Erectile dysfunction in patients treated with selpercatinib for RET altered thyroid cancer.

BACKGROUND: The highly selective RET inhibitor selpercatinib showed high efficacy and favorable toxicity profile in treating patients with RET-altered thyroid cancer (TC). Erectile dysfunction (ED) is a common adverse event observed in patients with advanced cancers. This study aims to evaluate the occurrence of ED in TC patients treated with selpercatinib. METHODS: In a multi-center retrospective cohort study, we investigated the prevalence of ED in 25 male patients treated with selpercatinib for advanced TC. The management of ED was also examined. RESULTS: 18/25 (78.3%) patients presented ED after starting selpercatinib treatment. However, only 2/18 (11.1%) spontaneously reported ED, while 16/18 (88.9%) reported ED only after specific questioning. Ten patients started treatment with phosphodiesterase-5 inhibitors (PDE-5i) with a significant improvement of ED. CONCLUSIONS: In this study, we observed that ED was not infrequently reported among men treated with selpercatinib for RET-altered TC. We believe that clinicians should actively inquire about ED in such patients at it may be underreported but may be amenable to treatment.

Association between lymphocytic thyroiditis and papillary thyroid cancer harboring mutant BRAF: a systematic review and meta-analysis.

BACKGROUND: Papillary thyroid cancer (PTC) and lymphocytic thyroiditis (LT) co-occur with a prevalence of about 30%. PTC harbouring BRAFV600E(PTC-BRAF) confers a worse prognosis, but it is unclear if LT alters prognostic features and recurrence of PTC. OBJECTIVE: We compared prevalence of PTC-BRAF with and without LT. The risk of adverse pathologic features in (i) PTC-BRAF, irrespective of LT status, was compared to (ii)PTC with LT, irrespective of BRAF status. METHODS: We searched PubMed, Embase and Web of Science Core Collection for observational studies published from 2010 to June 2023 on adult patients with PTC. The search strategy yielded 47 studies with relevant data. Data of baseline characteristics, clinicopathological features and the quality assessment tool was extracted by two reviewers. RESULTS: Of the 47 studies, 39 studies with a total cohort of 28 143, demonstrated the odds of PTC-BRAF was significantly lower in the presence on LT compared to its absence (OR 0.53, 95% CI: 0.48-0.58, p<0.00001). In PTC-BRAF patients, there was positive association of central neck nodal disease (CNND), PTC>1cm, extra-thyroidal extension, AJCC Stage 3-4 and multifocality with pooled OR 1.54 (95%CI:1.16-2.04), 1.14 (95%CI: 0.82- 1.58) , 1.66 (95%CI: 1.40-1.97), 1.53 (95% CI: 1.35-1.75) and 1.24 (95%CI: 1.11-1.40) respectively, compared to wild type PTC, irrespective of LT status. In the same studies, PTC with LT patients had lower pooled OR of 0.64 (95%CI: 0.51-0.81) for CNND, 0.83 (95%CI: 0.73 - 0.95) for PTC> 1cm, 0.71 (95%CI: 0.58-0.86) for ETE, 0.84 (95%CI: 0.75-0.94) for AJCC Stage 3-4 compared to PTC without LT, irrespective of BRAF status. PTC recurrence was not affected by BRAF or LT with pooled OR of 1.12 (95%CI: 0.66-1.90, p=0.67) and 0.60 (95%CI: 0.28-1.30, p=0.20) respectively. Similar results were seen with recurrence expressed as hazard ratio in this limited data-set. CONCLUSION: The odds of PTC-BRAF is significantly lower in the presence of LT than without. PTC with LT, irrespective of BRAF status, was significantly associated with better prognostic factors. Further studies are required to evaluate if LT inhibits PTC-BRAF, and weather this is relevant to the role of immunotherapy in advanced thyroid cancer.

A novel sequential treatment approach between denosumab and romosozumab in patients with severe osteoporosis.

