Search

Introduction: The bone matrix protein osteocalcin (OC), secreted by osteoblasts, displays endocrine effects. We tested the hypothesis that OC modulates parathyroid tumor cell function., Methods: Primary cell cultures derived from parathyroid adenomas (PAds) and HEK293 cells transiently transfected with the putative OC receptor GPRC6A or the calcium sensing receptor (CASR) were used as experimental models to investigate γ-carboxylated OC (GlaOC) or uncarboxylated OC (GluOC) modulation of intracellular signaling., Results: In primary cell cultures derived from PAds, incubation with GlaOC or GluOC modulated intracellular signaling, inhibiting pERK/ERK and increasing active β-catenin levels. GlaOC increased the expression of PTH, CCND1 and CASR , and reduced CDKN1B/p27 and TP73 . GluOC stimulated transcription of PTH , and inhibited MEN1 expression. Moreover, GlaOC and GluOC reduced staurosporin-induced caspase 3/7 activity. The putative OC receptor GPRC6A was detected in normal and tumor parathyroids at membrane or cytoplasmic level in cells scattered throughout the parenchyma. In PAds, the membrane expression levels of GPRC6A and its closest homolog CASR positively correlated; GPRC6A protein levels positively correlated with circulating ionized and total calcium, and PTH levels of the patients harboring the analyzed PAds. Using HEK293A transiently transfected with either GPRC6A or CASR, and PAds-derived cells silenced for CASR , we showed that GlaOC and GluOC modulated pERK/ERK and active β-catenin mainly through CASR activation., Conclusion: Parathyroid gland emerges as a novel target of the bone secreted hormone osteocalcin, which may modulate tumor parathyroid CASR sensitivity and parathyroid cell apoptosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Verdelli, Tavanti, Forno, Vaira, Maggiore, Vicentini, Dalino Ciaramella, Perticone, Lombardi and Corbetta.)

Background: The increase in cardiovascular disease cases that require minimally invasive treatment is inducing a new need to train physicians to perform them safely and effectively. Nevertheless, adaptation to simulation-based training has been slow, especially for complex procedures., Objectives: We describe a newly developed mitral valve repair (MVR) simulator, equipped with new objective performance assessment methods, with an emphasis on its use for training the MitraClip™ procedure., Methods: The MVR contains phantoms of all anatomical structures encountered during mitral valve repair with a transvenous, transseptal approach. In addition, several cameras, line lasers, and ultraviolet lights are used to mimic echocardiographic and fluoroscopic imaging and with a remote eye tracker the cognitive behaviour of the operator is recorded. A pilot study with a total of 9 interventional cardiologists, cardiac surgeons and technical experts was conducted. All participants performed the MitraClip procedure on the MVR simulator using standard interventional tools. Subsequently, each participant completed a structured questionnaire to assess the simulator., Results: The simulator functioned well, and the implemented objective performance assessment methods worked reliably. Key performance metrics such as x-ray usage were comparable with results from studies assessing these metrics in real interventions. Fluoroscopy imaging is realistic for the transseptal puncture but reaches its limits during the final steps of the procedure., Conclusion: The functionality and objective performance assessment of the MVR simulator were demonstrated. Especially for complex procedures such as the MitraClip procedure, this simulator offers a suitable platform for risk-free training and education., (© 2021. The Author(s).)

Whether to conduct remnant ablation or adjuvant radioactive iodine (RAI) therapy in patients with intrathyroidal differentiated thyroid carcinoma (DTC), sized 1.1-4 cm, is debated. We evaluated the impact of RAI on outcome in this category of DTCs. We retrospectively enrolled 308 patients submitted to total thyroidectomy: 198 had tumors sized 1.1-2 cm (Group 1) and 110 of 2.1-4 cm (Group 2). Both groups were divided into patients receiving and not receiving RAI after surgery. RAI+ and RAI- patients did not significantly differ, regarding several clinical and pathological features. Final outcome was defined according to dynamic risk stratification. Remission was observed in the majority of Group 1 and Group 2 patients and outcome did not significantly differ between RAI+ and RAI- patients: respectively, 95.8% vs. 93.7% in Group 1, and 87.7% vs. 86.5% in Group 2. The majority of persistent cases, either RAI+ or RAI-, received therapeutic RAI administration, and about 50% of RAI- cases had an excellent response at final follow up, whereas no RAI+ persistent patients had a beneficial effect. Our findings demonstrate that patients with an intrathyroidal DTC sized 1.1-4 cm do not benefit from RAI. The outcome of these patients remains favorable, and the few patients with persistent diseases can be treated with RAI during follow up.

