 20 mm, or with multiple metastasized sites (> 1), the others significantly benefit from PTR. PTR significantly improves prognosis in selected DMMTC patients. The decision to undergo PTR in other patients should be based on a comprehensive assessment of the disease, surgeon’s experience, and family discussions for potential survival benefits.

Background: Thyroid cancer is a common thyroid malignancy. The majority of thyroid lesion needs intraoperative frozen pathology diagnosis, which provides important information for precision operation. As digital whole slide images (WSIs) develop, deep learning methods for histopathological classification of the thyroid gland (paraffin sections) have achieved outstanding results. Our current study is to clarify whether deep learning assists pathology diagnosis for intraoperative frozen thyroid lesions or not. Methods: We propose an artificial intelligence-assisted diagnostic system for frozen thyroid lesions that applies prior knowledge in tandem with a dichotomous judgment of whether the lesion is cancerous or not and a quadratic judgment of the type of cancerous lesion to categorize the frozen thyroid lesions into five categories: papillary thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid tumor, and non-cancerous lesion. We obtained 4409 frozen digital pathology sections (WSI) of thyroid from the First Affiliated Hospital of Sun Yat-sen University (SYSUFH) to train and test the model, and the performance was validated by a six-fold cross validation, 101 papillary microcarcinoma sections of thyroid were used to validate the system's sensitivity, and 1388 WSIs of thyroid were used for the evaluation of the external dataset. The deep learning models were compared in terms of several metrics such as accuracy, F1 score, recall, precision and AUC (Area Under Curve). Results: We developed the first deep learning-based frozen thyroid diagnostic classifier for histopathological WSI classification of papillary carcinoma, medullary carcinoma, follicular tumor, anaplastic carcinoma, and non-carcinoma lesion. On test slides, the system had an accuracy of 0.9459, a precision of 0.9475, and an AUC of 0.9955. In the papillary carcinoma test slides, the system was able to accurately predict even lesions as small as 2 mm in diameter. Tested with the acceleration component, the cut processing can be performed in 346.12 s and the visual inference prediction results can be obtained in 98.61 s, thus meeting the time requirements for intraoperative diagnosis. Our study employs a deep learning approach for high-precision classification of intraoperative frozen thyroid lesion distribution in the clinical setting, which has potential clinical implications for assisting pathologists and precision surgery of thyroid lesions. [ABSTRACT FROM AUTHOR]

Background: Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that originates from the parafollicular C cells of thyroid gland. Understanding the fundamental pathophysiology of MTC is essential for clinical management. Single-cell RNA sequencing (scRNA-seq) technology is a powerful tool for identifying distinct cell types, offering a new biological foundation for comprehending the MTC ecosystem and developing precise treatment. Methods: Formalin fixed and paraffin-embedded (FFPE) samples of primary and adjacent non-cancerous tissues of three MTC cases were collected, and single-cell transcriptome data of MTC were obtained by using scRNA-seq technology. Annotated cell subpopulations were categorized and functionally enriched by principal component analysis, differential gene expression, and cell clustering analysis, to explore the biological process of tumor evolution that may be involved in each cell subpopulation. The copy number variation (CNV) profile was used to distinguish the malignancy of parafollicular thyroid cells, and the evolutionary trajectories of normal cells and tumor cells were revealed by the proposed time series analysis. The highly expressed genes in each cell subpopulation were analyzed by the FindAllMarker function of Seurat software, and verified by immunohistochemistry and fluorescence in situ hybridization. The prognostic value of specific cell subtypes was validated using large-scale public datasets. Results: A total of 32,544 cells were obtained from the MTC tissue samples and 11,751 cells from the adjacent non-cancerous samples, which were classified into 7 heterogenous subpopulations by using R package of Seurat module. Copy number variations (CNVs) were significantly higher in tumor tissues than in adjacent non-tumor samples, predominantly enriched in subtypes C2 and C4. In addition, the pseudo-time for trajectory analysis suggested that the evolution of MTC tumor cells might begin with the C2 subtype, then transition to the early cancer subgroup C3, and further differentiate into four major malignant cell subpopulations C0, C1, C5 and C6. Survival analysis of a thyroid cancer cohort using the TCGA dataset revealed that high expression of genes linked to the C0 subcluster was correlated with poorer overall survival compared to low expression. Immunohistochemical staining showed that MAP3K4 was highly expressed in MTC tissues compared to adjacent non-cancerous tissues. Fluorescence in situ hybridization also confirmed the amplification of these two genes in MTC samples. Conclusions: By conducting scRNA-seq on FFPE samples, we mapped the single-cell transcriptome of MTC, uncovering the tumor heterogeneity and unique biological features of each cellular subpopulation. The biological roles of identified tumor cell subpopulations such as C0 and C3 subtypes of parafollicular cells suggested the potential to discover new therapeutic targets and biomarkers for MTC, providing valuable insights for future translational and clinical research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This editorial published in the journal Frontiers in Endocrinology discusses the advancements in thyroid cancer research, specifically focusing on molecular characterization and prediction models for recurrence. The article emphasizes the importance of accurate molecular and genetic characterization to differentiate between less aggressive and more aggressive thyroid tumors. It also explores the use of biomarkers and prediction models to improve the diagnosis and management of thyroid nodules. The document provides a summary of three studies related to thyroid cancer research, which identify genes associated with recurrence, analyze the genetic landscape of thyroid cancer in Chinese patients, and investigate the shared molecular mechanisms between thyroid cancer and Hashimoto's thyroiditis. These studies contribute to our understanding of thyroid cancer and may lead to personalized treatment options. [Extracted from the article]

