Papillary Thyroid Microcarcinoma: Differences between Lesions in Incidental and Nonincidental Settings-Considerations on These Clinical Entities and Personal Experience.

Papillary thyroid microcarcinoma (PTMC) represents 35-40% of all papillary cancers; it is defined as a nodule ≤ 10 mm at the time of histological diagnosis. The clinical significance of PTMC is still controversial, and it may be discovered in two settings: incidental PTMC (iPTMC), in which it is identified postoperatively upon histological examination of thyroid specimens following thyroid surgery for benign disease, and nonincidental PTMC (niPTMC), in which it is diagnosed before surgery. While iPTMC appears to be related to mild behavior and favorable clinical outcomes, niPTMC may exhibit markers of aggressiveness. We retrospectively review our experience, selecting 54 PTMCs: 28 classified as niPTMC (52%) and 26 classified as iPTMC (48%). Patients with niPTMC showed significant differences, such as younger age at diagnosis (p < 0.001); a lower male/female ratio (p < 0.01); a larger mean nodule diameter (p < 0.001); and a higher rate of aggressive pathological findings, such as multifocality, capsular invasion and/or lymphovascular invasion (p = 0.035). Other differences found in the niPTMC subgroup included a higher preoperative serum TSH level, higher hospital morbidity and a greater need for postoperative iodine ablation therapy (p < 0.05), while disease-free long-term survival did not differ between subgroups (p = 0.331) after a mean follow-up (FU) of 87 months, with one nodal recurrence among niPTMCs. The differences between iPTMC and niPTMC were consistent: patients operated on for total thyroidectomy and showing iPTMC can be considered healed after surgery, and follow-up should be designed to properly calibrate hormonal supplementation; conversely, niPTMC may sometimes exhibit aggressive behavior, and so the FU regimen should be closer and aimed at early detection of cancer recurrence.

Metastasis of lung carcinoid in the thyroid gland after 18 years: it is never too late. A case report and review of the literature.

Metastasis to the thyroid gland is a rare event. To date, only 11 cases of metastasis from neuroendocrine tumors (NETs) originating in the lung have been reported. We present a case of a patient in his 40s harboring two nodules in the thyroid gland that were diagnosed as well-differentiated NET (G1). Eighteen years before the patient underwent a lung lobectomy of the right upper lobe for a bronchial typical carcinoid with metastasis in one lymph node. Normal blood levels of calcitonin virtually ruled out the diagnosis of medullary thyroid carcinoma (MTC) and supported the diagnosis of a possible thyroid metastasis of the previous bronchial NET. Mutational analysis performed on both primary and metastasis tumor tissue did not show any mutation in the 409 genes analyzed.

Calcium Citrate Versus Calcium Carbonate in the Management of Chronic Hypoparathyroidism: A Randomized, Double-Blind, Crossover Clinical Trial.

In hypoparathyroidism (HypoPT), calcium supplementation is virtually always required, although the disease is likely to be associated with an increased risk of nephrolithiasis. The use of calcium citrate (Ca-Cit) theoretically could have a positive impact on the nephrolithiasis risk because citrate salts are used to reduce this risk. Our objective was to evaluate the potential therapeutic advantage of Ca-Cit in comparison with calcium carbonate (CaCO3 ) in HypoPT, on nephrolithiasis risk factors, as well as to their ability to maintain desirable serum calcium levels. We also evaluated these preparations on quality of life (QOL). This randomized, double-blind, crossover trial recruited 24 adults with postsurgical chronic hypoparathyroidism at Campus Bio-Medico University of Rome. Participants were randomized 1:1 to Ca-Cit or CaCO3 for 1 month and then crossed over to the other treatment for another month. The primary outcomes were changes in albumin-adjusted serum calcium and in ion activity product of calcium oxalate levels (AP[CaOx] index). Secondary efficacy outcomes included changes in SF-36 survey score, fatigue score, constipation, and adverse events. No difference in terms of AP(CaOx) index was observed between the two groups. However, Ca-Cit was associated with a significant reduction in the oxalate/creatinine ratio compared with CaCO3 (-2.46 mmol/mol [SD 11.93] versus 7.42 mmol/mol [SD 17.63], p = 0.029). Serum calcium and phosphorus concentration was not different between the two calcium preparations. Ca-Cit was associated with less constipation (p = 0.047). No difference was found in QOL scores. Although Ca-Cit did not modify the AP(CaOx) index when compared with CaCO3, it was associated with a reduction in urinary oxalate excretion that could have a potential beneficial effect on nephrolithiasis risk. These results are likely to have clinical implications in HypoPT, particularly those who do not tolerate CaCO3 and those affected by nephrolithiasis. A longer-term experience is needed to confirm these findings. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Current protocols and clinical efficacy of human fetal liver cell therapy in patients with liver disease: A literature review.

