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The transcription factors involved in epithelial–mesenchymal transition (EMT-TFs) silence the genes expressed in epithelial cells (e.g., E-cadherin) while inducing those typical of mesenchymal cells (e.g., vimentin). The core set of EMT-TFs comprises Zeb1, Zeb2, Snail1, Snail2, and Twist1. To date, information concerning their expression profile and clinical utility during thyroid cancer (TC) progression is still incomplete. We evaluated the EMT-TF, E-cadherin, and vimentin mRNA levels in 95 papillary TC (PTC) and 12 anaplastic TC (ATC) tissues and correlated them with patients’ clinicopathological parameters. Afterwards, we corroborated our findings by analyzing the data provided by a case study of the TGCA network. Compared with normal tissues, the expression of E-cadherin was found reduced in PTC and more strongly in ATC, while the vimentin expression did not vary. Among the EMT-TFs analyzed, Twist1 seems to exert a prominent role in EMT, being significantly associated with a number of PTC high-risk clinicopathological features and upregulated in ATC. Nonetheless, in the multivariate analysis, none of the EMT-TFs displayed a prognostic value. These data suggest that TC progression is characterized by an incomplete EMT and that Twist1 may represent a valuable therapeutic target warranting further investigation for the treatment of more aggressive thyroid cancers.

The American Joint Committee on Cancer has revised the Tumor-Node-Metastasis (TNM) staging system for papillary thyroid cancer (PTC) patients. We examined the impact of this new classification (TNM-8) on patient stratification and estimated the prognostic value of clinicopathological features for the disease-free interval (DFI) in a cohort of 1148 PTC patients. Kaplan&ndash, Meier analyses showed that all clinicopathological parameters analyzed, except age and multifocality, were associated significantly with DFI. Cox regression identified tall cell PTC variant and stage as independent risk factors for DFI. When the stage was replaced with age, tumor size, and lymph node (LN) metastases in the set of covariates, the lateral LN metastases stood out as the strongest independent predictor of DFI, followed by tall cell variant and age. A noteworthy result emerging from these analyzes is that regression models had lower Akaike and Bayesian information criterions if variables were categorized based on the TNM-7. In addition, we examined data from a different PTC patient cohort, acquired from The Cancer Genome Atlas database, to verify whether the DFI prediction could be enhanced by further clinicopathological and molecular parameters. However, none of these was found to be a significant predictor of DFI in the Cox model.

Background: Computer-guided technologies are adopted in various fields of surgery to limit invasiveness and obtain patient benefits in terms of surgery duration and post-operative course. Surgical templates realized through CAD/CAM technologies are widely diffused in implant dentistry. The aim of this work is to propose, beyond implantology, the feasibility of application of 3D printed surgical templates in oral surgery procedures requiring osteotomies (like maxillary cyst enucleation and tooth disimpaction) in order to obtain accurate surgeries, avoid anatomical damage of surrounding structures and decrease patient’s morbidity, using a simple, low-cost protocol of fabrication. Objective: To provide a reliable CAD-CAM workflow for the realization of surgical templates in oral surgery. Methods: Three clinical scenarios are described: A maxillary canine disimpaction, a mandibular cyst removal, and an orthodontic miniscrew placement. Each one was managed using custom surgical templates realized using the proposed workflow. A Stereolithography (STL) file of maxillary structures was obtained by the use of a 3D medical image processing software (Materialise Mimics 20.0) a segmentation toolbox acquiring RX volumes by Cone-Beam Computed Tomography (CBCT). Digital models of the teeth, acquired as STL files directly, are imported in the same 3D medical image processing freeware (Materialise Mimics 20.0) to merge STL files of maxillary structures and teeth. Data are transported into Blue Sky Plan 4.0 (Blue Sky Bio, LLC), a software for 3D implant guides fabrication, together with the DICOM images package of maxillary volumes to carry out the pre-surgical treatment planning. Anatomical structures at risk are identified; a contour of ideal incision shape and bone osteotomy extent is drawn. Finally, the resulting three-dimensional guide is digitally generated and the surgical guide printed. The resulting 3D template shows the following major features: teeth support, flap management and bone osteotomy design. Results: The proposed work-flow aided the surgeon in both pre-operative and intra-operative work phases through accurate virtual planning and the fabrication of precise surgical guides to be used in oral surgery practice. In each clinical scenario, the use of custom 3D templates allowed better control of the osteotomy planes and flap management. No adverse events occurred during both surgical and healing phases. Conclusion: The proposed digital workflow represents a reliable and straightforward way to produce a surgical guide for oral surgery procedures. These templates represent a versatile tool in maxillary cyst enucleations, tooth disimpaction, and other surgical procedures, increasing accuracy, minimizing surgical complications, and decreasing patient’s morbidity.

Simple Summary Over the last couple of decades, the prognostic stratification systems of differentiated thyroid cancer (DTC) patients have been revised several times in an attempt to achieve a tailored clinical management reflecting the single patients’ needs. Such revisions are likely to continue in the near future, since the prognostic value of a number of promising clinicopathological features and new molecular biomarkers are being evaluated. Here, we will review the current staging systems of thyroid cancer patients and discuss the most relevant clinicopathological parameters and new molecular markers that are potentially capable of refining the prognosis. Abstract Over the last few years, a great advance has been made in the comprehension of the molecular pathogenesis underlying thyroid cancer progression, particularly for the papillary thyroid cancer (PTC), which represents the most common thyroid malignancy. Putative cancer driver mutations have been identified in more than 98% of PTC, and a new PTC classification into molecular subtypes has been proposed in order to resolve clinical uncertainties still present in the clinical management of patients. Additionally, the prognostic stratification systems have been profoundly modified over the last decade, with a view to refine patients’ staging and being able to choose a clinical approach tailored on single patient’s needs. Here, we will briefly discuss the recent changes in the clinical management of thyroid nodules, and review the current staging systems of thyroid cancer patients by analyzing promising clinicopathological features (i.e., gender, thyroid auto-immunity, multifocality, PTC histological variants, and vascular invasion) as well as new molecular markers (i.e., BRAF/TERT promoter mutations, miRNAs, and components of the plasminogen activating system) potentially capable of ameliorating the prognosis of PTC patients.