In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed. PURPOSE/INTRODUCTION: In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover. METHODS: We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers. RESULTS: Patients experienced a ~ 5-22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment. CONCLUSIONS: A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk.

Pulmonary BRAF-driven Langerhans cell histiocytosis following selpercatinib use in metastatic medullary thyroid cancer.

Summary: RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition. Learning points: Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib). LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation. Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation. We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.

Neoadjuvant therapy to improve resectability of advanced thyroid cancer: A real-world experience.

BACKGROUND: Experience with targeted neoadjuvant treatment for locoregionally advanced thyroid cancer is nascent. METHODS: Multicenter retrospective case series examining targeted neoadjuvant treatment for locoregionally advanced thyroid cancer. The primary outcome was change in surgical morbidity as measured by two metrics developed for use in clinical trials to characterize surgical complexity and morbidity. Secondary outcomes included percentage of patients proceeding to surgery and percentage receiving an R0/R1 resection. RESULTS: Seventeen patients with varied molecular alterations, pathologies, and treatment regimens were included. Mean surgical complexity scores decreased between time points for baseline and postneoadjuvant treatment, postneoadjuvant treatment and surgery, and between baseline and surgery. Eleven patients (64.7%) underwent surgical resection, with 10 (58.8%) receiving an R0/R1 resection. CONCLUSIONS: Neoadjuvant treatment of advanced thyroid cancer improves resectability and decreases the morbidity of required surgical procedures. However, treatment is not uniformly effective.

Unraveling sources of emission heterogeneity in Silicon Vacancy color centers with cryo-cathodoluminescence microscopy.

Diamond color centers have proven to be versatile quantum emitters and exquisite sensors of stress, temperature, electric and magnetic fields, and biochemical processes. Among color centers, the silicon-vacancy (SiV[Formula: see text]) defect exhibits high brightness, minimal phonon coupling, narrow optical linewidths, and high degrees of photon indistinguishability. Yet the creation of reliable and scalable SiV[Formula: see text]-based color centers has been hampered by heterogeneous emission, theorized to originate from surface imperfections, crystal lattice strain, defect symmetry, or other lattice impurities. Here, we advance high-resolution cryo-electron microscopy combined with cathodoluminescence spectroscopy and 4D scanning transmission electron microscopy (STEM) to elucidate the structural sources of heterogeneity in SiV[Formula: see text] emission from nanodiamond with sub-nanometer-scale resolution. Our diamond nanoparticles are grown directly on TEM membranes from molecular-level seedings, representing the natural formation conditions of color centers in diamond. We show that individual subcrystallites within a single nanodiamond exhibit distinct zero-phonon line (ZPL) energies and differences in brightness that can vary by 0.1 meV in energy and over 70% in brightness. These changes are correlated with the atomic-scale lattice structure. We find that ZPL blue-shifts result from tensile strain, while ZPL red shifts are due to compressive strain. We also find that distinct crystallites host distinct densities of SiV[Formula: see text] emitters and that grain boundaries impact SiV[Formula: see text] emission significantly. Finally, we interrogate nanodiamonds as small as 40 nm in diameter and show that these diamonds exhibit no spatial change to their ZPL energy. Our work provides a foundation for atomic-scale structure-emission correlation, e.g., of single atomic defects in a range of quantum and two-dimensional materials.

The changing incidence of childhood epilepsy in Finland.