Background: Controversies remain about the ideal risk-based surgical approach for differentiated thyroid cancer (DTC)., Methods: At a single tertiary care institution, 370 consecutive patients with low- or intermediate-risk DTC were submitted to either lobectomy (LT) or total thyroidectomy (TT) and were followed up., Results: Event-free survival by Kaplan-Meier curves was significantly higher after TT than after LT for the patients with either low-risk (P = 0.004) or intermediate-risk (P = 0.032) tumors. At the last follow-up visit, the prevalence of event-free patients was higher in the TT group than in the LT low-risk group (95% and 87.5%, respectively; P = 0.067) or intermediate-risk group (89% and 50%; P = 0.008). No differences in persistence prevalence were found among microcarcinomas treated by LT or TT (low risk, P = 0.938 vs. intermediate-risk, P = 0.553). Nevertheless, 15% of the low-risk and 50% of the intermediate-risk microcarcinomas treated by LT were submitted to additional treatments. On the other hand, macrocarcinomas were significantly more persistent if treated with LT than with TT (low-risk, P = 0.036 vs. intermediate-risk, P = 0.004). Permanent hypoparathyroidism was more frequent after TT (P = 0.01). After LT, thyroglobulin (Tg)/thyroid-stimulating hormone (TSH) had shown decreasing trend in 68% of the event-free patients and an increasing trend in the persistent cases., Conclusions: Lobectomy can be proposed for low-risk microcarcinomas, although in a minority of cases, additional treatments are needed, and a longer follow-up period usually is required to confirm an event-free outcome compared with that for patients treated with TT. On the other hand, to achieve an excellent response, TT should be favored for intermediate-risk micro- and macro-DTCs despite the higher frequency of postsurgical complications.

Tumors of the parathyroid glands are the second most common endocrine neoplasia. Epigenetic studies revealed an embryonic signature involved in parathyroid tumorigenesis. Here, we investigated the expression of the stem core genes SOX2, POU5F1/OCT4, and NANOG . Rare cells within normal parathyroid glands expressed POU5F1/OCT4 and NANOG , while SOX2 was undetectable. Nuclear SOX2 expression was detectable in 18% of parathyroid adenomas (PAds, n = 34) involving 5-30% of cells, while OCT4 and NANOG were expressed at the nuclear level in a more consistent subset of PAds involving 15-40% of cells. Most parathyroid carcinomas expressed the core stem genes. SOX2 -expressing cells co-expressed parathormone (PTH). In PAds-derived primary cultures, silencing of the tumor suppressor gene MEN1 induced the expression of SOX2 , likely through a MEN1/HAR1B/SOX2 axis, while calcium-sensing receptor activation increased SOX2 mRNA levels through YAP1 activation. In addition, inducing nuclear β-catenin accumulation in PAds-derived primary cultures by short-term incubation with lithium chloride (LiCl), SOX2 and POU5F1/OCT4 expression levels increased, while NANOG transcripts were reduced, and LiCl long-term incubation induced an opposite pattern of gene expression. In conclusion, detection of the core stem genes in parathyroid tumors supports their embryogenic signature, which is modulated by crucial genes involved in parathyroid tumorigenesis.

Cytology is the gold standard method for the differential diagnosis of thyroid nodules, though 25-30% of them are classified as indeterminate. We aimed to set up a 'thyroid risk score' (TRS) to increase the diagnostic accuracy in these cases. We prospectively tested 135 indeterminate thyroid nodules. The pre-surgical TRS derived from the sum of the scores assigned at cytology, EU-TIRADS classification, nodule measurement, and molecular characterization, which was done by our PTC-MA assay, a customized array able to cost-effectively evaluate 24 different genetic alterations including point mutations and gene fusions. The risk of malignancy (ROM) increased paralleling the score: in the category >4 and ≤ 6 (low suspicion), >6 ≤ 8 (intermediate suspicion), and >8 (high suspicion); ROM was 10, 47 and 100%, respectively. ROC curves selected the score >6.5 as the best threshold to differentiate between malignant and benign nodules (P < 0.001). The TRS > 6.5 had a better performance than the single parameters evaluated separately, with an accuracy of 77 and 82% upon inclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features among malignant or benign cases, respectively. In conclusion, for the first time, we generated a score combining a cost-effective molecular assay with already validated tools, harboring different specificities and sensitivities, for the differential diagnosis of indeterminate nodules. The combination of different parameters reduced the number of false negatives inherent to each classification system. The TRS > 6.5 was highly suggestive for malignancy and retained a high accuracy in the identification of patients to be submitted to surgery.