Thyroid nodules are very common, affecting 19%–67% of the adult population. However, about 10% of them harbor a malignant lesion. Consequently, the first aim in their clinical evaluation is to exclude malignancy. Fine-needle aspiration cytology (FNAC) represents the main diagnostic tool for the evaluation of thyroid nodules. However, FNAC has a main diagnostic limit, namely cellular atypias of indeterminate significance, which require surgical excision and histological examination to differentiate benign from malignant lesions. Histology reports show that approximately 80% of these patients harbor a benign lesion. Therefore, in order to reduce unnecessary thyroidectomy, over the last years, the cytological classification of thyroid nodules has been revised and a number of new instrumental and molecular approaches have been proposed. In the present article, we will attempt to summarize the most recent cytological, molecular and echographic strategies to enhance the diagnostic accuracy of preoperative thyroid follicular lesions. In particular, we will discuss the new cytological classifications from the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), the British Thyroid Association-Royal College of Pathologists (PTA-RCPath) and the new Italian Society for Anatomic Pathology and Cytology (SIAPEC 2014. We will review molecular tests evaluated to ameliorate follicular lesion diagnosis as well as the clinical utility of the new echographic Thyroid Imaging Reporting and Data System (TI-RADS) score.

International audience; Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI). The analysis of VHL mRNA in tumor tissues, compared to normal matched tissues, revealed that its expression was either up- or down-regulated in the majority of PTC. In particular, V1 and V2 mRNA levels were altered, respectively, in 78 (81.3%) and 65 (67.7%) out of the 96 PTCs analyzed. A significant positive correlation between the two mRNA variants was observed (p

The new Italian cytological classification (2014) of thyroid nodules replaced the TIR3 category of the old classification (2007) with two subclasses, TIR3A and TIR3B, with the aim of reducing the rate of surgery for benign diseases. Moreover, thyroid imaging reporting and data system (TI-RADS) score appears to ameliorate the stratification of the malignancy risk. We evaluated whether the new Italian classification has improved diagnostic accuracy and whether its association with TI-RADS score could improve malignancy prediction. We retrospectively analyzed 70 nodules from 70 patients classified as TIR3 according to the old Italian classification who underwent surgery for histological diagnosis. Of these, 51 were available for cytological revision according to the new Italian cytological classification. Risk of malignancy was determined for TIR3A and TIR3B, TI-RADS score, and their combination. A different rate of malignancy (p=0.0286) between TIR3A (13.04%) and TIR3B (44.44%) was observed. Also TI-RADS score is significantly (p=0.003) associated with malignancy. By combining cytology and TI-RADS score, patients could be divided into three groups with low (8.3%), intermediate (21.4%), and high (80%) risk of malignancy. In conclusion, the new Italian cytological classification has an improved diagnostic accuracy. Interestingly, the combination of cytology and TI-RADS score offers a better stratification of the malignancy risk.

Epithelial thyroid cancers (TC) comprise two differentiated histotypes (DTC), the papillary (PTC) and the follicular (FTC) thyroid carcinomas which, following dedifferentiation, are assumed to give rise to the poorly differentiated thyroid carcinomas and the rare, but highly aggressive and invariably fatal, anaplastic thyroid carcinomas. Although thyroid cancer mortality has not been changed, its annual incidence has increased over the last two decades, mainly because of the improved ability to diagnose malignant transformation in small non-palpable thyroid nodules. Despite DTC patients have a favorable prognosis, aggressive disease is more frequently observed in the elderly showing a higher disease-specific mortality. Of relevance is the high prevalence of nodular thyroid disease in aged patients being higher than 90%, in women older than 60 year, and 60% in men older than 80 year. This implies a careful evaluation of thyroid nodules in this group of patients in order to exclude malignancy. In fact, despite the tremendous progress in the comprehension of the underlying molecular mechanisms deregulated in DTC progression, several aspects of their clinical management remain to be solved and novel diagnostic strategies are sorely needed. Here, we will attempt to review new molecular approaches, which are currently being exploited in order to ameliorate the diagnosis of thyroid nodules.

The skin is the largest organ of the body, at the boundary with the outside environment. Primarily, it provides a physical and chemical barrier against external insults, but it can act also as immune organ because it contains a whole host of immune-competent cells of both the innate and the adaptive immune systems, which cooperate in eliminating invading pathogens following tissue injury. On the other hand, improper skin immune responses lead to autoimmune skin diseases (AISD), such as pemphigus, bullous pemphigoid, vitiligo, and alopecia. Although the interplay among genetic, epigenetic, and environmental factors has been shown to play a major role in AISD etiology and progression, the molecular mechanisms underlying disease development are far from being fully elucidated. In this context, epidemiological studies aimed at defining the association of different AISD with other autoimmune pathologies revealed possible shared molecular mechanism(s) responsible for disease progression. In particular, over the last decades, a number of reports have highlighted a significant association between thyroid diseases (TD), mainly autoimmune ones (AITD), and AISD. Here, we will recapitulate the epidemiology, clinical manifestations, and pathogenesis of the main AISD, and we will summarize the epidemiological evidence showing the associations with TD as well as possible molecular mechanism(s) underlying TD and AISD pathological manifestations.