The fetal liver is unique because of the coexistence of cells with endodermal and mesenchymal origins, making it a potential source of hepatic and pancreatic regenerative medicine. The liver appears at about the third week of gestation, growing rapidly from the fifth to the 10th week. We define fetal liver from 10 weeks of gestation, when hematopoietic progenitor cells gradually migrate from the aorta-mesonephros-gonad region to colonize the liver. Indeed, the fetal liver may be the most available source of cell therapy for liver disease. We conducted a review of the literature using Medline and EMBASE (up to May 2021) to identify clinical studies in which patients with liver disease had been given fetal liver cell therapy. This literature review highlighted the heterogeneity of cell isolation and selection protocols, which hinders the ability to pool data and perform a meta-analysis. A limitation of the studies analyzed was the scarcity of reports (n = 8) and the extremely small sample sizes (median sample size of treated patients was two), although there was a fairly long follow-up (median 12 months). The weeks after conception ranged from 16 to 34. There were no randomized controlled trials, and therefore no study was stratified as being of good methodological quality. Cryopreservation may help to circumvent the critical logistic issues that hamper the use of fetal liver cell therapy in clinical practice. To help consolidate the role of the fetal liver in regenerative medicine, good preclinical translational studies are necessary, whereas tracing strategies and biopsy-based endpoints are crucial in the clinic, along with well-designed, large, multicenter, randomized controlled trials using clinically applicable primary outcomes and refined imaging assessment.

Effect of Chlorhexidine Digluconate in Early Wound Healing of Human Gingival Tissues. A Histological, Immunohistochemical and Biomolecular Analysis.

Chlorhexidine digluconate (CHX) is considered the gold standard for oral cavity antiseptic treatment. Nevertheless, several in vitro studies have reported detrimental effects in oral tissue repair. The aim of the present study was to evaluate the in vivo effect of post-surgical CHX mouth rinse on gingival tissue (G) 24 h after injury. G biopsies were obtained in three patients 24 h after surgery with the indication of post-surgical 0.12% CHX use and were compared with those obtained from the same patients without any antiseptic use. Changes in collagen production, cell proliferation, and apoptosis were examined by histological and Ki-67/P53 immunohistochemical analysis. Fibrotic markers (COL1A1, αSMA), proapoptotic protein (BAX) expression, and wound healing-related gene modulation (RAC1, SERPINE1, TIMP1) were analyzed by quantitative real-time PCR analysis. CHX was able to reduce cellular proliferation and increase collagen deposition, proapoptotic molecule and fibrotic marker expression, and myofibroblast differentiation, reduce expression of RAC1 and trigger expression of SERPINE1 and TIMP1, showing "scar wound healing response" pattern. This study assessed for the first time the in vivo effects of CHX on gingival tissue. The demonstration of a CHX-induced fibrotic transformation, leading to scar repair, supports the need for new post-surgical clinical protocols based on a strategic and personalized use of CHX.

Improvement of the Collection, Maintenance, and Analysis of Neoplastic Cells from Urine Specimens with the Use of CytoMatrix.