INTRODUCTION: to investigate the childhood epilepsy incidence, population trends, associated factors, and validate the national population registers. METHODS: a comprehensive comparative analysis of childhood epilepsy in the population during two distinct time intervals using medical records, appropriate national medical and population registers, and two random samples for control. RESULTS: In 1961-1964, the average incidence of epilepsy was 38/100,000 and during 1991-2000 65.9 (95 % CI 59.6 to 72.2) and 65.6/100,000 person-years after adjustment for the European Standard Population. This increase was significant (p<0.0001) as was a decline (p<0.003) from 1991 to 1995 to 1996-2000. The decline in incidence for girls occurred at a younger age compared to boys. Epilepsy cases associated with prenatal and perinatal factors were 50 % lower in 1991-2000 than in 1961-1964, especially related to asphyxia, infections, pre-eclampsia, and imminent abortion. The national Register for Healthcare independently identified 94.5 % of relevant cases (University Hospital alone 81.2 %, and Drug Register alone 74.3 %). DISCUSSION: Over the past five decades, the incidence rate of childhood epilepsy has exhibited a dynamic pattern, with a notable increase until the 1990's, followed by a stabilization at an incidence rate of approximately 60-70 per 100,000 person-years. Our findings, in line with other recent Finnish research, support a significant decrease in incidence since the mid-1990's. The underlying reasons for the increase and decrease remain unclear. Finnish national registers for epilepsy have established themselves as highly dependable resources for conducting epidemiological research. CONCLUSION: Childhood epilepsy incidence in Finland is similar to other industrialized countries, but there are signs of a declining trend emerging.

Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma.

AIMS: Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC. METHODS AND RESULTS: Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. CONCLUSIONS: Using well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/.

The Clinical Utility of Gallium-68-DOTATATE Positron Emission Tomography Scanning in Medullary Thyroid Cancer.

OBJECTIVE: Somatostatin receptor (SST) functional imaging with positron emission tomography (PET)/computed tomography (CT) has broadened the diagnostic and staging capabilities for medullary thyroid cancer (MTC). Gallium-68 (68Ga)-DOTA-conjugated peptide (Tyr3)-octreotate (DOTATATE) is a radiotracer with a high affinity for type 2 SSTs expressed in several, but not all, MTCs. The utility of 68Ga-DOTATATE PET/CT and 18fluorine-labeled fluoro-2-deoxy-D-glucose (18F-FDG)-PET/CT imaging in predicting MTC prognosis is also unknown. METHODS: In this single-center retrospective study, 103 of patients with MTC underwent assessment of SST2 and SST5 immunohistochemistry (IHC). A subgroup of 37 patients received 68Ga-DOTATATE PET/CT imaging, and 13 received contemporaneous 18F-FDG-PET/CT imaging. The maximum standardized uptake value (SUV), mean SUV, metabolic tumor volume, and total lesion activity (TLA) were assessed. RESULTS: Forty-two patients (41%) demonstrated positive expression of SST2, and 45 (44%) had a positive SST5 IHC result. Seventeen patients (17%) expressed both SST2 and SST5. No survival advantage was identified with SST2 or SST5 IHC positivity. No correlation was noted between the maximum SUV, mean SUV, metabolic tumor volume, or TLA and SST2 and/or SST5 expression by IHC. Shorter survival was associated with a TLA of >20 (P = .04). A RET-negative status also appeared to have shorter survival, although this may be because the small numbers did not reach statistical significance (P = .12). CONCLUSION: Assessment of TLA from 68Ga-DOTATATE PET/CT may predict survival. SST2 IHC was not correlated with 68Ga-DOTATATE avidity. Metastatic disease may be optimally assessed by concurrent 18F-FDG and 68Ga-DOTATATE imaging.

A Detailed Histologic and Molecular Assessment of the Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma.

Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAFV600E mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAFV600E mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAFV600E-mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called "BRAF-like" atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAFV600E-negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions.

Development of a novel clinical support tool for active surveillance of low risk papillary thyroid cancer.