Long-lived animals have low rates of mitochondrial reactive oxygen species (ROS) production and oxidative damage in their mitochondrial DNA (mtDNA). These two parameters also decrease in the four known manipulations that increase mammalian longevity: caloric, protein and methionine restriction, and rapamycin treatment. Oxidative damage to mtDNA is known to be repaired. And mtDNA mutations, including large deletions, do not reach levels high enough in homoplasmy to cause decrements in tissue function in old animals. However, mitochondrial ROS also cause double-strand breaks, which also cause mtDNA fragmentation simultaneously with deletions. These mtDNA fragments are now known to exit mitochondria and insert in nuclear DNA entering it via the pericentromeric region. These mtDNA fragments increase with age in yeast as well as in mice and rat tissues and accelerate chronological aging in yeast. Such mtDNA fragment accumulation in the nucleus can cause aging by various potential mechanisms by affecting nuclear genes and regulatory regions, or inducing aneuploidy and large chromosomal rearrangements due to their high levels near the centromeres.

Vitiligo represents the most common cause of acquired skin, hair, and oral depigmentation, affecting 0.5–1% of the population worldwide. It is clinically characterized by the appearance of disfiguring circumscribed skin macules following melanocyte destruction by autoreactive cytotoxic T lymphocytes. Patients affected by vitiligo usually show a poorer quality of life and are more likely to suffer from depressive symptoms, particularly evident in dark-skinned individuals. Although vitiligo is a non-fatal disease, exposure of affected skin to UV light increases the chance of skin irritation and predisposes to skin cancer. In addition, vitiligo has been associated with other rare systemic disorders due to the presence of melanocytes in other body districts, such as in eyes, auditory, nervous, and cardiac tissues, where melanocytes are thought to have roles different from that played in the skin. Several pathogenetic models have been proposed to explain vitiligo onset and progression, but clinical and experimental findings point mainly to the autoimmune hypothesis as the most qualified one. In this context, it is of relevance the strong association of vitiligo with other autoimmune diseases, in particular with autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves’ disease. In this review, after a brief overview of vitiligo and its pathogenesis, we will describe the clinical association between vitiligo and autoimmune thyroid disorders and discuss the possible underlying molecular mechanism(s).

The World Health Organization, the United Nations Children's Fund, and the International Council for the Control of Iodine Deficiency Disorders recommend a median urinary iodine concentration (UIC) in pregnant women between 150 µg/L and 249 µg/L. In the present study, we evaluated whether in the urban area of Cassino (central Italy), after a national salt iodination program (30 mg/kg) was introduced in 2005, the increased demand of iodine during pregnancy was satisfied.Between January 2016 and April 2017, 99 pregnant women were enrolled to evaluate UIC in spot urine samples, serum level of thyrotropin, free thyroxine, antithyroglobulin and antithyroperoxidase autoantibodies, and thyroid volume by ultrasonography. Eighty clinically healthy non-pregnant women were evaluated as controls.The median UIC was of 97.7 µg/L and 110.3 µg/L, respectively, in control and pregnant women. A significant increase (P 0.001) of median thyroid volume was found in pregnant women, relative to control women, being, respectively, 10.4 mL (range 3.68-19.49 mL) and 7.16 mL (range 2.57-14.00 mL). A positive correlation was found between thyroid volume and anthropometric parameters, and an inverse correlation was identified between free thyroxine serum levels and anthropometric parameters.This observational study found that the majority of pregnant women and their fetuses appear not to be protected from the detrimental consequences of iodine deficiency. Therefore, the identification of new strategies to increase the knowledge and awareness of the general population regarding the beneficial effects of iodine supplementation during pregnancy is highly required.

Endoscopic mucosal resection (EMR) of early superficial colorectal carcinomas is nowadays accepted as the gold standard treatment for this type of neoplasia. This study aims to evaluate the efficacy and safety of mucosectomy in elderly patients considering the predictive value of submucosal infiltration. A retrospective study of all patients referred for EMR of sessile colorectal polyps classified IIa by the Paris classification between April 2013 and April 2015. A total of 50 patients (30 males (60 %); age range = 44–86; mean age = 67.7) were enrolled. Patients were divided in two groups considering 65 years as cutoff to individuate the elderly patients. EMR was performed in 53 lesions: 39 were performed en bloc and 14 by piecemeal technique. 30 % of lesions were in the rectum; 11 % in the sigmoid colon; 15 % in the descending colon; 6 % in the transverse colon; 24 % in the ascendant colon; and 14 % in the cecum. The mean size of the resected specimens was 20 mm (range 8–80 mm). The rate of complete resection was 79.2 %, incomplete 13.2 %, not estimable 7 %. Ten patients underwent surgery because of an incomplete resection and/or histological evaluation. Colon EMR is safe and effective in elderly patients. Endoscopy is still helped in the correct indication for surgery in high-risk surgical patients.

Results from national cancer registries reveal an association of thyroid cancers with extra-thyroidal malignancies. In this study, we evaluated the prevalence of breast cancer (BC) in women affected by both benign and malignant thyroid diseases (TD) in comparison to the general population. To this end, 3,921 female patients from central and southern regions of Italy were evaluated. Age-matched analysis of the prevalence of BC was carried out after dividing the patients into three diagnostic categories: (1) 1,149 patients with non-nodular TD; (2) 2350 patients with nodular TD; (3) 422 patients affected by differentiated thyroid cancers. Furthermore, the patients were grouped according to the absence (2,344 patients) or presence (1,453 patients) of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (TPOAb) or anti-TSH receptor auto-antibodies (124 patients). BC prevalence in TD patients as a whole was significantly higher compared to the general population, with an odds ratio (OR) of 3.33. Age-matched analysis showed that the risk of a BC in TD patients was higher in younger patients (age 0-44 years), with an OR of 15.24, which decreased with increasing age. Patients without thyroid auto-antibodies showed a higher OR for BC (p = 0.0005) than TD patients with TgAb and/or TPOAb. The results demonstrate that women affected by either benign or malignant thyroid disease have a significantly greater risk of BC, which is higher at a younger age. Furthermore, thyroid auto-antibodies appear to be protective against BC. These findings may contribute to the identification of common genetic and environmental factors underlying this disease association.