Urine cytology is a non-invasive test used in combination with cystoscopy for screening and follow-up of urothelial carcinoma (UC). Although cytology can be used to efficiently identify high-grade UC, it has a lower accuracy for the diagnosis of low-grade UC or patients with presence of atypical urothelial cells (AUC). For these reasons, ancillary tests have been added to urine cytology in order to improve the accuracy. However, the poor abundance of neoplastic cells in most samples and the absence of a "tissue-like" structure remains a major challenge. We used a novel synthetic support called CytoMatrix which has the property of capturing and storing cells and micro-macro aggregates within its three-dimensional structure. The urine specimens were obtained from 12 patients: 6 with suspected urothelial neoplasia (low- and high-grade) and 6 with AUC or non-neoplastic samples. The first step is the urine samples preparation, through several centrifugation passages; the second step consists in absorbing cells on the CytoMatrix, and in the subsequent formalin fixation, standard processing and paraffin embedding to prepare FFPE-CytoMatrix block. In the final step, sections are consecutively cut, stained with hematoxylin-eosin (H&E), and analyzed via UroVysion FISH and immunohistochemistry (IHC). Using our simple and reliable protocol, we can improve the quality of urine specimens, allowing a better collection, maintenance, and analysis of cells, with the advantage of using ancillary tests to support cytological diagnosis and the advantage of storing cellular material in a FFPE-CytoMatrix block.

DCLK1, a Putative Stem Cell Marker in Human Cholangiocarcinoma.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a very aggressive cancer showing the presence of high cancer stem cells (CSCs). Doublecortin-like kinase1 (DCLK1) has been demonstrated as a CSC marker in different gastroenterological solid tumors. Our aim was to evaluate in vitro the expression and the biological function of DCLK1 in intrahepatic CCA (iCCA) and perihilar CCA (pCCA). APPROACH AND RESULTS: Specimens surgically resected of human CCA were enzymatically digested, submitted to immunosorting for specific CSC markers (LGR5 [leucine-rich repeat-containing G protein-coupled receptor], CD [clusters of differentiation] 90, EpCAM [epithelial cell adhesion molecule], CD133, and CD13), and primary cell cultures were prepared. DCLK1 expression was analyzed in CCA cell cultures by real-time quantitative PCR, western blot, and immunofluorescence. Functional studies have been performed by evaluating the effects of selective DCLK1 inhibitor (LRRK2-IN-1) on cell proliferation (MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, cell population doubling time), apoptosis, and colony formation capacity. DCLK1 was investigated in situ by immunohistochemistry and real-time quantitative PCR. DCLK1 serum concentration was analyzed by enzyme-linked immunosorbent assay. We describe DCLK1 in CCA with an increased gene and protein DCLK1 expression in pCCALGR5+ and in iCCACD133+ cells compared with unsorted cells. LRRK2-IN-1 showed an anti-proliferative effect in a dose-dependent manner. LRRK2-IN-1 markedly impaired cell proliferation, induced apoptosis, and decreased colony formation capacity and colony size in both iCCA and pCCA compared with the untreated cells. In situ analysis confirmed that DCLK1 is present only in tumors, and not in healthy tissue. Interestingly, DCLK1 was detected in the human serum samples of patients with iCCA (high), pCCA (high), HCC (low), and cirrhosis (low), but it was almost undetectable in healthy controls. CONCLUSIONS: DCLK1 characterizes a specific CSC subpopulation of iCCACD133+ and pCCALGR5+ , and its inhibition exerts anti-neoplastic effects in primary CCA cell cultures. Human DCLK1 serum might represent a serum biomarker for the early CCA diagnosis.

Analytical validation of a novel targeted next-generation sequencing assay for mutation detection in thyroid nodule aspirates and tissue.