Background: Active surveillance (AS) is an alternative to surgery in select patients with very low risk papillary thyroid cancer (PTC). Many clinicians feel ill-equipped in selecting appropriate patients. We aimed to 1) Develop an evidence-based web delivered decision support tool to assist clinicians in identifying patients appropriate for AS; and 2) Evaluate the prevalence of patients suitable for AS in a tertiary high volume thyroid cancer centre. Method: A REDCap web based clinical support tool was developed utilising evidence-based characteristics for AS suitability available to clinicals during initial assessment. A retrospective database was interrogated for patients who underwent hemithyroidectomy between 2012 - 2021 with final histopathology demonstrating PTC. Patients with PTCs>2cm, missing data, benign disease on surgical histopathology or incidental PTC were excluded. Results: Between 2012 - 2021, 763 patients underwent hemithyroidectomy with final histopathology confirming PTC. Of these, 316 patients were excluded (missing data, incidental PTC, concomitant hyperparathyroidism were most common reasons for exclusion) and 114/447 remaining patients had a pre-operative fine needle aspirate (FNA) of Bethesda V or VI (high likelihood of malignancy). Using the tool, 59/114 (52%) met criteria for AS. The majority of patients were female (85% vs 15% male); median age 36 years (range 19 - 78). Following initial surgery, 10/59 patients had a completion thyroidectomy, with 4/10 demonstrating malignancy in contralateral lobe and eight of those patients undergoing I131 ablation. During a median follow up of over 3 years, 49/59 (83%) did not require further surgery or intervention with no patients developing recurrence. A subgroup analysis with second radiology assessment excluded 4/59 patients as meeting criteria for AS based on presence of ETE on preoperative ultrasound. None of these 4 patients had completion thyroidectomy. Conclusion: Our clinical support tool identifies patients with PTC potentially suitable for AS which could be utilised during initial patient assessment. In a retrospective cohort of patients who had hemithyroidectomy for PTC with a pre-operative FNA diagnosis of Bethesda V or VI, 55/114 (48%) patients may have been suitable for AS. Prospective validation studies are required for implementation of the tool in clinical practice.

Medullary Thyroid Cancer: Updates and Challenges.

A personalized approach to the management of medullary thyroid cancer (MTC) presents several challenges; however, in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline rearranged in transfection (RET) testing in multiple endocrine neoplasia 2 and 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. Positron emission tomography imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors that have shown improved progression-free survival with better tolerability than outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients: from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve.

Challenges and Strategies to Combat Resistance Mechanisms in Thyroid Cancer Therapeutics.

Background: BRAFV600E and N/H/K RAS mutations and oncogenic kinase fusions involving neurotrophin tyrosine receptor kinase (NTRK), RET, anaplastic lymphoma kinase (ALK), and ROS1 have been identified as actionable targets in thyroid cancer. These driver alterations lead to oncogene addiction, which has been successfully exploited through tyrosine kinase inhibitors. Acquired resistance may develop following an initial response requiring a therapeutic pivot to new therapies. Summary: Several pathways for development of acquired resistance have been identified. These encompass acquired on-target gene mutation impeding drug activity and upregulation of bypass kinase signaling pathways leading to tumor progression. Biopsy of resistant lesions (liquid or tissue) and subsequent molecular analysis can assist with new therapeutic strategies. Conclusions: Progression-free survival is curtailed by developing acquired resistance. To minimize this therapeutic liability, clinicians must be anticipatory in identifying the drivers and characterizing mechanisms of on-target resistance.

Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone.