CONTEXT It has been suggested that patients with papillary thyroid cancer (PTC) harbouring the BRAF(V600E) mutation have a worse prognosis. We showed in PTC that high levels of urokinase plasminogen activator (uPA) and its cognate receptor (uPAR) inversely correlate with disease-free interval (DFI). OBJECTIVES To investigate the effects of BRAF(V600E) on the expression of uPA and uPAR and to evaluate the prognostic relevance of BRAF(V600E) alone or in combination with uPA and uPAR. DESIGN/SETTING/PATIENTS/INTERVENTION: The case study included 91 patients with PTC. All patients underwent thyroidectomy and radioiodine therapy. Follow-up was available for 75 patients. MAIN OUTCOME MEASURES The BRAF(V600E) mutation was analysed by sequencing and mutant allele-specific PCR amplification; uPA and uPAR expression by quantitative RT-PCR. RESULTS BRAF(V600E) was found in 44 of the 91 patients and associated with older age, but not with high-risk clinicopathological features. Urokinase PA and uPAR mRNA levels were higher in tumour tissues by 9·51 ± 1·30 and 4·64 ± 0·44 fold, respectively, compared to normal matched tissues, being significantly higher in BRAF(V600E) -positive patients. In vitro induction of BRAF(V600E) in PCCL3 cells caused a significant increase in both uPA and uPAR mRNAs. Higher levels of uPA and uPAR correlated with lymph node metastases, TNM stage and disease recurrences. Kaplan-Meier and multivariate analyses demonstrated that uPA and uPAR were associated with shorter DFI, while the BRAF(V600E) was not. CONCLUSION In PTC, BRAF(V600E) induces uPA and uPAR expression. The latter, but not BRAF(V600E) , associates with advanced stages and shorter DFI. If confirmed in larger case studies, they may represent reliable prognostic markers for more accurate risk stratification and postoperative decision-making in patients with PTC.

Collar transverse incision is the typical surgical access for operations on thyroid and parathyroids. The cosmetic outcome resulting from its closure is of paramount importance given its anatomical exposure. The traditional methods of closure include metal clips, subcuticular stitch and glue.In this study we evaluated the cosmetic results on 10 patients who had their cervicotomy wound closed with clips comparing it to a second group of 10 patients who had the same incision closed with subcuticular stitch. The cosmetic outcome was evaluated with a questionnaire answered by the patients, by the operating surgeon and by a surgical nurse who was blinded to the technique used. The results of the questionnaire were grossly similar with no differences in the two groups. Only two complications were recorded in the subcuticular group.Both the techniques associate to similar cosmetic outcome, and the choice between the two should be left to the surgeon's personal preference.

Background The aim of this meta-analysis was to evaluate the safety and efficacy of vascular closure devices (VCDs). Methods This meta-analysis was performed in accordance with the Cochrane Handbook for Systematic Reviews . Results The literature search yielded 31 prospective, randomized studies including 7,528 patients who were randomized to VCDs or manual/mechanical compression after diagnostic angiography and/or endovascular procedures. Most of these studies have excluded patients at high risk of puncture site complications. Meta-analysis showed similar results in the study groups in terms of groin hematoma, bleeding, pseudoaneurysm, and blood transfusion. Lower limb ischemia and other arterial ischemic complications (0.3% vs 0%, P = .07) as well as need of surgery for vascular complications (0.7% vs 0.4%, P = .10) were somewhat more frequent with arterial puncture closure devices. The incidence of groin infection was significantly more frequent with VCDs (0.6% vs 0.2%, P = .02). The use of VCD was uniformly associated with a significantly shorter time to hemostasis. Such differences where more evident in patients undergoing percutaneous coronary intervention, whereas these methods were associated with similar rates of adverse events among patients undergoing diagnostic coronary angiography. Conclusions The use of VCDs is associated with a significantly shorter time to hemostasis and thus may shorten recovery. However, the use of VCDs is associated with a somewhat increased risk of infection, lower limb ischemia/arterial stenosis/device entrapment in the artery, and need of vascular surgery for arterial complications. Further studies are needed to get more conclusive results, particularly in patients at high risk of femoral puncture-related complications.