PURPOSE: The identification of somatic mutations in cancer specimens enables detection of molecular markers for personalized treatment. We recently developed a novel molecular assay and evaluated its clinical performance as an ancillary molecular method for indeterminate thyroid nodule cytology. Herein we describe the analytical validation of the novel targeted next-generation sequencing (NGS) assay in thyroid samples from different sources. METHODS: We present validation data of a novel NGS-based panel on 463 thyroid samples, including 310 fine-needle aspiration (FNA) specimens from different sources (FNA collected in preservative solution, liquid-based, and stained smears), 10 fresh frozen, and 143 formalin-fixed paraffin-embedded (FFPE) thyroid tissue specimens. Sequencing performance in the different samples was evaluated along with reproducibility, repeatability, minimum nucleic acid input to detect variants, and analytical sensitivity of the assay. RESULTS: All thyroid samples achieved high sequencing performance, with a mean base coverage depth ranging from 2228 × (in liquid-based FNA) to 3661 × (in FNA stained smears), and coverage uniformity ranging from 86% (in FFPE) to 95% (in FNA collected in preservative solution), with all target regions covered above the minimum depth required to call a variant (500×). The minimum nucleic acid input was 1 ng. Analytic sensitivity for mutation detection was 2-5% mutant allele frequency. CONCLUSIONS: This validation study of a novel NGS-based assay for thyroid nodules demonstrated that the assay can be reliably used on multiple thyroid sample types, including FNA from different sources and FF and FFPE thyroid samples, thus providing a robust and reliable assay to genotype thyroid nodules, which may improve thyroid cancer diagnosis and care.

Computer-aided diagnostic system for thyroid nodule sonographic evaluation outperforms the specificity of less experienced examiners.

PURPOSE: Computer-aided diagnosis (CAD) may improve interobserver agreement in the risk stratification of thyroid nodules. This study aims to evaluate the performance of the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) classification as estimated by an expert radiologist, a senior resident, a medical student, and a CAD system, as well as the interobserver agreement among them. METHODS: Between July 2016 and 2018, 107 nodules (size 5-40 mm, 27 malignant) were classified according to the K-TIRADS by an expert radiologist and CAD software. A third-year resident and a medical student with basic imaging training, both blinded to previous findings, retrospectively estimated the K-TIRADS classification. The diagnostic performance was calculated, including sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristic curve. RESULTS: The CAD system and the expert achieved a sensitivity of 70.37% (95% CI 49.82-86.25%) and 81.48% (61.92-93.7%) and a specificity of 87.50% (78.21-93.84%) and 88.75% (79.72-94.72%), respectively. The specificity of the student was significantly lower (76.25% [65.42-85.05%], p = 0.02). CONCLUSION: In our opinion, the CAD evaluation of thyroid nodules stratification risk has a potential role in a didactic field and does not play a real and effective role in the clinical field, where not only images but also specialistic medical practice is fundamental to achieve a diagnosis based on family history, genetics, lab tests, and so on. The CAD system may be useful for less experienced operators as its specificity was significantly higher.

Cardiovascular autonomic neuropathy as a cause of fatigue in chronic hypoparathyroidism.

PURPOSE: Hypoparathyroidism (hypoPT) results in an impairment of quality of life (QoL), an increase in fatigue and a higher risk of mortality. Cardiovascular autonomic neuropathy (CAN) is an impairment of the cardiovascular autonomic system and is associated with increased mortality and fatigability. Patients with hypoPT show an increased risk of CAN. However, no previous studies have investigated the association between CAN and QoL in hypoPT. To test whether CAN is associated with fatigue and impaired QOL in hypoPT patients. METHODS: We enrolled 48 subjects with postsurgical hypoPT treated with calcium and calcitriol and 38 healthy subjects who underwent thyroidectomy. Subjects completed the RAND 36-Item Short Form (SF-36) Health Survey, evaluating physical (PCS) and mental (MCS) health, and fatigue score. CAN was assessed using cardiovascular autonomic reflex tests (CARTs). Participants were considered to have "early CAN" (EC) if they had one abnormal CART and "definite CAN" (DC) with two or more abnormal CARTs. RESULTS: Compared with controls, hypoPT population had lower fatigue scores (44.5 IQRː9 vs 38.5 IQRː12.3, P = 0.031). In the hypoPT group, only participants with DC had a lower fatigue score than subjects without CAN (DC: ß: -9.55, P = 0.005) after adjusting for age, duration of disease, calcium concentration, TSH, calcitriol and calcium supplementation. No differences were found in the PCS and MCS scores in the hypoPT group. CONCLUSIONS: CAN may explain fatigue, a common complaint of postsurgical hypoPT patients. Further larger and prospective investigations are needed to confirm our findings.