Transcatheter tricuspid valve intervention (TTVI) is an emerging treatment for patients with symptomatic severe tricuspid regurgitation (TR). Currently, the issues that arise during TTVI are unclear. Here, a 78-year-old woman with severe TR underwent transcatheter tricuspid valve annuloplasty using a Cardioband (Edwards Lifesciences, Irvine, CA). We attempted to cinch the Dacron band after anchoring; however, it was impossible to connect the distal tip of the size adjustment tool and the Dacron band because the cinching wire was tangled around the Dacron band. We resolved this issue without surgical intervention, and eventually cinched the annulus. Final echocardiography revealed dramatic TR reduction. To our knowledge, no study has reported a tangled wire in a Dacron band during Cardioband use. Clinicians should be aware of the risks accompanying this concern in case where it is impossible to connect the distal tip of the size adjustment tool and the Dacron band during cinching., (© 2020 Wiley Periodicals, Inc.)

The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1 (MEN1) , while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61 , CTGF , and WNT5A , and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.

Tumors of the parathyroid glands are highly vascularized and display a microRNA (miRNA) profile divergent from normal parathyroid glands (PaNs). Angiogenic miRNAs, namely miR-126-3p, miR-126-5p, and miR-296-5p, have been found downregulated in parathyroid tumors. Here, we show that miR-126-3p expression levels are reduced in parathyroid adenomas (PAds; n = 12) compared with PaNs (n = 4). In situ hybridization (ISH) of miR-126-3p and miR-296-5p in 10 PAds show that miR-126-3p is expressed by endothelial cells lining the walls of great vessels and by cells within the thin stroma surrounding acinar structures. At variance, miR-296-5p was detectable in most PAd epithelial cells. Combining ISH for miR-126-3p with immunohistochemistry for the endothelial and mesenchymal markers CD34, CD31 and α-smooth muscle actin (αSMA), we could identify that miR-126-3p is localized in the αSMA-positive thin stroma. Further, miR-126-3p-expressing cells are enriched in the CD34-positive stromal cells surrounding epithelial cell acinar structures, a cellular pattern consistent with tumor-associated myofibroblasts (TAMs). In line with this, CD34-positive cells, sorted by FACS from PAds tissues, express miR-126-3p at higher levels than CD34-negative cells, suggesting that miR-126-3p downregulation promotes the endothelial-to-αSMA+ mesenchymal transition. In human mesenchymal stem cells derived from bone marrow (hBM-MSCs), a model of TAMs, the co-culture with PAds-derived cells for 5 days decreases miR-126-3p, while it increases VEGFA expression. At variance, adrenomedullin (ADM) expression is unaffected. Finally, overexpression of the miR-126-3p mimic in both hBM-MSCs and PAds-derived explants downregulates VEGFA expression levels. In conclusion, miR-126-3p is expressed by both endothelial cells and TAMs in PAds, and its downregulation promotes neoangiogenesis, possibly through VEGFA overexpression.

Background: Cerebral embolic protection devices (CEPDs) have emerged as a mechanical barrier to prevent debris from reaching the cerebral vasculature, potentially reducing stroke incidence. Bovine aortic arch (BAA) is the most common arch variant and represents challenge anatomy for CEPD insertion during transcatheter aortic valve replacement (TAVR)., Methods: Cohort study reporting the Sentinel TM Cerebral Protection System insertion's feasibility and safety in 165 adult patients submitted to a transfemoral TAVR procedure from April 2019 to April 2020. Patients were divided into 2 groups: (1) BAA; (2) non-BAA., Results: Median age, EuroScore II, and STS score were 79 years (74-84), 2.9% (1.7-6.2), and 2.2% (1.6-3.2), respectively. BAA was present in 12% of cases. Successful two-filter insertion was 86.6% (89% non-BAA vs. 65% BAA; p = 0.002), and debris was captured in 95% (94% non-BAA vs. 95% BAA; p = 0.594). No procedural or vascular complications associated with Sentinel insertion and no intraprocedural strokes were reported. There were two postprocedural non-disabling strokes, both in non-BAA., Conclusion: This study demonstrated Sentinel insertion feasibility and safety in BAA. No procedural and access complications related to Sentinel deployment were reported. Being aware of the bovine arch prevalence and having the techniques to navigate through it allows operators to successfully use CEPDs in this anatomy.

