Bone-active drugs in premenopausal women with breast cancer under hormone-deprivation therapies.

BACKGROUND: Bone health management in premenopausal women with breast cancer (BC) under hormone-deprivation therapies (HDTs) is often challenging, and the effectiveness of bone-active drugs is still unknown. METHODS: This retrospective multicenter study included 306 premenopausal women with early BC undergoing HDTs. Bone mineral density (BMD) and morphometric vertebral fractures (VFs) were assessed 12 months after HDT initiation and then after at least 24 months. RESULTS: After initial assessment, bone-active drugs were prescribed in 77.5% of women (151 denosumab 60 mg/6 months, 86 bisphosphonates). After 47.0 ± 20.1 months, new VFs were found in 16 women (5.2%). Vertebral fracture risk was significantly associated with obesity (odds ratio [OR] 3.87, P = .028), family history of hip fractures or VFs (OR 3.21, P = .040], chemotherapy-induced menopause (OR 6.48, P < .001), preexisting VFs (OR 25.36, P < .001), baseline T-score less than or equal to -2.5 standard deviation (SD) at any skeletal site (OR 4.14, P = .036), and changes at lumbar and total hip BMD (OR 0.94, P = .038 and OR 0.88, P < .001, respectively). New VFs occurred more frequently in women untreated compared to those treated with bone-active drugs (14/69, 20.8% vs 2/237, 0.8%; P < .001) and the anti-fracture effectiveness remained significant after correction for BMI (OR 0.03; P < .001), family history of fractures (OR 0.03; P < .001), chemotherapy-induced menopause (OR 0.04; P < .001), and preexisting VFs (OR 0.01; P < .001). CONCLUSIONS: Premenopausal women under HDTs are at high risk of VFs in relationship with high BMI, densitometric diagnosis of osteoporosis, preexisting VFs, and family history of osteoporotic fractures. Vertebral fractures in this setting might be effectively prevented by bisphosphonates or denosumab.

Romosozumab versus parathyroid hormone receptor agonists: which osteoanabolic to choose and when?

Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide (ABL) increase bone formation, bone mineral density (BMD), and bone strength by activating PTH receptors on osteoblasts. Romosozumab (ROMO), a humanized monoclonal antibody against sclerostin, dramatically but transiently stimulates bone formation and persistently reduces bone resorption. Osteoanabolic agents increase BMD and bone strength while being more effective than antiresorptives in reducing fracture risk in postmenopausal women. However, direct comparisons of the antifracture benefits of osteoanabolic therapies are limited. In a direct comparison of TPTD and ABL, the latter resulted in greater BMD increases at the hip. While no differences in vertebral or non-vertebral fracture risk were observed between the two drugs, ABL led to a greater reduction of major osteoporotic fractures. Adverse event profiles were similar between the two agents except for hypercalcemia, which occurred more often with TPTD. No direct comparisons of fracture risk reduction between ROMO and the PTH1R agonists exist. Individual studies have shown greater increases in BMD and bone strength with ROMO compared with TPTD in treatment-naive women and in women previously treated with bisphosphonates. Some safety aspects, such as a history of tumor precluding the use of PTH1R agonists, and a history of major cardiovascular events precluding the use of ROMO, should also be considered when choosing between these agents. Finally, convenience of administration, reimbursement by national health systems and length of clinical experience may influence patient choice.

Restless leg syndrome as a complication of primary hyperparathyroidism: insights from a retrospective study.