Functions and the Emerging Role of the Foetal Liver into Regenerative Medicine.

During foetal life, the liver plays the important roles of connection and transient hematopoietic function. Foetal liver cells develop in an environment called a hematopoietic stem cell niche composed of several cell types, where stem cells can proliferate and give rise to mature blood cells. Embryologically, at about the third week of gestation, the liver appears, and it grows rapidly from the fifth to 10th week under WNT/ß-Catenin signaling pathway stimulation, which induces hepatic progenitor cells proliferation and differentiation into hepatocytes. Development of new strategies and identification of new cell sources should represent the main aim in liver regenerative medicine and cell therapy. Cells isolated from organs with endodermal origin, like the liver, bile ducts, and pancreas, could be preferable cell sources. Furthermore, stem cells isolated from these organs could be more susceptible to differentiate into mature liver cells after transplantation with respect to stem cells isolated from organs or tissues with a different embryological origin. The foetal liver possesses unique features given the co-existence of cells having endodermal and mesenchymal origin, and it could be highly available source candidate for regenerative medicine in both the liver and pancreas. Taking into account these advantages, the foetal liver can be the highest potential and available cell source for cell therapy regarding liver diseases and diabetes.

Indeterminate thyroid nodules (TIR3A/TIR3B) according to the new Italian reporting system for thyroid cytology: A cytomorphological study.

OBJECTIVE: The Italian reporting system for thyroid cytology classifies indeterminate lesions as TIR3A (low risk) or TIR3B (high risk) and is meant to provide practical guidance rather than a detailed consideration of morphological features. We aimed to assess which cytological features have the most diagnostic value and whether they are effective in classifying nodules as either TIR3A or TIR3B and in predicting histological outcomes. METHODS: Thyroid fine-needle aspirates from 111 indeterminate nodules were reviewed blinded to clinical information, TIR3A/TIR3B classification, and histology in order to assess which cytological features (pooled into artefacts, smear background, architectural and nuclear atypia, and oncocytes) differentiate TIR3A from TIR3B, and benign from malignant histological outcomes. RESULTS: Of the cytological features examined, those specific for TIR3B included high cellularity, nuclear atypia, oncocyte predominance and transgressing vessels. Features specific for TIR3A included artefacts, low cellularity and oncocyte sparseness. Other features, such as microfollicules/trabeculae, were non-specific. Due to the different distributions of these features, three TIR3B subgroups were identifiable: follicular lesions with oncocytic changes, pure follicular lesions, and follicular lesions with nuclear atypia, whereas no subgroups were identifiable in TIR3A. Nuclear atypia was a significant indicator of malignancy, whereas oncocyte predominance was not a reliable predictor of malignancy. High cellularity and microfollicules/trabeculae were not indicative of any histological outcome. CONCLUSIONS: The majority of the assessed features were good predictors of histological outcomes. The TIR3A category included undefined nodules due to the absence of characterising features, whereas the TIR3B category included nodules with a greater number of distinguishing features.

Prospective Evaluation of Semiquantitative Strain Ratio and Quantitative 2D Ultrasound Shear Wave Elastography (SWE) in Association with TIRADS Classification for Thyroid Nodule Characterization.