A role for long non-coding RNAs (lncRNAs) in endocrine cancer pathogenesis is emerging. However, knowledge regarding their expression pattern, correlation with known genetic defects, and clinical implications in parathyroid tumors is still unclear. Here, we profiled 90 known lncRNAs in a first series of normal (PaN = 2), adenomatous (PAd = 12), and carcinomatous (PCa = 4) parathyroid glands and we confirmed deregulation of 11 lncRNAs using an independent cohort of patients (PaN = 4; PAd = 26; PCa = 9). Expression of lncRNAs was correlated with cytogenetic aberrations, status of genes multiple endocrine neoplasia 1 (MEN1) and cell division cycle 73 (CDC73), or clinical features. Globally, lncRNAs discriminate according to tissue histology. BC200 consistently identifies parathyroid cancers from adenomas and atypical adenomas. Loss-of-heterozygosity (LOH) at chromosomes 1, 11, 15, 21, and 22 significantly impacts expression of lncRNAs in PAds. Silencing of the key parathyroid gene MEN1 modulates the expression of six lncRNAs in primary PAds-derived cultures. Analogous levels of lncRNAs are measured in PAds with the mutation in the MEN1 gene compared with PAds with wild-type MEN1. Similarly, carcinomas with mutated CDC73 differ from PCas with wild-type protein in terms of expression of lncRNAs. PCas harboring CDC73 mutations overexpress BC200 compared to wild-type carcinomas. Overall, these findings shed light on deregulation of lncRNAs in human parathyroid tumors and propose that circuits between lncRNAs and the oncosuppressors MEN1 or CDC73 may have a role in parathyroid tumorigenesis as epigenetic modulators. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Transcatheter aortic valve implantation has become an established procedure to treat severe aortic stenosis. Correct device sizing/positioning is crucial for optimal outcome. Lotus valve sizing is based upon multiple aortic root dimensions. Hence, it often occurs that two valve sizes can be selected. In this study, patient-specific computer simulation is adopted to evaluate the influence of Lotus size/position on paravalvular aortic regurgitation (AR) and conduction abnormalities, in patients with equivocal aortic root dimensions. First, simulation was performed in 62 patients to validate the model in terms of predicted AR and conduction abnormalities using postoperative echocardiographic, angiographic and ECG-based data. Then, two Lotus sizes were simulated at two positions in patients with equivocal aortic root dimensions. Large valve size and deep position were associated with higher contact pressure, while only large size, not position, significantly reduced the predicted AR. Despite general trends, simulations revealed that optimal device size/position is patient-specific.

Anomalous origin of the right coronary artery from the left sinus of Valsalva has a very low prevalence in the general population. Although the vast majority of patients are asymptomatic, the clinical consequence of this heart disorder can be sudden death. In many of these sudden death cases the right coronary artery is running between the anterior aspect of the aorta and behind the common trunk of the pulmonary artery, where systolic compression may have an impact on myocardial perfusion. Asymptomatic patients with this malignant course present the surgeon with a difficult decision, and they should be carefully evaluated in order to facilitate a tailored surgical approach.  In this video tutorial we present a patient with this anomalous course of the right coronary artery, which was documented by coronary computed tomography angiography using a 3D reconstruction. The patient received an off-pump coronary artery bypass graft using an original surgical technique that prevents any type of flow competition. The case had an excellent final outcome, with good results at follow-up.  Finally, a systematic review of the literature with a discussion of the different treatment modalities is provided., (© The Author 2016. Published by MMCTS on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: The need to integrate the classification of cancer with information on the genetic pattern has emerged in recent years for several tumors., Methods: The genomic background of a large series of 208 papillary thyroid cancers (PTC) followed at a single center was analyzed by a custom MassARRAY genotyping platform, which allows the simultaneous detection of 19 common genetic alterations, including point mutations and fusions., Results: Of the PTCs investigated, 71% were found to have pathognomonic genetic findings, with BRAF V600E and TERT promoter mutations being the most frequent monoallelic alterations (42% and 23.5%, respectively), followed by RET/PTC fusions. In 19.2% of cases, two or more point mutations were found, and the co-occurrence of a fusion with one or more point mutation(s) was also observed. Coexisting BRAF V600E and TERT promoter mutations were detected in a subgroup of aggressive PTCs (12%). A correlation between several aggressive features and mutation density was found, regardless of the type of association (i.e., only point mutations, or point mutations and fusions). Importantly, Kaplan-Meier curves demonstrated that mutation density significantly correlated with a higher risk of persistent disease. In most cases, the evaluation of the allelic frequencies normalized for the cancer cell content indicated the presence of the monoallelic mutation in virtually all tumor cells. A minority of cases was found to harbor low allelic frequencies, consistent with the presence of the mutations in a small subset of cancer cells, thus indicating tumor heterogeneity. Consistently, the presence of coexisting genetic alterations with different allelic frequencies in some tumors suggests that PTC can be formed by clones/subclones with different mutational profiles., Conclusions: A large mono-institutional series of PTCs was fully genotyped by means of a cost- and time-effective customized panel, revealing a strong impact of mutation density and genetic heterogeneity on the clinical features and on disease outcomes, indicating that an accurate risk stratification of thyroid cancer cannot rely on the analysis of a single genetic event. Finally, the heterogeneity found in some tumors warrants attention, since the occurrence of this phenomenon is likely to affect response to targeted therapies.