INTRODUCTION: Restless leg syndrome (RLS) is an invalidating neurological disorder with a complex, largely unknown pathophysiology. While RLS is observed in Parkinson's disease and in renal failure, idiopathic cases are common. Limited reports associate RLS with parathyroid hormone (PTH). This study analyzes a cohort of patients with primary hyperparathyroidism (PHPT) and chronic post-surgical hypoparathyroidism (hypo PTH), to investigate RLS prevalence, and associated risk factors. METHODS: Ninety-five patients (54 PHPT, 41 hypo PTH) were consecutively enrolled at the bone metabolism outpatient clinic. The revised IRLSSG diagnostic criteria were used to diagnose RLS, with assessments conducted through face-to-face interviews and neurological examination. When RLS was confirmed, the RLS severity scale was applied. Retrospective records included calcium-phosphate metabolism-related parameters, surgery details, renal lithiasis, fragility fractures, and densitometric features (T-score). RESULTS: RLS was diagnosed in 22.2% PHPT patients, compared to 4.9% of patients with hypo PTH (p = 0.02). Of RLS diagnosed patients, 91.7% had a history of parathyroidectomy, compared to 47.6% of patients without RLS (p = 0.01). Most of the operated patients reported that surgery determined an improvement of symptoms; however, mean score severity of RLS at our evaluation was 15/40, defined as moderate. PTH and calcium levels were not statistically associated to the presence of RLS. CONCLUSION: Our study suggests that PHPT may be one of the etiologies of RLS. Parathyroidectomy alleviates symptoms in the vast majority of the cases but does not remove them.

An eXplainable Artificial Intelligence analysis of Raman spectra for thyroid cancer diagnosis.

Raman spectroscopy shows great potential as a diagnostic tool for thyroid cancer due to its ability to detect biochemical changes during cancer development. This technique is particularly valuable because it is non-invasive and label/dye-free. Compared to molecular tests, Raman spectroscopy analyses can more effectively discriminate malignant features, thus reducing unnecessary surgeries. However, one major hurdle to using Raman spectroscopy as a diagnostic tool is the identification of significant patterns and peaks. In this study, we propose a Machine Learning procedure to discriminate healthy/benign versus malignant nodules that produces interpretable results. We collect Raman spectra obtained from histological samples, select a set of peaks with a data-driven and label independent approach and train the algorithms with the relative prominence of the peaks in the selected set. The performance of the considered models, quantified by area under the Receiver Operating Characteristic curve, exceeds 0.9. To enhance the interpretability of the results, we employ eXplainable Artificial Intelligence and compute the contribution of each feature to the prediction of each sample.

Real-Time Evaluation of Thyroid Cytology Using New Digital Microscopy Allows for Sample Adequacy Assessment, Morphological Classification, and Supports Molecular Analysis.

Thyroid cytological examination, a key tool in preoperative thyroid nodule evaluation, is specific and accurate; some drawbacks are due to inadequate or indeterminate cytological reports and there is a need for an innovative approach overcoming the limits of traditional cytological diagnostics. Fluorescence laser confocal microscopes (FCM) is a new optical technique for allowing immediate digital imaging of fresh unfixed tissues and real-time assessment of sample adequacy and diagnostic evaluation for small biopsies and cytological samples. Currently, there are no data about the use of FCMs in the field of thyroid nodular pathology. The aims of this study were to test FCM technology for evaluating the adequacy of FNA samples at the time of the procedure and to assess the level of concordance between FCM cytological evaluations, paired conventional cytology, and final surgical histology. The secondary aim was to define the integrity of nucleic acids after FCM evaluation through NGS molecular analysis. Sample adequacy was correctly stated. Comparing FCM evaluation with the final histology, all cases resulting in malignant or suspicious for malignancy at FCM, were confirmed to be carcinomas (PPV 100%). In conclusion, we describe a successful application of FCM in thyroid preoperative cytological evaluation, with advantages in immediate adequacy assessment and diagnostic information, while preserving cellular specimens for permanent morphology and molecular analysis, thus improving timely and accurate patient management.

Clinical Use of Raman Spectroscopy Improves Diagnostic Accuracy for Indeterminate Thyroid Nodules.