Thyroid nodules that are read on cytology as follicular or Hürthle cell neoplasms (FN and HN, respectively) and indeterminate for malignancy require surgery to differentiate benign from malignant nodules. We analyzed FN and HN with indeterminate cytology to determine if there were differences in the rate and types of thyroid malignancy and if the rate of thyroid malignancy was influenced by age or sex.We analyzed 463 nodules with an indeterminate cytological diagnosis of FN and 140 nodules with an indeterminate cytological diagnosis of HN. The histopathological diagnosis after thyroidectomy was the method for establishing the diagnosis and type of malignancy.For the entire series of 603 patients there were 106 (17.6%) with thyroid cancer; 80 of these had a cytology reading of FN and 26 had HN. Extrathyroidal invasion in the grouped HN and FN patients who had papillary thyroid carcinoma (PTC) was more common in females than in males (62% vs. 25 %, p0.05). The rate of thyroid cancer was similar in FN (17.3%) and HN (18.6%). The rate of Hürthle cell thyroid cancer was significantly higher in HN than in FN (5.0% vs. 0.7%, p0.01) and the rate of the oncocytic variant of PTC was also significantly greater in HN compared to FN nodules (23.1% vs. 1.7%, p0.05). The rate of follicular thyroid carcinoma was almost identical in patients with HN and FN (19.2% vs. 18.8 %).There is little difference in the rate of malignancy between thyroid nodules with a cytological reading of FN indeterminate for malignancy and HN indeterminate for malignancy but there is a difference in the types of thyroid cancers in these groups. Hürthle cell thyroid cancer and the oncocytic variant of PTC is more common in nodules with an HN indeterminate for malignancy cytology reading than in nodules with a FN indeterminate for malignancy cytology reading. Since Hürthle cell thyroid cancer and the oncocytic variant of PTC are more aggressive than other thyroid cancers, it is likely that patients with an HN indeterminate for malignancy cytology will, as a group, have more aggressive thyroid cancers than those with an FN indeterminate for malignancy cytology.

Deregulated expression of the Aurora kinases (Aurora-A, B, and C) is thought to be involved in cell malignant transformation and genomic instability in several cancer types. Over the last decade, a number of small-molecule inhibitors of Aurora kinases have been developed, which have proved to efficiently restrain malignant cell growth and tumorigenicity. Regarding medullary thyroid carcinoma (MTC), we previously showed the efficacy of a pan-Aurora kinase inhibitor (MK-0457) in impairing growth and survival of the MTC-derived cell line TT. In the present study, we sought to establish if one of the Aurora kinases might represent a preferential target for MTC therapy. The effects of selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) were analyzed on TT cell proliferation, apoptosis, cell cycle, and ploidy. The two inhibitors reduced TT cell proliferation in a time- and dose-dependent manner, with IC50 of 19.0 ± 2.4 nM for MLN8237 and 401.6 ± 44.1 nM for AZD1152. Immunofluorescence experiments confirmed that AZD1152 inhibited phosphorylation of histone H3 (Ser10) by Aurora-B, while it did not affect Aurora-A autophosphorylation. MLN8237 inhibited Aurora-A autophosphorylation as expected, but at concentrations required to achieve the maximum antiproliferative effects it also abolished H3 (Ser10) phosphorylation. Cytofluorimetry experiments showed that both inhibitors induced accumulation of cells in G2/M phase and increased the subG0/G1 fraction and polyploidy. Finally, both inhibitors triggered apoptosis. We demonstrated that inhibition of either Aurora-A or Aurora-B has antiproliferative effects on TT cells, and thus it would be worthwhile to further investigate the therapeutical potential of Aurora kinase inhibitors in MTC treatment.

A number of reports indicated that Aurora-A or Aurora-B overexpression represented a negative prognostic factor in several human malignancies. In thyroid cancer tissues a deregulated expression of Aurora kinases has been also demonstrated, but no information regarding its possible prognostic role in differentiated thyroid cancer is available. Here, we evaluated Aurora-A and Aurora-B mRNA expression and its prognostic relevance in a series of 87 papillary thyroid cancers (PTC), with a median follow-up of 63 months. The analysis of Aurora-A and Aurora-B mRNA levels in PTC tissues, compared to normal matched tissues, revealed that their expression was either up- or down-regulated in the majority of cancer tissues. In particular, Aurora-A and Aurora-B mRNA levels were altered, respectively, in 55 (63.2%) and 79 (90.8%) out of the 87 PTC analyzed.A significant positive correlation between Aurora-A and Aurora-B mRNAs was observed (p=0.001). The expression of both Aurora genes was not affected by the BRAFV600E mutation. Univariate, multivariate and Kaplan-Mayer analyses documented the lack of association between Aurora-A or Aurora-B expression and clinicopathological parameters such as gender, age, tumor size, histology, TNM stage, lymph node metastasis and BRAF status as well as disease recurrences or disease-free interval. Only Aurora-B mRNA was significantly higher in T(3-4) tissues, with respect to T(1-2) PTC tissues. The data reported here demonstrate that the expression of Aurora kinases is deregulated in the majority of PTC tissues, likely contributing to PTC progression. However, differently from other human solid cancers, detection of Aurora-A or Aurora-B mRNAs is not a prognostic biomarker in PTC patients.

Ectopic lingual thyroid tissue is an uncommon congenital anomaly. Tumors with identical pathological characteristics to those arising in thyroid tissue may be present in ectopic locations, but there are very few cases of malignant ectopic thyroid tumors reported in the literature. We present a review of this phenomenon and report a case of papillary carcinoma of the base of the tongue, located in ectopic lingual thyroid tissue, in a 30-year-old woman. The patient's presenting symptoms were dysphagia and oral bleeding, and we performed radical resection of the neoformation at the base of the tongue with part of the muscles of the floor of the mouth and the body of the hyoid bone, as well as total thyroidectomy. Histological examination revealed a "sclerosing" papillary carcinoma. The patient was treated with 131I and substitutive thyroid hormonal therapy. An ultrasonogram done 5 years later showed bilateral laterocervical lymph node recurrence, which was effectively treated with bilateral laterocervical lymphectomy.