Parathyroid tumors deregulate microRNAs belonging to the two clusters on the chromosome 19, the C19MC and miR-371-373 clusters. Here, we report that the embryonic miR-372 is aberrantly expressed in half of parathyroid adenomas (PAds) in most of atypical adenomas and carcinomas ( n  = 15). Through in situ hybridization, we identified that miR-372-positive parathyroid tumor cells were scattered throughout the tumor parenchyma. In PAd-derived cells, ectopic miR-372 inhibited the expression of its targets CDKN1A /p21 and LATS2 at both mRNA and protein levels. Although the viability of parathyroid cells was not affected by miR-372 overexpression, the miRNA blunted camptothecin-induced apoptosis in primary PAd-derived cultures. miR-372 overexpression in parathyroid tumor cells increased parathormone ( PTH ) mRNA levels, and it positively correlated in vivo with circulating PTH levels. Conversely, the parathyroid-specific genes TBX1 and GCM2 were not affected by miR-372 mimic transfection. Finally, miR-372 dampened the Wnt pathway in parathyroid tumor cells through DKK1 upregulation. In conclusion, miR-372 is a novel mechanism exploited by a subset of parathyroid tumor cells to partially decrease sensitivity to apoptosis, to increase PTH synthesis and to deregulate Wnt signaling., (© 2018 Society for Endocrinology.)

For the past few decades, the transaortic septal myectomy (Morrow's procedure) has been the gold standard for treating severe left ventricular outflow tract obstruction in hypertrophic obstructive cardiomyopathy (HOCM) patients. 30-day mortality has been reported at less than 1% in dedicated centers. However, in a subgroup of patients, the interventricular septal obstruction is localized very distally, below the aortic valve plane, and the transaortic approach can be very challenging. A subset of these patients can present with residual obstruction after surgery, due to inadequate length of septal excision, leading to reoperation. The aim of this work is to illustrate an original application of cryoenergy to improve the transaortic exposure of the interventricular septum and thus enable surgeons to perform very distal myectomies in HOCM patients.

Background: Multicellular spheroids represent an interesting experimental model with promising applications in the pre-clinical studies on anticancer drugs. We recently demonstrated that thyroid spheroids recapitulate the features of the original tissues, in either the differentiated and "stem-like" components. Here we were aimed to characterize thyroid spheroids and to investigate in vivo the proangiogenic potential of patient-derived xenografts (PDX) of spheroids obtained from papillary thyroid cancer (PTC) and the matched normal tissues., Methods: Spheroids cultures were obtained from 11 PTCs and matched normal tissues and characterized by immunohistochemistry. The expression of p53, involved in the regulation of stem cell homeostasis, was evaluated. The proangiogenic effect of thyroid spheroids was assessed by the injection in zebrafish embryos., Results: Thyroid spheroids are enriched in stem-like cells, as shown by the positivity for the stem cell marker OCT4, and by the low level of p53 expression. Interestingly, PTCs and normal thyroid tissues have a detectable p53 expression, whereas the derived spheroids are mainly constituted by cells that express p53 at a lower level. Finally, we show that PDXs derived from PTC or normal spheroids stimulate the migration and the growth of sprouting vessels toward the implant into the zebrafish embryos., Conclusions: We report the characterization of multicellular spheroids obtained from PTCs and normal thyroid tissues, showing that they are enriched in stem-like cells. Moreover, we established xenografts of spheroids in zebrafish, demonstrating that they stimulate neoangiogenesis. This in vivo model could be considered as a valuable platform to test the effects of anticancer drugs.