Purpose: Lateral lymph node metastasis (LLNM) is very common in medullary thyroid carcinoma (MTC), but there is still controversy about how to manage cervical lateral lymph nodes, especially for clinically negative MTC. The aim of this study is to develop and validate a nomogram for predicting LLNM risk in MTC. Materials and methods: A total of 234 patients from two hospitals were retrospectively enrolled in this study and divided into LLNM positive group and LLNM negative group based on the pathology. The correlation between LLNM and preoperative clinical and ultrasound variables were evaluated by univariable and multivariable logistic regression analysis. A nomogram was generated to predict the risk of the LLNM of MTC patients, validated by external dataset, and evaluated in terms of discrimination, calibration, and clinical usefulness. Results: The training, internal, and external validation datasets included 152, 51, and 31 MTC patients, respectively. According to the multivariable logistic regression analysis, gender (male), relationship to thyroid capsule and serum calcitonin were independently associated with LLNM in the training dataset. The predictive nomogram model developed with the aforementioned variables showed favorable performance in estimating risk of LLNM, with the area under the ROC curve (AUC) of 0.826 in the training dataset, 0.816 in the internal validation dataset, and 0.846 in the external validation dataset. Conclusion: We developed and validated a model named MTC nomogram, utilizing available preoperative variables to predict the probability of LLNM in patients with MTC. This nomogram will be of great value for guiding the clinical diagnosis and treatment process of MTC patients. [ABSTRACT FROM AUTHOR]

Background: Progastrin-releasing peptide (ProGRP) is the precursor of the gastrin-releasing peptide, a neuropeptide secreted by cells of neural and endocrine origin. Recently, ProGRP has emerged as a circulating biomarker for small cell lung cancer (SCLC), a subtype of aggressive and poorly differentiated neuroendocrine neoplasm (NEN). Given the ability of the neuroendocrine SCLC cells to secrete this peptide, we performed an in-depth narrative review aimed at collecting, summarizing, and critically analyzing the available literature about the possible value of ProGRP as a biomarker for pulmonary NENs other than SCLC, and for NENs of non-pulmonary origin. Methods: We conducted an extensive search on international databases (PubMed, Web of Science, and Scopus). Results: We selected 21 pertinent published articles (12 original studies and 9 case reports). Overall, the original studies included 1,711 patients, and the case reports described the clinical course of 10 patients. Conclusion: The data analyzed suggest a potential role for ProGRP as a diagnostic biomarker for typical and atypical lung carcinoids, pulmonary large cell neuroendocrine carcinoma, medullary thyroid carcinoma, non-pulmonary neuroendocrine carcinomas, prostate cancer with neuroendocrine differentiation, and the pancreatobiliary neuroendocrine carcinoma. Despite these promising results, additional studies are needed, to clarify the role of ProGRP as the diagnostic biomarker for specific NENs. [ABSTRACT FROM AUTHOR]