SummaryBackground The rapid and dramatic incursion of the Internet and social networks in everyday life has revolutionised the methods of exchanging data. Web 2.0 represents the evolution of the Internet as we know it. Internet users are no longer passive receivers, and actively participate in the delivery of information. Medical education cannot evade this process. Increasingly, students are using tablets and smartphones to instantly retrieve medical information on the web or are exchanging materials on their Facebook pages. Medical educators cannot ignore this continuing revolution, and therefore the traditional academic schedules and didactic schemes should be questioned. Analysing opinions collected from medical students regarding old and new teaching methods and tools has become mandatory, with a view towards renovating the process of medical education. Methods A cross-sectional online survey was created with Google® docs and administrated to all students of our medical school. Students were asked to express their opinion on their favourite teaching methods, learning tools, Internet websites and Internet delivery devices. Data analysis was performed using spss. Results The online survey was completed by 368 students. Although textbooks remain a cornerstone for training, students also identified Internet websites, multimedia non-online material, such as the Encyclopaedia on CD–ROM, and other non-online computer resources as being useful. Discussion The Internet represented an important aid to support students’ learning needs, but textbooks are still their resource of choice. Among the websites noted, Google and Wikipedia significantly surpassed the peer-reviewed medical databases, and access to the Internet was primarily through personal computers in preference to other Internet access devices, such as mobile phones and tablet computers. Increasingly, students are using tablets and smartphones to instantly retrieve medical information

Epithelial thyroid cancers are represented by the differentiated papillary and follicular thyroid carcinomas which, following dedifferentiation, are thought to give rise to the highly aggressive and incurable anaplastic thyroid carcinomas. Although derived from the same cell type, the different thyroid tumors show specific histological features, biological behavior and degree of differentiation as a consequence of different genetic alterations. Over the last few years, our knowledge regarding the molecular alterations underlying thyroid cell malignant transformation and cancer progression has considerably increased; however, the prognosis of differentiated thyroid cancer patients still relies on high-risk clinic-pathological variables. In particular, the actual staging systems provides only a rough prediction for cancer mortality and risk of recurrences, including in each risk group patients with highly different tumor-specific progression, disease-free interval and survival time. In order to improve DTC patient's risk stratification, both the European and the American Thyroid Associations proposed practical guidelines to integrate the actual staging systems with additional clinical features such as the tumor histological variant, the results of post-ablative whole body scan and the serum thyroglobulin levels. Despite that, patients within the same risk group still show a very heterogeneous behavior in terms of disease-free interval. As a consequence, the identification of new prognostic molecular biomarkers able to testify tumor aggressiveness is highly required. Here we'll review recently characterized new molecular markers potentially able to ameliorate the prognosis in DTC patients.

Anaplastic thyroid carcinomas (ATC) are highly aggressive tumours unresponsive to any available radio- or chemotherapeutic protocol, with a median survival rate of 4-5 months from the time of diagnosis. We previously demonstrated that ATC are characterized by increased expression of the kinases Aurora-A, -B and -C, involved in the regulation of multiple steps of the mitotic phase. In this study, the in vitro effects of SNS-314 mesylate, a pan-inhibitor of the Aurora kinases, on growth and tumorigenicity of ATC cells were evaluated.The effects of SNS-314 mesylate were assessed on the ATC derived cell lines CAL-62, 8305C, 8505C and BHT-101 by means of cell proliferation assay, immunofluorescence, cytofluorimetry, time lapse microscopy, and colony formation in soft agar.Treatment of the different ATC cells with SNS-314 mesylate inhibited proliferation in a time- and dose-dependent manner, with IC(50) comprised between 2.6 nM and 26.6 nM. CAL-62 cells exposed for 24 h to SNS-314 mesylate 100 nM evidenced a significant augmentation of the apoptotic index. Time-lapse video-microscopy of CAL-62 cells showed that SNS-314 mesylate prevents the completion of mitosis leading to polyploidy. Western blot experiments demonstrated that the auto-phosphorylation of the Aurora kinases as well as histone H3 phosphorylation in CAL-62 treated cells was inhibited. Finally, the drug inhibited colony formation in soft agar of all cell lines.Our results demonstrated that SNS-314 mesylate is capable to efficiently reduce cell growth and tumorigenicity of different ATC derived cell lines suggesting its potential therapeutic value for ATC treatment.

Context: The urokinase plasminogen activating system is implicated in neoplastic progression, and high tissue levels of urokinase plasminogen activating system components correlate with poor prognosis in various human cancers. Objective: The objective of the study was to investigate the prognostic relevance of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR), and the plasminogen activator inhibitor 1 (PAI-1) in human papillary thyroid cancer (PTC). Design: The expression of uPA, uPAR, and PAI-1 genes was analyzed in PTC and normal matched tissues by quantitative RT-PCR. The case study consisted of 99 patients (21 males and 78 females) affected by PTC including 77 classical, 15 follicular, four tall cell, and three oncocytic variants. Forty-one patients had lymph node metastases at the time of diagnosis. All the patients underwent thyroidectomy and radioiodine therapy followed by thyroid hormone replacement therapy. Follow-up data were available for 76 patients up to 64 months. Results: The uPA, uPAR, and PAI-1 mRNA levels were significantly higher in PTC compared with normal matched tissues by 9.63 ± 1,29-, 4.82 ± 0.45-, and 5.64 ± 0.71-fold, respectively. The increased expression of uPA and uPAR correlated statistically with advanced pT and N status. The uPA was also significantly associated with advanced tumor node metastasis stages. The Kaplan-Meier analysis showed a significant association of uPA and uPAR levels with reduced patient disease-free interval (DFI), and this association was stronger in stage I patients. Conclusion: The study demonstrated that in PTC the increased gene expression of uPA and uPAR is associated with tumor invasiveness, advanced stages, and shorter DFI, suggesting their prognostic relevance. These observations warrant further investigation in larger patient populations with longer follow-up.

Reason for Withdrawal The authors have asked for their protocol to be removed from the Cochrane Library. To view the published versions of this article, please click the 'Other versions' tab.