BACKGROUND AND OBJECTIVE: Molecular analysis of thyroid fine-needle aspiration (FNA) specimens is believed to improve the management of indeterminate nodules. Raman spectroscopy (RS) can differentiate benign and malignant thyroid lesions in surgically removed tissues, generating distinctive structural profiles. Herein, the diagnostic performance of RS was tested on FNA biopsies of thyroid gland. DESIGN: Prospective, blinded, and single-center study. METHODS: We enrolled 123 patients with indeterminate or more ominous cytologic diagnoses (TIR3A-low-risk indeterminate lesion, TIR3B-high-risk indeterminate lesion, TIR4-suspicious of malignancy, TIR5-malignant). All subjects were surgical candidates (defined by international guidelines) and submitted to FNA procedures for RS analysis. We compared RS data, cytologic findings, and final histologic assessments (as reference standard) using various statistical techniques. RESULTS: The distribution of our study population was as follows: TIR3A:37, TIR3B:32, TIR4:16, and TIR5:38. In 30.9% of patients, histologic diagnoses were benign. For predicting thyroid malignancy in FNA samples, the overall specificity of RS was 86.8%, with 86.5% specificity in indeterminate cytologic categories. In patients with high-risk ultrasound categories, the specificity of RS increased to 87.5% for TIR3A, reaching 100% for TIR3B. Benign histologic diagnoses accounted for 72.9% of patients classified as TIR3A and 31.3% of those classified as TIR3B. Based on positive RS testing, unnecessary surgery was reduced to 7.4% overall (TIR3A-33.3%, TIR3B-6.7%). CONCLUSIONS: This premier use of RS for thyroid cytology confirms its role as a valuable diagnostic tool and a valid alternative to molecular studies, capable of improving the management of indeterminate nodules and reducing unnecessary surgery.

Unraveling the Effects of Carotenoids Accumulation in Human Papillary Thyroid Carcinoma.

Among the thyroid cancers, papillary thyroid cancer (PTC) accounts for 90% of the cases. In addition to the necessity to identify new targets for PTC treatment, early diagnosis and management are highly demanded. Previous data indicated that the multivariate statistical analysis of the Raman spectra allows the discrimination of healthy tissues from PTC ones; this is characterized by bands typical of carotenoids. Here, we dissected the molecular effects of carotenoid accumulation in PTC patients by analyzing whether they were required to provide increased retinoic acid (RA) synthesis and signaling and/or to sustain antioxidant functions. HPLC analysis revealed the lack of a significant difference in the overall content of carotenoids. For this reason, we wondered whether the carotenoid accumulation in PTC patients could be related to vitamin A derivative retinoic acid (RA) biosynthesis and, consequently, the RA-related pathway activation. The transcriptomic analysis performed using a dedicated PCR array revealed a significant downregulation of RA-related pathways in PTCs, suggesting that the carotenoid accumulation in PTC could be related to a lower metabolic conversion into RA compared to that of healthy tissues. In addition, the gene expression profile of 474 PTC cases previously published in the framework of the Cancer Genome Atlas (TGCA) project was examined by hierarchical clustering and heatmap analyses. This metanalysis study indicated that the RA-related pathways resulted in being significantly downregulated in PTCs and being associated with the follicular variant of PTC (FV-PTC). To assess whether the possible fate of the carotenoids accumulated in PTCs is associated with the oxidative stress response, the expression of enzymes involved in ROS scavenging was checked. An increased oxidative stress status and a reduced antioxidant defense response were observed in PTCs compared to matched healthy thyroids; this was possibly associated with the prooxidant effects of high levels of carotenoids. Finally, the DepMap datasets were used to profile the levels of 225 metabolites in 12 thyroid cancer cell lines. The results obtained suggested that the high carotenoid content in PTCs correlates with tryptophan metabolism. This pilot provided novel possible markers and possible therapeutic targets for PTC diagnosis and therapy. For the future, a larger study including a higher number of PTC patients will be necessary to further validate the molecular data reported here.

Long-term efficacy and safety of percutaneous ethanol injection (PEI) in cystic thyroid nodules: A systematic review and meta-analysis.