Background: Medullary Thyroid Carcinoma (MTC) is a neuroendocrine tumor that arises from the thyroid C-cells. Most cases are sporadic (sMTC) while, approximately 25%, are hereditary (hMTC) due to germline mutations of REarranged during Transfection (RET) gene mutations and manifest in the framework of multiple endocrine neoplasia (MEN) 2A or 2B, or as pure familial MTC syndrome (FMTC). Objective: The aim of this study is to evaluate the clinical, histopathological, biochemical and outcome differences between sMTC and hMTC. Methods: Retrospective analysis of a consecutive series of 102 patients with histologically proven MTC diagnosed in the period between 2000 and 2022. For the analysis patients with MTC diagnosed during screening through genetic test were excluded. Results: Patients with hMTC had higher incidence of multifocal and bilateral MTC and younger age at diagnosis. We did not found differences on tumor stage at diagnosis between sMTC and hMTC, such as time to progression and rate of persistent and recurrent disease. At univariate analysis, factors associated with persistent and recurrent disease during follow-up in patients with sMTC were tumor size, extrathyroidal extension, presence of lymph node metastases at diagnosis, pre- and post-operative calcitonin, post-operative CEA; in patients with hMTC, features associated with persistent and recurrent disease were lymph node metastases, post-operative calcitonin and pre- and post-operative CEA values. Conclusion: Patients with hMTC and sMTC had similar histopathological characteristics and clinical outcome. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) can often have an indolent course despite distant metastatic disease. Additionally, given that metastatic MTC is incurable and systemic therapies have non-negligeable toxicities, localized treatments are often favored in presence of oligo-progressive disease. Transarterial radioembolization (TARE) with yttrium-90 (Y90) has emerged as a safe and efficacious treatment for nonresectable primary and metastatic liver tumors, yet data supporting its use in metastatic MTC are limited. We present the case of a patient with hereditary MTC and large bilobar liver metastases who demonstrated tumor response and resolution of their paraneoplastic diarrhea following TARE with Y90 microspheres. [ABSTRACT FROM AUTHOR]

Introduction: Graves' disease (GD) is an autoimmune disorder affecting the thyroid gland, leading to systemic manifestations such as hyperthyroidism, Graves' orbitopathy, and pretibial myxedema. Contrary to previous beliefs that hyperthyroidism protects against thyroid cancer, recent studies reveal an increased incidence of thyroid malignancies in GD patients, particularly differentiated thyroid carcinomas and, in rare cases, medullary thyroid carcinoma (MTC). Case series: This case series presents three female GD patients diagnosed with MTC, highlighting the complexities of diagnosis and management. All patients exhibited thyroid nodules with suspicious ultrasonographic features, elevated plasma calcitonin levels, and required total thyroidectomy. Histological examination confirmed MTC. Discussion: These cases underscore the importance of routine calcitonin screening in GD patients with thyroid nodules to facilitate early detection and improve prognosis. Our findings suggest that while the coexistence of GD and MTC is likely incidental, vigilant monitoring and comprehensive evaluation are crucial for timely intervention. Conclusions: This study advocates for integrating calcitonin testing into the standard diagnostic protocol for GD patients presenting with thyroid abnormalities. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Spindle epithelial tumor with thymus‐like element should be included in the differential diagnosis of thyroid gland cancers, particularly in medullary carcinoma, younger patients and indolent clinical presentation, because it may influence treatment and prognosis. [ABSTRACT FROM AUTHOR]

Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline mutations in the rearranged during transfection (RET) protooncogene, a tumor suppressor gene on chromosome 10q11.2, were identified 30 years ago as the genetic basis of MEN2 and published in 1993 and 1994. These seminal findings gave rise to the concept of prophylactic thyroidectomy for asymptomatic gene mutation carriers based on a positive RET gene test, which has become the standard of care ever since. Clinical genetic investigations showed genotype-phenotype correlations with respect to the individual gene mutation regarding the penetrance and onset of MTC and to a lesser extent also with respect to the other components of MEN2, pheochromocytoma and primary hyperparathyroidism. From this a clinically relevant risk stratification could be derived. Initially, the optimal timing of prophylactic thyroidectomy was primarily based on the RET genotype alone, which was not sufficient for a precise age recommendation and subsequently required additional consideration of calcitonin serum levels for fine tuning. Calcitonin levels first show the risk of lymph node metastasis when they exceed the upper normal limit of the assay independent of carrier age and RET mutation. Routine calcitonin screening of patients with nodular thyroid disease, screening of families on identification of MEN2 index patients, and pre-emptive thyroidectomy in carriers of gene mutations with normal calcitonin levels have led to the fact that nowadays, 30 years after the first description of the gene mutations causing the disease, the life-threatening hereditary MTC has become curable: a shining example for the success of translational transnational medical research for the benefit of patients. [ABSTRACT FROM AUTHOR]

Few studies have investigated the impact of primary tumor resection (PTR) on patients with distant metastasis medullary thyroid carcinoma (DMMTC). This population-based study aims to assess the application of PTR in DMMTC patients, ascertain its benefits, and identify optimal surgical indications. DMMTC Patients diagnosed between 2010 and 2020 were included through the Surveillance, Epidemiology, and End Results (SEER) program. Logistic regression analysis identified driving factors of surgical decision-making. Propensity score matching (PSM), Kaplan–Meier method, and Cox regression were utilized to compare overall survival (OS) and disease-specific survival (DSS) between surgical and non-surgical groups. Subgroup analyses were performed to determine optimal surgical indications. Of 238 DMMTC patients included, 122 (51.3%) patients underwent PTR. Extrathyroidal extension and N1 stage emerged as independent factors promoting the surgical decision. PSM-adjusted survival analyses revealed significant advantages in both OS and DSS for the surgical group. Moreover, subgroup analyses indicated that except for patients aged ≥ 65 years, tumors ≤ 20 mm, or with multiple metastasized sites (> 1), the others significantly benefit from PTR. PTR significantly improves prognosis in selected DMMTC patients. The decision to undergo PTR in other patients should be based on a comprehensive assessment of the disease, surgeon's experience, and family discussions for potential survival benefits. [ABSTRACT FROM AUTHOR]

Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, themedian PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm(HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP), an active regulator of the innate immune system, has been related to COVID-19 severity. CRP is a dynamic protein undergoing conformational changes upon activation in inflammatory microenvironments between pentameric and monomeric isoforms. Although pentameric CRP is the circulating isoform routinely tested for clinical purposes, monomeric CRP shows more proinflammatory properties. Therefore, we aimed to determine the potential of monomeric CRP in serum as a biomarker of disease severity in COVID-19 patients (admission to intensive care unit [ICU] and/or in-hospital mortality). We retrospectively determined clinical and biological features as well as pentameric and monomeric CRP levels in a cohort of 97 COVID-19 patients within 72h of hospital admission. Patients with severe disease had higher levels of both pentameric and monomeric CRP. However, multivariate analysis showed increased mCRP but not pCRP to be independently associated to disease severity. Notably, mCRP levels higher than 4000 ng/mL (OR: 4.551, 95% CI: 1.329-15.58), together with number of co-morbidities, low lymphocyte count, and procalcitonin levels were independent predictors of disease severity in the multivariate model. Our results show the potential of mCRP levels as a marker of clinical severity in COVID-19 disease. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of thyroid tumours is increasing worldwide. The most common malignant tumours of the thyroid gland include well-differentiated carcinomas (WDTC), especially papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). Medullary thyroid carcinoma (MTC) is less commonly diagnosed. Genetic changes determine the aggressive behavior of tumours and increase the metastatic potential of thyroid tumours. The aim of the study is to determine the incidence of point gene mutations and gene fusions in patients with Bethesda III–VI cytology as a possible predictor of indication of the extent of surgical procedures on the thyroid gland. Materials and methods: The study was prospective-retrospective and included patients operated on at the Department of Otorhinolaryngology and Maxillofacial Surgery of the 3rd Faculty of Medicine, Charles University and the Military University Hospital from July 1, 2019 to July 1, 2022, i.e. a period of 36 months. In the detection of the BRAF V600E gene, the allele of specific Real-Time PCR (LC480, Roche), the TERT gene mutation by direct sequencing (CEQ 8000, Beckman Coulter) was used, samples were analyzed by PCR (MiSeq, Illumina), and the Thyro-ID panel (4base) was used to detect another 12 genes. In addition, 23 fusion genes were tested, including ALK, BRAF, GLIS3, NTRK1, NTRK3, PPARG, and RET gene using Real-Time PCR, and MTC test for mutations in the RET gene and RAS. Results: The study included 273 patients with preoperative cytology Bethesda III–VI. The study was based on 21 (7.7%) men and 256 (93.77%) women. In the group, 103 (37.72%) cancers were histologically confirmed and 170 (62.27%) were found to have a benign tumour. Bethesda III were benign histologies with 118 (63.78%) that were verified, and 67 patients (36.21%) were diagnosed with any type of carcinoma. In Bethesda IV, there were 50 (70.42%) confirmed benign histologies and 21 patients (29.58%) had malignant tumours. BRAF V600E point mutation was detected in 63.85% of papillary thyroid carcinoma and only once in a benign tumour, and one NIFTP case was confirmed. Papillary carcinoma was presented in 83 (76.14%) patients, follicular carcinoma and its variants was in 14 (12.84%) patients, and medullary carcinoma was detected in 6 (5.5%) cases in the group. Conclusions: BRAF V600E point mutation was detected in 63.85% of well differentiated thyroid carcinomas and in other diagnoses, any mutation detected was rare. [ABSTRACT FROM AUTHOR]

Background: Surgical resection is not always achievable in thyroid cancer patients. Neoadjuvant therapy is rarely used, but recent trends favor multikinase inhibitors or selective tyrosine kinase inhibitors. These aim to reduce tumor volume, enabling previously unfeasible surgeries. Patients and Methods: Consecutive patients with locally advanced malignant thyroid tumors who received systemic therapies with a neoadjuvant intention were included in this retrospective multicenter case series conducted in five Latin American referral centers. Primary outcomes were pre- versus postneoadjuvant response evaluations using the Response Evaluation Criteria in Solid Tumors, feasibility of surgery, and completeness of resection. Secondary outcomes were mortality and status at the last visit. Results: Twenty-seven patients were included in this analysis. Patients with unresectable differentiated thyroid cancer (DTC) or poorly differentiated thyroid cancer (PDTC) received sorafenib (n = 6) or lenvatinib (n = 12), those with medullary thyroid cancer (MTC) were treated with vandetanib (n = 5) or selpercatinib (n = 1), and those with anaplastic thyroid cancer (ATC) harboring a BRAFV600E mutation (n = 3) received dabrafenib and trametinib. The median patient age was 66 years (range 12–82), and 52% of the patients were female. In patients with PTC and PDTC, the median reduction in the diameter of the primary tumor was 25% (range 0–100%) after a median of 6 months of treatment. Surgical intervention was performed in 10 (55%) of the patients. Among these, six patients (60%) achieved R0/R1 resection status. Six patients with MTC had a median reduction in tumor diameter of 24.5% (range 1–49) after a median treatment time of 9.5 months. Only one patient receiving selpercatinib, with a tumoral reduction of 25% could undergo surgery, resulting in an R2 resection due to extensive mediastinal extension. Three patients with ATC showed a median tumor diameter reduction of 42% (range 6.7–50) after a median treatment time of 2 months. Two patients underwent surgical intervention and achieved R1 and R2 resection, respectively. Conclusions: While neoadjuvant therapy achieved tumoral responses, surgical resection was feasible in 55% of DTC, 33% of ATC, and 16% of MTC patients, with R0/R1 resection in 26% of the cohort, underscoring the need for patient selection and further research in this area. [ABSTRACT FROM AUTHOR]