INTRODUCTION: We have conducted a clinical controlled trial (CCT) on patients who had undergone thyroidectomy for goitre or thyroid carcinoma. The endpoint of this study was to evaluate the benefits of ultrasonic dissector vs conventional technique (vessel ligation and tight) in patients undergoing thyroid surgery. PATIENT AND METHODS: Between January 2007 and December 2009 a CCT was conducted on 2.736 consecutive patients admitted to our clinical wards, who had undergone thyroidectomy for goitre or thyroid carcinoma. They were divided in two group: 1.021 patients (203 male and 818 female) underwent thyroidectomy with ultrasonic dissector (UAS) and 1.715 patients (369 male and 1.346 female) underwent throidectomy with conventional technique (vessel ligation and tight) (CT). RESULTS: The operative time (UAS 80 minutes mean, 50 to 120 min., vs CT 120 minutes, 70 to 180 minutes) was much lower in the thryoidectomy with UAS group. The incidence of transient laryngeal nerve palsy (UAS 17/1.021 patients. 1.6% vs CT 16/1.715 patients, 0.9%) was higher in the thyroidectomy with UAS group; the incidence of permanent laryngeal nerve palsy was similar in two groups(UAS group; there are no relevant difference in the incidence of permanent hypocalcemia (UAS 26/1.021 patients, 2.5% vs 35/1.715 patients, 2%) which was similar in two groups. Also the average post-operative hospitalization was similar in two groups (2 days). CONCLUSIONS: Actually, the only significant advantage shown from this CCT is represented in terms of cost-effectiveness (reduction of the usage of operating room and hospitalization) for patients treated with UAS, subsequent to the significant reduction of operative duration. Although the analysis showed that the patients who were treated with ultrasonic dissection don't present more favourable results in incidence of post-operative transient complication:transient laryngeal nerve palsy (1.6% in UAS vs 0.9% in CT) and transient hypocalcaemia (9.5% in UAS vs 7.7% in CT). There is no significant difference in the incidence of permanent laryngeal nerve palsy (0.9% in UAS vs in 1% CT). The experience of surgeon is the only important factor which can influence the appearance of these complications; the usage of Ultrasonic dissector can only help surgical action but can't repair the experience of the operator.

The new staging technique of sentinel node biopsy facilitates the identification of pathological node negative patients in whom axillary dissection may be avoided; however, patients with a positive sentinel node biopsy would require a thorough examination of their nodal status. Axillary dissection provides good local control, accurate staging and prognostic information for decisions about adjuvant therapy. We describe a technique of radical axillary clearance that includes levels I, II and III; this isn't associated with additional morbidity to patients and involves minimal extension of operative time.

We here analyzed the prevalence of extra-thyroidal malignancies (EM) in 6,386 female patients affected by different thyroid disease (TD). At first, an age-matched analysis of EM in all patients was performed. We then evaluated EM prevalence in four TD diagnostic categories: non-nodular TD (n = 2,159); solitary nodule (n = 905); multinodular TD (n = 2,871); differentiated thyroid cancers (n = 451). Finally, patients were grouped based on the absence (n = 3,820) or presence of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (TPOAb) (n = 2,369), or anti-Thyroid Stmulating Hormone (TSH) receptor autoantibodies (n = 197). A total of 673 EM were recorded. EM prevalence in TD patients was higher compared to the general population (Odds Ratio, OR 3.21) and the most frequent EM was breast cancer (OR 3.94), followed by colorectal (OR 2.18), melanoma (OR 6.71), hematological (OR 8.57), uterus (OR 2.52), kidney (OR 3.40) and ovary (OR 2.62) neoplasms. Age-matched analysis demonstrated that the risk of EM was maximal at age 0-44 yr (OR 11.28), remaining lower, but significantly higher that in the general population, in the 45-59 and 60-74 year age range. Breast and hematological malignancies showed an increased OR in all TD, while other cancers associated with specific TD. An increased OR for melanoma, breast and hematological malignancies was observed in both TPOAb and/or TgAb autoantibody negative and positive patients, while colorectal, uterus, kidney and ovary cancers showed an increased OR only in thyroid autoantibody negative patients. In conclusions, women affected by both benign and malignant TD, especially at a younger age and in absence of thyroid autoimmunity, have an increased risk of developing primary EM, thus requiring a careful follow-up and surveillance.

The aim of this work was to reveal through sentinel node study the intraoperative presence of preoperatively undetected pathological lymph nodes.At the Surgical Science Department of La Sapienza University of Rome The Authors studied from January 2003 to June 2004 18 patients with papillary carcinoma of the thyroid, who presented no clinical evidence of lymph node metastasis; they performed a total thyroidectomy in all cases, removing and histologically examining all lymph nodes of the upper anterior mediastinum. Where negative they were then subjected to immunohistochemical analysis with Pan Cytokeratin.The method was positive in 10 patients: 2 pure papillary carcinomas, 1 papillary carcinoma with poorly differentiated areas, 1 tall cell papillary carcinoma, 5 sclerosing carcinoma and 1 follicular variant papillary carcinoma; and negative in 8:5 pure papillary carcinomas, 2 sclerosing carcinoma and 1 case of follicular variant papillary carcinoma. Lymph node micrometastasis was found in 2 cases through study with Pan Cytokeratin on final histological examination.Analysis of the Authors' preliminary data shows that sentinel lymph node detection has 83.3% sensitivity and 100% specificity for Upper Anterior Mediastinum lymph nodes. The Authors can propose two main applications: select for dissection only patients with a positive sentinel node and reduce the number of cases to be subjected to postoperative treatment with iodine ablation, in patients with "low risk" thyroid tumours and negative sentinel nodes.