Transcription factors active in embryonic parathyroid cells can be maintained in adult parathyroids and be involved in tumorigenesis. TBX1, the candidate gene of 22q11.2-DiGeorge syndrome, which includes congenital hypoparathyroidism, is involved in parathyroid embryogenesis. The study aimed to investigate expression, function, and regulation of the parathyroid embryonic transcription factor TBX1 in human parathyroid adult normal and tumor tissues. TBX1 transcripts were detected in normal parathyroids and were deregulated in parathyroid tumors. Using immunohistochemistry, TBX1 protein was detected, mainly at the nuclear level, in a consistent proportion of cells in normal adult parathyroids, whereas TBX1 immunoreactivity was absent in fetal parathyroids. TBX1-expressing cells were markedly reduced in about a half of adenomas (PAds) and two-thirds of carcinomas and the proportion of TBX1-expressing cells negatively correlated with the serum albumin-corrected calcium levels in the analyzed tumors. Moreover, a subset of TBX1-expressing tumor cells coexpressed PTH. TBX1 silencing in HEK293 cells, expressing endogenous TBX1, increased the proportion of cells in the G0/G1 phase of cell cycle; concomitantly, CDKN1A/p21 and CDKN2A/p16 transcripts increased and ID1 mRNA levels decreased. TBX1 silencing exerted similar effects in PAd-derived cells, suggesting cell cycle arrest. Moreover, in PAd-derived cells GCM2 and PTH mRNA levels were unaffected by TBX1 deficiency, whereas it was associated with reduction of WNT5A, an antagonist of canonical WNT/β-catenin pathway. WNT/β-catenin activation by lithium chloride inhibited TBX1 expression levels both in HEK293 and PAd-derived cells. In conclusion, TBX1 is expressed in adult parathyroid cells and deregulated in parathyroid tumors, where TBX1 deficiency may potentially contribute to the low proliferative nature of parathyroid tumors.

Objectives: Systolic anterior motion (SAM) can be an insidious complication after mitral repair. Predicting SAM represents a challenge, even for very experienced mitral valve surgeons. The goal of this pilot work was to illustrate for the first time, a computational software able to calculate and prevent SAM during mitral repair., Methods: Using MATLAB graphical user interface, a clinical software to predict SAM, we tested the performances of the software on 136 patients with degenerative mitral valves undergoing repair with standard techniques. A combination of 6 key echocardiographic parameters was used to calculate the SAM risk score. The discriminative performance of the model was assessed by the area under the receiver-operating characteristic curve. The receiver-operating characteristic was used to divide patients into low, medium and high risk for SAM. Simulation of virtual mitral repair (posterior leaflet resection and mitral ring annuloplasty) was also tested to reduce the risk of SAM., Results: The incidence of SAM was 8.1%; 73% were detected as high risk by the software. The area under the receiver-operating characteristic model discriminant performance was 0.87 (95% confidence interval: 0.78-0.95). Simulating a posterior leaflet resection with the leaflet length fixed at 15 mm, the estimated SAM risk was updated, and all patients were then classified at low risk., Conclusions: This software is the first computational model designed to predict SAM during mitral repair to show excellent discrimination. This software has the potential to predict SAM risk preoperatively and, after a virtual step-by-step mitral repair simulation, depending on the technique adopted, to always achieve a low-risk SAM profile., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The assessment and management of tricuspid valve (TV) disease evolved significantly in the last decade. Tricuspid regurgitation (TR) is a frequent heart valve disease and it is most often secondary, due to annular dilatation and leaflet tethering from right ventricular remodeling. The indications for TV surgery are several and mainly related to the underlying disease, to the severity of the regurgitation and to the right ventricular function. Moreover, surgical tricuspid repair has been avoided for years, because of the erroneous concept that TR should disappear once the primary pathology on the left heart has been resolved. Instead, during the last few years, many investigators have reported evidence in favor of a more aggressive surgical approach to functional TR, recognizing the risk of progressive tricuspid insufficiency in patients with annular dilatation and only moderate regurgitation (or less) at the time of surgery. This concept, along with the acute and long-term outcomes of tricuspid surgical repair techniques and tricuspid replacement are discussed in this review.