PURPOSE: To evaluate the diagnostic performance of strain ratio elastography (SRE) and shear wave elastography (SWE) alone and in combination with Thyroid Imaging Reporting and Data System (TIRADS) classification parameters to improve differentiation between benign and malignant thyroid nodules. MATERIALS AND METHODS: In this prospective study benign (n = 191) and malignant (n = 52) thyroid nodules were examined with high-resolution ultrasound (US) features using the TIRADS lexicon and SRE semiquantitative and SWE quantitative findings using histology or cytology as the gold standard with a 12-month follow-up. Sensitivity (Se), specificity (Sp) and the area under the ROC curve (AUROC) were used to evaluate the diagnostic performance of each feature and combinations of the methods. RESULTS: TIRADS score showed a sensitivity of 59.6 %, a specificity of 83.8 % with an AUROC of 0.717, a PPV of 50.0 % and an NPV of 88.4 %. SRE yielded the highest performance with a sensitivity of 82.7 %, a specificity of 92.7 % with AUROC of 0.877, a PPV 75.4 % and an NPV of 95.2 %. SWE (kPa) had a sensitivity and specificity of 67.3 % and 82.7 %, respectively, with an AUROC of 0.750, a PPV of 51.5 % and an NPV of 90.3 %. Differences were significant for SRE only but not for SWE. CONCLUSION: Ultrasound elastography may improve thyroid nodule discrimination. In particular, SRE has a better performance than TIRADS classification, while their combination improves sensitivity.

Treatment of thyroid nodules with radiofrequency: a 1-year follow-up experience.

PURPOSE: The aim of this study is to assess the effectiveness and safety of radiofrequency ablation (RFA) in debulking benign solid thyroid nodules. MATERIALS AND METHODS: This is a retrospective review of 77 patients with predominantly solid thyroid nodules treated with RFA in a single center between 2013 and 2016. All patients declined or were not eligible for surgery. Benign proven thyroid nodules causing compressive symptoms and cosmetic concerns were considered for treatment. Nodule volume, thyroid nodule related compressive symptoms, cosmetic concerns and thyroid function were evaluated. RESULTS: All patients underwent a single treatment session. Mean nodule volume decreased from 17.9 ± 15.6 mL at baseline to 5.2 ± 7.4 after 12 months with a volume reduction ratio (VRR) of 70.9% ± 20.8%. There were no identifiable factors predictive of response to RFA. Median cosmetic and symptom scores of the entire population decreased from 3 [2-4] and 3 [0-10] to 1 [1-3] (p < 0.001) and 0 [0-5] (p < 0.001), respectively. No major complications occurred and RFA did not affect thyroid function when normal. CONCLUSION: RFA induces substantial volume reduction of predominantly solid thyroid nodules and improves compressive symptoms and cosmetic concerns. RFA does not impact normal thyroid function and has an acceptable safety profile.

Importance of a careful clinical evaluation in the diagnosis of cystic pancreatic tumors.

INTRODUCTION: Intraductal papillary mucinous neoplasms (IPMN) are a rare group of pancreatic neoplasms. Often are asymptomatic and, when are symptomatic, patients complain sensation of weight in the abdomen or compression at the neighboring structures. In many cases the diagnosis is incidental, during a CT or MR performed for other raisons. CASE REPORT: We report a case of a 59-year-old woman with diagnosis of post-pancreatitis pseudocyst who, instead, was affected by an intraductal papillary mucinous neoplasm (IPMN), treated by us with pancreatoduodenectomy. DISCUSSION: The diagnosis of IPMN has increased in recent years thanks to an improvement in radiological investigation. The study of pancreatic lesions must be very careful and it is absolutely necessary that diagnostic imaging be accompanied by a correct clinical evaluation of the patient. CONCLUSION: A thorough anamnesis is required in patient with history of acute pancreatitis to avoid the mistake of exchanging an IPMN for a pseudocyst.

Reducing the Number of Unnecessary Thyroid Biopsies While Improving Diagnostic Accuracy: Toward the "Right" TIRADS.