Like other secreted peptides, nascent parathyroid hormone (PTH) is synthesized with a pre- and a pro-sequence (25 and 6 amino acids, respectively). These precursor segments are sequentially removed in parathyroid cells before packaging into secretory granules. Three patients from two unrelated families who presented during infancy with symptomatic hypocalcemia were found to have a homozygous serine (S) to proline (P) change affecting the first amino acid of the mature PTH. Unexpectedly, biological activity of synthetic [P1]PTH(1-34) was indistinguishable from that of unmodified [S1]PTH(1-34). However, in contrast to conditioned medium from COS-7 cells expressing prepro[S1]PTH(1-84), medium from cells expressing prepro[P1]PTH(1-84) failed to stimulate cAMP production despite similar PTH levels when measured by an intact assay that detects PTH(1-84) and large amino-terminally truncated fragments thereof. Analysis of the secreted, but inactive PTH variant led to the identification of pro[P1]PTH(-6 to +84). Synthetic pro[P1]PTH(-6 to +34) and pro[S1]PTH(-6 to +34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(-6 to +34), pro[P1]PTH(-6 to +34) was resistant to cleavage by furin suggesting that the amino acid variant impairs preproPTH processing. Consistent with this conclusion, plasma of patients with the homozygous P1 mutation had elevated proPTH levels, as determined with an in-house assay specific for pro[P1]PTH(-6 to +84). In fact, a large fraction of PTH detected by the commercial intact assay represented the secreted pro[P1]PTH. In contrast, two commercial biointact assays that use antibodies directed against the first few amino acid residues of PTH(1-84) for capture or detection failed to detect pro[P1]PTH.

Metastatic papillary thyroid cancer to cerebellum with incidental medullary microcarcinoma.

Thyroid cancer is the most common endocrine cancer, with papillary thyroid carcinoma (PTC) accounting for the majority of these cases. Cerebellar metastasis is rarely the presenting feature and confers poor prognosis. Genetic mutations in this setting are most commonly TERTp, in contrast to BRAF V600E in the majority of PTC. We report the case of an 82 year-old male who presented with a symptomatic right cerebellar lesion and underwent surgical resection to demonstrate metastatic PTC. Extensive workup with computed tomography, neck ultrasound and FDG-PET was suggestive of a left thyroid primary lesion, with FNA confirming PTC. However, total thyroidectomy demonstrated incidental microMTC (medullary thyroid microcarcinoma, defined as tumour <10mm) without any evidence of PTC, whereas the left level VI neck dissection demonstrated a 30mm nodule of PTC without identifiable normal thyroid or lymph node tissue.

Outcomes of Papillary Thyroid Microcarcinoma Presenting with Palpable Lateral Lymphadenopathy.

Purpose: Papillary thyroid microcarcinoma (PTMC) is typically indolent in nature, allowing management with active surveillance protocols. Occasionally, a more aggressive phenotype can present and may lead to poor outcomes such as patients presenting with clinically significant lateral lymphadenopathy (cN1b). Prior analysis of the outcomes of this cohort is largely from papillary thyroid cancer (PTC) (>1 cm) or from institutions where use of radioactive iodine (RAI) is limited. Hence, we aim to describe the outcomes of patients with PTMC who presented with palpable cN1b disease, treated with total thyroidectomy and RAI. Methodology: We performed a retrospective cohort study. Outcomes of patients with PTMC who presented with palpable lateral lymph node (LN) metastases (microPTC cN1b) treated between 1997 and 2020 at Royal North Shore Hospital were compared with two control groups' outcomes: patients with clinically detected PTMC without evidence of involved LNs (microPTC cN0) and with larger PTC (>10 mm) who presented with palpable lateral lymphadenopathy (larger PTC cN1b). We assessed clinicopathological variables, postoperative risk stratification, rates of disease recurrence, reoperative surgery, and structural disease-free survival (DFS). Results: In total, 1534 PTMCs were diagnosed following thyroid surgery in the study period; of these, 157 (10%) were clinically detected microPTC cN0 and 26 microPTC cN1b (1.7%). There were 138 patients in the larger PTC cN1b control group. All cN1b patients were treated with total thyroidectomy and adjuvant RAI. Mean size of the largest LN deposit was similar between the microPTC cN1b and larger PTC cN1b groups (23 vs. 27 mm, p = 0.11). Patients with microPTC cN1b were more likely to have biochemical or structural persistence or recurrence compared with microPTC cN0 (19%, 5/26 vs. 3.8%, 6/157, p = 0.002) but less likely than larger PTC cN1b patients (19%, 5/26 vs. 42%, 58/138, p = 0.04). All patients in the microPTC cN1b group who had an excellent response to initial therapy (85%, 22/26) were disease free at last follow-up. The rate of reoperation was similar for the microPTC cN1b and microPTC cN0 groups (4%, 1/26 vs. 2%, 3/157, p = 0.461) and significantly lower than the larger PTC cN1b group (4%, 1/26 vs. 26%, 36/138, p = 0.002). Five-year DFS estimates were significantly better for microPTC cN1b patients than for larger PTC cN1b patients (94% vs. 59%, p = 0.001). Conclusions: MicroPTC cN1b patients treated with thyroidectomy and adjuvant RAI have inferior clinical outcomes compared with microPTC cN0 patients but have better outcomes than their larger PTC cN1b counterparts with respect to disease persistence and recurrence. Response to initial therapy provides valuable prognostication in microPTC cN1b patients: if these patients had an excellent response to initial treatment, they achieved long-term DFS in this series.