There is evidence of adverse health impacts from human exposure to particulate air pollution, including increased rates of respiratory and cardiovascular illness, hospitalizations, and pre-mature mortality. Most recent hypotheses assign an important role to ultrafine particles (UFP) (<0.1 μm) and to associated transition metals (in particular Fe). In a large city like Rome, where many active people spend more than one hour per day in private or public transportation, it may be important to evaluate the level of exposure to harmful pollutants which occurs during urban travelling. In this context, the aim of this work was to examine the relative contribution of different transport modes to total daily exposure. We performed experimental measurements during both morning and evening traffic peak hours throughout the winter season (December 2013-March 2014), for a total of 98 trips. Our results suggest that the lowest UFP exposures are experienced by underground train commuters, with an average number concentration of 14 134 cm -3 , and are largely a reflection of the routes being at greater distance from vehicular traffic. Motorcyclists experienced significantly higher average concentrations (73 168 cm -3 ) than all other exposure classes, and this is most likely a result of the presence of high-concentration and short-duration peaks which do not occur when the same routes are traveled by car. UFP concentrations in subway train environments were found to be comparable to urban background levels. Still, in underground trains we found the highest values of PM 10 mass concentration with a maximum value of 422 μg/m 3 . PM 10 concentration in trains was found to be four and two times higher than what was measured in car and motorbike trips, respectively. Transport mode contribution to total integrated UFP daily exposure was found to be 16.3%-20.9% while travelling by car, 28.7% for motorbike trips, and 8.7% for subway trips. Due to lower exposure times, commuting by car and motorbike is comparable to other daily activities in terms of exposure. Our data can provide relevant information for transport decision-making and increase environmental awareness in the hope that the information about inhaled pollutants can translate into a more rational approach to urban travelling., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To report the long-term results of the clover technique for the treatment of complex forms of tricuspid regurgitation (TR)., Methods: Ninety-six consecutive patients (mean age 60 ± 16.4, left ventricular ejection fraction 58 ± 8.8%) with severe or moderately-severe TR due to important leaflets prolapse/flail (81 patients), tethering (13 patients) or mixed (2 patients) lesions underwent clover repair combined with annuloplasty. The aetiology of TR was degenerative in 74 cases (77.1%), post-traumatic in 9 (9.4%) and secondary to dilated cardiomyopathy in 13 (13.5%). All patients but 3 (96.8%) underwent ring (59 patients, 61.5%) or suture (34 patients, 35.4%) annuloplasty. Concomitant procedures (mainly mitral surgery) were performed in 82 patients (85.4%)., Results: Hospital mortality was 7.2%. At hospital discharge 92 (95.8%) patients had no or mild TR. Follow-up was 98% complete (median 9 years, interquartile range 5.1; 10.9). At 12 years the overall survival was 71.6 ± 7.22% and the cumulative incidence function of cardiac death with non-cardiac death as competing risk 16 ± 4.1% [95% confidence interval (95% CI) 9.5-25.7]. At 12 years the cumulative incidence function of TR ≥ 3+ and TR ≥ 2+ with death as competing risk were 1.2 ± 1.2% (95% CI 0.1-5.8) and 28 ± 7.7% (95% CI 14.3-43.5), respectively. Preoperative left ventricular ejection fraction (hazard ratio 0.9, CI 0.9-1, P  = 0.05) and previous cardiac surgery (hazard ratio 2.7, 95% CI 1-7.1, P  = 0.03) were predictors of recurrent TR ≥ 2+ at univariable but not at multivariable analysis., Conclusions: Complex forms of TR due to severe prolapse or tethering of the leaflets can be effectively treated with the clover technique with very satisfactory long-term results and extremely low recurrence of severe TR., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: A single MitraClip implant is often considered enough to achieve adequate mitral regurgitation (MR) reduction. The aim of this study was to compare MR recurrence in patients with an initial optimal result treated with a single clip versus those treated with two clips., Methods: From October 2008 to May 2016, 322 patients were treated with the MitraClip procedure at our institution. We retrospectively selected all patients treated for functional MR (FMR) and degenerative MR (DMR) aetiologies with residual MR ≤1+, excluding patients who required >2 clips. FMR and DMR were analysed separately., Results: In FMR, a single clip was used in 45 patients and 2 clips in 99 patients. The single clip group had smaller coaptation depth (1.1 ± 0.3 vs 1.3 ± 0.3 mm, P  = 0.022) and jet extension (10.5 ± 2.1 vs 13.0 ± 3.6 mm, P  = 0.026) as well as left ventricular end-diastolic diameter (64.4 ± 7.3 vs 69.0 ± 7.9 mm, P  = 0.001). Freedom from MR ≥ 3+ after 4 years was 71.9 ± 8.9% in patients receiving a single clip vs 88.0 ± 5.2% in those receiving 2 clips, single clip use being an independent predictor of MR recurrence (HR 3.48, CI 1.24-9.81, P  = 0.018). In DMR, a single clip was deployed in 24 patients and 2 clips in 30 patients. The single clip group had a smaller flail gap (3.6 ± 0.7 vs 6.8 ± 2.5, P  = 0.002). Freedom from MR ≥ 3+ after 2 years was 82.5 ± 8% in patients with a single