Context: The prevalence of thyroid nodules in the general population is increasingly high, and at least half of those biopsied prove to be benign. Sonographic risk-stratification systems are being proposed as "rule-out" tests that can identify nodules that do not require fine-needle aspiration (FNA) cytology. Objective: To comparatively assess the performances of five internationally endorsed sonographic classification systems [those of the American Thyroid Association, the American Association of Clinical Endocrinologists, the American College of Radiology (ACR), the European Thyroid Association, and the Korean Society of Thyroid Radiology] in identifying nodules whose FNAs can be safely deferred and to estimate their negative predictive values (NPVs). Design: Prospective study of thyroid nodules referred for FNA. Setting: Single academic referral center. Patients: Four hundred seventy-seven patients (358 females, 75.2%); mean (SD) age, 55.9 (13.9) years. Main Outcome Measures: Number of biopsies classified as unnecessary, false-negative rate (FNR), sensitivity, specificity, predictive values, and diagnostic ORs for each system. Results: Application of the systems' FNA criteria would have reduced the number of biopsies performed by 17.1% to 53.4%. The ACR Thyroid Imaging Reporting and Data System (TIRADS) allowed the largest reduction (268 of 502) with the lowest FNR (NPV, 97.8%; 95% CI, 95.2% to 99.2%). Except for the Korean Society of Thyroid Radiology TIRADS, all other systems exhibited significant discriminatory performance but produced significantly smaller reductions in the number of procedures. Conclusions: Internationally endorsed sonographic risk stratification systems vary widely in their ability to reduce the number of unnecessary thyroid nodule FNAs. The ACR TIRADS outperformed the others, classifying more than half the biopsies as unnecessary with a FNR of 2.2%.

Cardiovascular Autonomic Neuropathy as a New Complication of Postsurgical Chronic Hypoparathyroidism.

Postsurgical hypoparathyroidism (hypoPT) increases fatigue and seems to affect the risk of mortality. Cardiovascular autonomic neuropathy (CAN) is an impairment of the cardiovascular autonomic system, a cause of increased mortality, and associated with increased fatigability. The aim of this study is to evaluate CAN in hypoPT and its relationship with hypocalcemia, PTH levels, and hyperphosphatemia. This is a cross-sectional study comparing 51 postsurgical hypoPT patients treated with calcium and calcitriol and 43 control subjects without any PTH/calcium/phosphate disorders who underwent thyroidectomy. CAN was assessed by heart rate (HR) response to deep breathing, HR response to the lying-to-standing test, HR response to the Valsalva maneuver, and blood pressure response to standing. Participants were considered to have "early CAN" if they had one abnormal result in the HR tests and "definite CAN" with two or more abnormal results. The prevalence of CAN was 23% in the control group and 78% in the hypoPT group (OR 11.48; 95% CI, 4.48 to 32.17). Patients with hypoPT and serum calcium (sCa) ≥8.5 mg/dL had a prevalence of early CAN of 72.4% and the prevalence was 86.4% in those with sCa <8.5 mg/dL. Definite CAN was found in 2.3% of the control group, 24.1% of the hypoPT group without hypocalcemia, and 59.1% of the hypoPT group with hypocalcemia. In the hypoPT group, the OR for definite CAN in the patients with hypocalcemia compared to the patients with normocalcemia was 4.54 (95% CI, 1.36 to 15.11). The association between low sCa and definite CAN was confirmed after adjustment for confounders with OR 13.62 (95% CI, 2.12 to 149.84). No association was found between definite CAN and PTH levels or high phosphate levels. HypoPT is associated with CAN and hypocalcemia seems to affect its severity. Larger and prospective studies are needed to confirm our findings. © 2018 American Society for Bone and Mineral Research.

Sonographic Presentation of Metastases to the Thyroid Gland: A Case Series.

Incidental sonographic discovery of thyroid nodules is an increasingly common event. The vast majority is benign, and those that are malignant, are generally associated with an indolent course and low mortality. Sonographic scoring systems have been developed to help clinicians identify nodules that warrant prompt fine-needle aspiration cytology (FNAC), but they are based largely on experience with papillary thyroid cancers. We analyzed the performance of four scoring systems widely used for this purpose (American Thyroid Association Guidelines, American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines, European Thyroid Imaging Reporting and Data System, and Korean Thyroid Imaging Reporting and Data System) in patients whose nodules proved to be metastases from other solid cancers. Such nodules reportedly account for 0.2% to 3% of all thyroid malignancies. Each scoring system was used to assess retrospectively the malignancy risk and indications for FNAC of five patients' thyroid nodules that were ultimately diagnosed as metastases (from renal cell carcinoma, breast cancer, and lung cancer in two cases and esophageal cancer). The primaries identified in these cases are those most commonly reported to metastasize to the thyroid. In two cases, the thyroid metastases were the first sign of undetected neoplastic disease. Although sonography alone cannot distinguish thyroid metastases from primary thyroid malignancies, all four scoring systems classified the metastatic nodules as suspicious enough to require FNAC. The five cases accounted for 0.2% of those cytologically examined in our center. In most cases, cytology provided useful guidance for the subsequent management of these lesions, which differs from that of primary thyroid cancers and requires multidisciplinary input.