Background: Skip metastases, node metastases in the lateral neck sparing the ipsilateral central neck, challenge the current concept of central-to-lateral lymphatic spread. This study sought to delineate patterns of central and lateral neck involvement in unilateral papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). Methods: This was a retrospective correlative analysis of nodal patterns in surgical specimens from patients with unilateral PTC or MTC who had undergone thyroidectomy with at least ipsilateral central neck dissection between November 1994 and January 2024 at a tertiary referral center. Results: Included were 833 patients with unilateral PTC and 640 patients with unilateral MTC. Simultaneous presence or absence of node metastases was noted in ipsilateral central and lateral neck compartments in 76.6–78.1% of patients with PTC (both node positive in 27.0–54.7% and both node negative in 23.4–49.6%) and 77.3–80.0% of patients with MTC (both node positive in 26.6–33.2% and both node negative in 44.1–53.4%). Only one ipsilateral neck compartment was node positive in 21.9–23.4% of patients with PTC and 20.0–22.7% of patients with MTC. The ipsilateral central, but not the ipsilateral lateral compartment, was node positive in 8.8–16.9% with PTC and 8.6–8.8% of patients with MTC, whereas the ipsilateral lateral, but not the ipsilateral central compartment, was node positive in 6.5–13.1% with PTC and 11.3–14.1% with MTC. Ipsilateral lateral neck involvement sparing the ipsilateral central neck was 1.5–2 times more frequent in patients with node positive MTC than patients with node positive PTC (24.2–25.2% vs. 12.9–17.1%). Greater numbers of node metastases in the ipsilateral central neck compartment were associated with more frequent involvement of the ipsilateral lateral, contralateral central, and contralateral lateral neck compartments. Thyroid tumor diameter intensified nodal spread without changing nodal spread patterns. Conclusions: These histopathological findings, which need to be interpreted in light of the respective tumor biology, offer an unprecedented glimpse at the metastatic patterns of unilateral PTC and MTC. Customizing neck dissection to the patterns of nodal spread, considering operative status (initial vs. reoperative surgery) and experience with neck dissection, may require more frequent concomitant dissections of ipsilateral central and ipsilateral lateral neck compartments. [ABSTRACT FROM AUTHOR]

In this investigation, a novel electrochemical approach employing a bare carbon paste electrode (CPE) has been devised for the sensitive and expeditious quantification of the tyrosine kinase inhibitor vandetanib (VAN). VAN, a pivotal anti-tumor agent employed in various cancer types, notably medullary thyroid cancer, manifested an irreversible oxidation peak at approximately +1.17 V (vs. Ag/AgCl, 3 M NaCl) in 0.1 M HNO3, elucidated through cyclic voltammetry. The electrode reaction was determined to proceed via controlled adsorption. The study meticulously examined the influence of anionic surfactant sodium dodecyl sulfate (SDS), instrumental parameters, pH fluctuations, and the composition of the supporting electrolyte on the oxidation peak of VAN. Remarkably, the sensitivity of stripping voltammetric measurements markedly augmented upon the inclusion of 9 × 10−4 M SDS. Employing optimized parameters for SW-AdSV (square-wave adsorptive stripping voltammetry), the bare CPE demonstrated exceptional linearity within the dynamic ranges of 1.05×10−7 – 1.6×10−5 M for VAN. The limit of detection and limit of quantification were established at 2.7×10−8 and 9.0×10−8 M for VAN, respectively. Furthermore, the developed electrochemical methodology was effectively applied for the detection of VAN in spiked model serum samples. [ABSTRACT FROM AUTHOR]