Thyroid Hormone Abuse in Elite Sports: The Regulatory Challenge.

Abuse of androgens and erythropoietin has led to hormones being the most effective and frequent class of ergogenic substances prohibited in elite sports by the World Anti-Doping Agency (WADA). At present, thyroid hormone (TH) abuse is not prohibited, but its prevalence among elite athletes and nonprohibited status remains controversial. A corollary of prohibiting hormones for elite sports is that endocrinologists must be aware of a professional athlete's risk of disqualification for using prohibited hormones and/or to certify Therapeutic Use Exemptions, which allow individual athletes to use prohibited substances for valid medical indications. This narrative review considers the status of TH within the framework of the WADA Code criteria for prohibiting substances, which requires meeting 2 of 3 equally important criteria of potential performance enhancement, harmfulness to health, and violation of the spirit of sport. In considering the valid clinical uses of TH, the prevalence of TH use among young adults, the reason why some athletes seek to use TH, and the pathophysiology of sought-after and adverse effects of TH abuse, together with the challenges of detecting TH abuse, it can be concluded that, on the basis of present data, prohibition of TH in elite sport is neither justified nor feasible.

Translational Utility of Liquid Biopsies in Thyroid Cancer Management.

Liquid biopsies are a novel technique to assess for either circulating tumor cells (CTC) or circulating tumor DNA (ctDNA and microRNA (miRNA)) in peripheral blood samples of cancer patients. The diagnostic role of liquid biopsy in oncology has expanded in recent years, particularly in lung, colorectal and breast cancer. In thyroid cancer, the role of liquid biopsy in either diagnosis or prognosis is beginning to translate from the lab to the clinic. In this review, we describe the evolution of liquid biopsies in detecting CTC, ctDNA and miRNA in thyroid cancer patients, together with its limitations and future directions in clinical practice.

Papillary thyroid microcarcinoma: Is active surveillance always enough?

The incidence of papillary thyroid carcinoma (PTC) has increased over recent decades. This apparent epidemic has been attributed to the overdiagnosis of small PTC ≤10 mm in diameter (papillary thyroid microcarcinoma [PTMC]) incidentally detected on imaging for unrelated presentations. Although most PTMCs follow an indolent disease course, there is a small but significant proportion of cases that display more biologically aggressive features such as early metastasis and lymph node involvement. Management of PTMC diagnosed preoperatively should be distinguished from managing those PTMCs incidentally discovered after thyroidectomy. Here, we will focus on the challenge of managing the preoperative patient. Current guidelines recommend against routine biopsy of nodules ≤10 mm, even if they display highly suspicious features on ultrasound; however, it is not known how to identify those PTMCs at higher risk of disease progression. In view of their good prognosis even without surgical resection, active surveillance has emerged as an alternative to operative management for low-risk PTMC without lymph node involvement or distant metastasis. This review aims to summarise active surveillance data for PTMC and identify clinical features that may differentiate the indolent majority from those PTMCs that exhibit early disease progression and metastasis.