clip vs 100% in those with 2 clips, P  = 0.014. The residual mitral area was reduced in patients with 2 clips compared with those with single clip, both in FMR ( P  = 0.015) and DMR ( P  = 0.039), but it was not associated with increased death rate during the follow-up period (all P  > 0.05)., Conclusions: Despite favourable anatomical characteristics and an optimal initial result, implantation of a single clip was associated with an increased recurrence of MR compared with that of 2 clips, both in FMR and in DMR. Caution should be exercised with the implantation of a single clip., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To evaluate whether the adoption of a right minithoracotomy operative approach had an impact on the long-term results of edge-to-edge (EE) repair compared to conventional sternotomy in patients with Barlow's disease and bileaflet prolapse., Methods: We assessed the long-term results of 104 patients with Barlow's disease treated with a minimally invasive EE technique. An equal number of patients had a conventional median sternotomy EE repair for the same disease and were used as a control group. The inverse probability of treatment weighting was used to create comparable distributions of the covariates that were significantly different at baseline in the two groups. We performed a comparative analysis of the groups., Results: No hospital deaths were observed. Follow-up was 99.5% complete (median 11.3 years). The cumulative incidence function (CIF) of cardiac death at 12 years, with noncardiac death as a competing risk, showed no difference between the two groups ( P  = 0.87). At 12 years, the CIF of recurrent MR ≥ 3+, with death as the competing risk, was 7% in the sternotomy group and 5% in the minimally invasive group ( P  = 0.30), and the CIF of recurrence of MR ≥ 2+ was 15 and 14%, respectively ( P  = 0.63). The type of surgical approach was not a predictor of cardiac death, reoperation, recurrent MR ≥ 3+ or recurrent MR ≥ 2+., Conclusions: A minimally invasive approach does not have a negative impact on the effectiveness and long-term durability of the EE repair for bileaflet prolapse in Barlow's disease. Long-term outcomes are excellent, and valvular performance remains stable over time with no evidence of mitral stenosis., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and it is often poorly tolerated because of loss of atrial contraction and reduced filling time with rapid ventricular rates. Restoring sinus rhythm is of great clinical benefit to HCM patients. Very few data exist regarding surgical ablation of concomitant AF in this setting. The aim of this study was to evaluate the mid-term outcome of surgical AF ablation in patients who underwent cardiac surgery due to HCM., Methods: Thirty-one consecutive patients with primary HCM and drug-refractory symptomatic AF underwent surgical ablation with concomitant septal myectomy (77%) and/or mitral valve repair/replacement (39%). Follow-up was 97% complete with a median of 6.4 years [3.8-9.1]., Results: Hospital mortality was 6% and the overall survival at 7 years was 87 ± 6.1%. No stroke and thromboembolic events were documented at follow-up. The arrhythmia-free survival off antiarrhythmic drugs was 82 ± 7.3% at 1 year and 52 ± 10.2% at 6 years. The 1- and 6-year arrhythmia control (maintenance of sinus rhythm with or without antiarrhythmic drugs) was 96 ± 3.5 and 80 ± 8.1%, respectively. The recurrent arrhythmia was AF in all patients. No predictors of AF recurrence were detected., Conclusions: Concomitant surgical ablation of AF is a reasonable treatment option for drug refractory AF in patients with HCM undergoing surgical myectomy and/or mitral valve surgery. However, chronic antiarrhythmic drugs are needed to achieve a satisfactory mid-term arrhythmia control., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Recently, the G534E variant of the HABP2 gene was reported as the underlying genetic defect in a large kindred with nonsyndromic familial nonmedullary thyroid cancer (FNMTC). Nevertheless, this postulated role was not confirmed in additional cohorts. Contrasting data are also available on HABP2 expression in the thyroid., Objectives: To investigate HABP2 as a potential susceptibility gene in a large series of 27 unrelated families with FNMTC and to test its expression in thyroid tumour and matched normal tissues., Results: Three of the 27 FNMTC families (11·1%) carried the HABP2 G534E variant. The genotyping of these families showed that HABP2 G534E does not segregate with cancer. Indeed, affected individuals not carrying HABP2 G534E were identified, and the variant was present also in members without thyroid cancer. HABP2 mRNA had a very variable expression in tissues from FNMTC, sporadic papillary thyroid cancers (PTCs) or contralateral normal tissues, by either nonquantitative or quantitative RT-polymerase chain reaction. In almost all cases, the gene appeared down- or up-regulated in tumours with respect to the corresponding normal tissue. At immunohistochemistry, HABP2 was expressed in both tumour and matched control tissues, without differences between sporadic and familial cases., Conclusions: This study on a wide series of FNMTC indicates that the HABP2 G534E variant is frequent, but does not segregate with the disease. Nevertheless, the dysregulation of HABP2 expression found in either sporadic or familial PTCs or normal thyroid tissues is consistent with similar findings in other malignancies and could indicate a role of this gene also in thyroid cancer., (© 2017 John Wiley & Sons Ltd.)