Expression of disease resistance in genetically modified grapevines correlates with the contents of viral sequences in the T-DNA and global genome methylation.

Increased tolerance to pathogens is an important goal in conventional and biotechnology-assisted grapevine breeding programs worldwide. Fungal and viral pathogens cause direct losses in berry production, but also affect the quality of the final products. Precision breeding strategies allow the introduction of resistance characters in elite cultivars, although the factors determining the plant's overall performance are not fully characterized. Grapevine plants expressing defense proteins, from fungal or plant origins, or of the coat protein gene of grapevine leafroll-associated virus 3 (GLRaV-3) were generated by Agrobacterium-mediated transformation of somatic embryos and shoot apical meristems. The responses of the transformed lines to pathogen challenges were investigated by biochemical, phytopathological and molecular methods. The expression of a Metarhizium anisopliae chitinase gene delayed pathogenesis and disease progression against the necrotrophic pathogen Botrytis cinerea. Modified lines expressing a Solanum nigrum osmotin-like protein also exhibited slower disease progression, but to a smaller extent. Grapevine lines carrying two hairpin-inducing constructs had lower GLRaV-3 titers when challenged by grafting, although disease symptoms and viral multiplication were detected. The levels of global genome methylation were determined for the genetically engineered lines, and correlation analyses demonstrated the association between higher levels of methylated DNA and larger portions of virus-derived sequences. Resistance expression was also negatively correlated with the contents of introduced viral sequences and genome methylation, indicating that the effectiveness of resistance strategies employing sequences of viral origin is subject to epigenetic regulation in grapevine.

PTH(1-34) for Surgical Hypoparathyroidism: A 2-Year Prospective, Open-Label Investigation of Efficacy and Quality of Life.

Context: Daily parathyroid hormone (PTH) (1-34) administrations can reduce the required total daily dose of calcium and calcitriol and restore normocalcemia in refractory hypoparathyroidism. However, most PTH(1-34) trials have been conducted on small cohorts including subjects with hypoparathyroidism of various etiologies, and quality of life (QOL) was not investigated. Objective: To investigate the effects of 24-month PTH(1-34) treatment in a homogeneous cohort of adult subjects with postoperative hypoparathyroidism and to evaluate QOL changes. Design: Prospective open-label study. Setting: Italian multicenter study. Participants: 42 subjects. Intervention: Twice-daily PTH(1-34) 20 µg subcutaneous injection. Main Outcome Measures: Calcium and vitamin D supplementation requirements, serum calcium, phosphate, and urinary calcium excretion (3, 6, 12, 18, 24 months). At baseline and at 6 and 24 months, QOL was evaluated by the RAND 36-Item Short Form (SF-36) Health Survey, covering eight domains of physical and mental health. Results: Mean serum calcium concentration significantly increased from baseline to 3 months (7.6 ± 0.6 vs 8.9 ± 1.1 mg/dL, P < 0.001) and remained stable until the end of the study, despite reductions in calcium and vitamin D supplementation. Phosphate levels gradually decreased from baseline to 6 months (4.3 ± 1.1 vs 3.9 ± 0.6 mg/dL, P < 0.019), remaining stable until 24 months. Serum alkaline phosphatase and calcium excretion gradually increased from baseline to 24 months. Data from SF-36 showed a significant improvement in the mean scores of all eight domains (P < 0.001). Conclusion: This study demonstrates the efficacy and safety of PTH(1-34) to treat adult patients with postsurgical hypoparathyroidism. PTH(1-34) may improve their mental and physical health.