BACKGROUND: Percutaneous ethanol injection (PEI) is used for the treatment of benign cystic thyroid nodules. This systematic review and meta-analysis aimed to obtain strong evidence of its long-term efficacy and safety. METHODS: PubMed, CENTRAL, Scopus and Web of Science databases were searched until November 2020 for studies reporting data on volume reduction rate (VRR), compressive symptoms and cosmetic concerns. Associated complications were assessed. A random-effects model was designed to pool the data. RESULTS: Out of 385 papers, nine studies evaluating 1667 nodules were finally included. Overall, VRR at 6, 12, 24, 36, 60 and 120 months was 77%, 81%, 72%, 68%, 74% and 69%, respectively. Significant reductions in the compressive symptoms and cosmetic concerns were observed. No permanent complications were observed. CONCLUSIONS: The present meta-analysis showed that PEI could significantly reduce the volume of benign cystic thyroid nodules. This reduction was already effective at 6 months post-treatment, and the effect was stable over time.

Hobnail variant of papillary thyroid carcinoma showing goiter-like presentation and rapid growth.

SUMMARY: We present the case of a 47-year-old Caucasian previously healthy woman with a voluminous thyroid nodule occupying almost the entire anterior neck region. The lesion had progressively increased in size during the previous 3 months and the patient presented intermittent symptoms of dysphagia and odynophagia with a slight change in voice. Fine needle aspiration showed papillary carcinoma. Based on imaging and cytological findings, the patient underwent total thyroidectomy. The surgical sample revealed a totally enlarged thyroid gland (weight: 208 g) with the presence of a poly-lobulated lesion centrally located and involving the isthmus and both lobes. Hobnail features were present in more than 30% of the neoplastic cells in agreement with the criteria for this subtype. Psammoma bodies and focal necrosis were also present. The extra-thyroidal extension included strap muscles and peri-esophageal glands. Immunohistochemistry using VE1 antibody for detecting BRAF-V600E mutation resulted positive. The final diagnosis was papillary thyroid carcinoma (PTC) hobnail variant (HVPTC)-pT4a. The HVPTC is a rare entity and, in most cases, appears like a unifocal lesion with a maximum tumor size of 8 cm reported so far. To our knowledge, this represents the largest tumor ever described (14 cm), showing rapid growth and with multinodular goiter-like aspect. LEARNING POINTS: HVPTC is an aggressive variant of PTC, usually associated with radioactive iodine refractoriness, and a higher mortality rate compared to classic PTC. However, there is a marked individual variability in this association. HVPTC usually appears as small unifocal lesion but a multinodular goiter presentation may occur. The present case highlights that despite of the histology, our patient achieved a high ablation success rate after radioactive iodine therapy.

Thyroid cancer diagnosis by Raman spectroscopy.

Over the last 50 years, the incidence of human thyroid cancer disease has seen a significative increment. This comes along with an even higher increment of surgery, since, according to the international guidelines, patients are sometimes addressed to surgery also when the fine needle aspiration gives undetermined cytological diagnosis. As a matter of fact, only 30% of the thyroid glands removed for diagnostic purpose have a post surgical histological report of malignancy: this implies that about 70% of the patients have suffered an unnecessary thyroid removal. Here we show that Raman spectroscopy investigation of thyroid tissues provides reliable cancer diagnosis. Healthy tissues are consistently distinguished from cancerous ones with an accuracy of [Formula: see text] 90%, and the three cancer typology with highest incidence are clearly identified. More importantly, Raman investigation has evidenced alterations suggesting an early stage of transition of adenoma tissues into cancerous ones. These results suggest that Raman spectroscopy may overcome the limits of current diagnostic tools.

Regression of Papillary Thyroid Cancer during Nivolumab for Renal Cell Cancer.

Immune checkpoint inhibitors have been recently approved for cancer treatment. Nivolumab is a monoclonal antibody specific for programmed cell death-1 (PD-1) that modulates T-cell response. It was initially used for the treatment of malignant melanoma and then approved in other cancers, such as non-small cell lung cancer and clear cell renal cell carcinoma (ccRCC). So far, the activity of nivolumab in patients with thyroid malignancies has been reported in a single case of anaplastic thyroid cancer. Here, we report the case of a patient with ccRCC who developed a papillary thyroid carcinoma (PTC) under first-line sunitinib treatment. During nivolumab, the second-line treatment for ccRCC, we unexpectedly observed a complete regression of PTC.

Raman Spectroscopy Discloses Altered Molecular Profile in Thyroid Adenomas.

Follicular patterned nodules are sometimes complex to be classified due to ambiguous nuclear features and/or questionable capsular or vascular invasion. In this setting, there is a poor inter-observer concordance even among expert pathologists. Raman spectroscopy was recently used to separate benign and malignant thyroid nodules based on their molecular fingerprint; anyway, some histologically proved follicular adenomas were clustered as having a characteristic profile of malignant lesions. In this study, we analyzed five follicular thyroid adenomas with a malignant spectroscopic profile compared to five follicular adenomas with a benign Raman spectrum in order to assess possible molecular differences between the two groups. Morphological, immunohistochemical, and molecular analyses evidenced expression of malignancy-associated proteins in four out of five malignant clustered adenomas. The remaining malignant clustered adenoma showed a TSHR mutation previously associated with autonomously functioning follicular carcinomas. In conclusion, thyroid follicular adenomas are a group of morphologically benign neoplasms that may have altered the mutational or expression profile; cases of adenomas with altered immunophenotype are recognized as showing a profile associated with malignancy by Raman spectroscopy. This correlation warrants a more extensive evaluation and suggests a potential predictive value of spectroscopic assessment in recognizing characteristics associated with tumor progression in follicular thyroid neoplasms.

Calcium citrate: from biochemistry and physiology to clinical applications.

Adequate daily calcium intake should normally be achieved by dietary sources. Since low calcium diets are quite common in subjects that do not reach the recommended intake and particularly those at risk of fractures, calcium supplements may become necessary. Different forms of calcium salts are available, but products containing calcium citrate and calcium carbonate complexes are the most frequently used. Although only limited evidence on the efficacy and long-term safety of calcium citrate is available, these supplements may represent a valuable product for the management of different chronic pathological conditions. The aim of this review was to evaluate the current and potential clinical applications of calcium citrate. In particular, we focused on the use of calcium citrate supplementation in subjects with osteoporosis or in bariatric patients. Other pathological conditions that could benefit calcium citrate supplementation may include achloridria, chronic hypoparathyroidism and hypocitraturic subjects with moderate/high risk of nephrolithiasis. Indeed, citrate salts are widely used in the treatment of nephrolithiasis, since they have shown an inhibitory effect on kidney stone formation and recurrence.

A Rare Complication following Thyroid Percutaneous Ethanol Injection: Plummer Adenoma.

Percutaneous ethanol injection (PEI) is a technique used only for benign thyroid nodules, cystic or mixed cystic-solid with a large fluid component. It is a quite low-cost, safe, and outpatient method of treatment. Rare and severe complications have been described after PEI: jugular vein thrombosis and severe ethanol toxic necrosis of the larynx combined with necrotic dermatitis. Moreover, only four thyrotoxicosis cases due to Graves' disease have been reported. We report a case of 58-year-old female with a voluminous thyroid cystic nodule, occupying almost the entire left thyroid lobe. Our patient had already performed surgical visit and intervention of thyroidectomy had been proposed to her, which she refused. At baseline, our patient has a normal thyroid function with negative autoantibodies. According to the nodular structure, intervention of PEI has been performed with a significant improvement of compressive symptoms and cosmetic disorders. About 30 days after treatment, there was a significant volume reduction, but patient developed an acclaimed symptomatic thyrotoxicosis. After ruling out several causes of hyperthyroidism and according to the thyroid scintigraphy findings, we made the diagnosis of Plummer adenoma. To our knowledge, our patient is the first case of Plummer adenoma following PEI treatment of nontoxic thyroid nodule.