Objective: To conduct a retrospective study of 39 patients with papillary carcinoma of the thyroid with histologic vascular invasion (VI) and 361 patients without any sign of vascular invasion (VI). Summary Background Data: In the present study, we undertook a retrospective analysis of papillary carcinoma of the thyroid to assess whether histologically determined vascular invasion can be considered a predictive factor for prognosis. Methods: By means of a retrospective study, we evaluated the department’s database of patients with papillary thyroid carcinoma who had undergone total thyroidectomy from January 1993 to December 1999. Results: Group I consisted of papillary carcinoma without any sign of vascular invasion (VI) comprising 361 patients. Group II consisted of papillary carcinoma with vascular invasion (VI) comprising 39 patients. At the time of diagnosis, we observed no metastases in patients with VI, whereas a pulmonary metastasis was observed in 1 patient with VI (P 0.0023). In 3.6% patients with VI and in 20.5% patients with VI, we observed recurrences in the regional lymph nodes (P 0.001); we observed 6 (1.66%) distant metastases in patients with VI and in the 12.8% patients with VI (P 0.001). Three patients with VI (7.7%) and 2 patients with VI (0.6%) died of tumor-related causes; these figures were found to be statistically significant (P 0.001). Conclusions: In papillary carcinoma, it should be noted that histologic vascular invasion may be considered as a sign of an increased tendency toward hematogenic invasion and consequent increase in the relative percentage of metastases; ultimately, this means a poorer prognosis. In the presence of risk factors indicating a possible increase in biologic aggressiveness, adequate postoperative treatment and close follow up become essential.

Background and Objectives To determine whether thyroid carcinoma in elderly patients presents any peculiar characteristics, whether the greater biological aggressiveness of the neoplasm modifies the surgical treatment selected, and whether age greater than 70 years represents an independent prognostic factor. Methods Retrospective analysis of case histories from the Department of Surgery of “La Sapienza” University of Rome; 403 patients subjected to total thyroidectomy between 1993 and 1999, with a minimum follow-up period of 3 years subdivided into three groups: group I (patients aged between 20 and 50 years), group II (patients aged between 51 and 70 years) and group III (patients aged >70 years). The surgical and postoperative treatment is uniform in all study groups. Results Age greater than 70 years entails a significant increase in mortality; the mortality rate in the three groups was found to be 3%, 9% and 54%, respectively. Prognosis is significantly worse in the elderly patients group (group III) than in group I (P ≤ 0.001) and in group II (P ≤ 0.001); group II mortality was significantly higher than that of group I (P = 0.005); in group III, the neoplasm displays features of greater biological aggressiveness (greater incidence of undifferentiated forms, presence of lymph nodes at diagnosis and vascular invasion, locally advanced forms, greater incidence of stage IV). Conclusions Statistical analysis shows that the greater biological aggressiveness of the neoplasm in elderly patients worsens the prognosis, although an age exceeding 70 years itself represents an unfavourable prognostic factor; total thyroidectomy does not present any counter-indications in elderly patients. J. Surg. Oncol. 2004;88:217–222. © 2004 Wiley-Liss, Inc.

The study aims were to characterize patients with insular thyroid cancer and to provide data on patient outcome after surgical therapy. We compared nine patients with insular thyroid cancer at the Department of Surgical Science of “La Sapienza” University of Rome with 27 patients of similar age and tumor size who had follicular and papillary cancer, for a minimum follow-up period of 24 months (range, 24–72 months). All of the patients examined underwent total thyroidectomy. Vascular invasion was observed in 44.4 per cent of insular carcinomas ( P < 0.05 vs papillary carcinomas). No significant differences were observed regarding diagnostic method, multifocality, tumor nodes metastases (TNM), or stage. The death rate of patients with insular carcinoma (33.3%) was found to be higher than that of patients with follicular carcinoma ( P < 0.05) and papillary carcinoma ( P < 0.01). Relapsing lymph-node pathologies were observed in 4 patients (44.4%) with insular carcinoma ( P < 0.05 vs those with follicular and papillary carcinomas). Distant metastases were observed in 66.6 per cent of insular carcinomas ( P < 0.005 vs follicular carcinoma and P < 0.001 vs papillary carcinoma). At the end of follow-up, 2 patients (22.2%) with insular carcinoma were disease-free ( P < 0.001 vs those with follicular and papillary carcinomas). Our study demonstrates an unfavorable prognostic role of the insular phenotype of thyroid cancer, such that this tumor can be classified as an autonomous clinical and pathological entity.

Total parathyroidectomy with autograft represents an optimal surgical technique in the treatment of secondary hyperparathyroidism. Relapsing hyperparathyroidism due to miliary-type nodular formations scattered over the autograft site represents a complication that is rarely described in the literature. We examined five case histories of patients relapsing as a result of miliary-type nodular formations in the autograft site; in four cases the relapse was localized in the upper limb and in one case in a pouch of the sternocleidomastoid muscle. The patients underwent removal of the hyperfunctioning parathyroid formations accompanied by demolition of the surrounding muscle tissue. The relapsing hyperparathyroidism caused by multiple miliary-type nodular formations is a rare occurrence, akin to parathyromatosis. The increasingly widespread use of total parathyroidectomy with autograft to treat secondary hyperparathyroidism can lead to an increase in the incidence of this complication. Correct surgical technique and a careful selection of the parathyroid tissue to be autografted can prevent this complication. Furthermore, extensive demolition of the muscle tissue in the autograft site can prevent further relapses. Intraoperative rapid parathormone assay was found to be predictive of the disease's persistence and recurrence.

In this study the authors examine the experience of their department in treating parotid tumours, evaluating in particular the various surgical techniques as a function of the prognosis and the incidence of relapses. Between 1 January 1970 and 31 December 2002, 336 patients with parotid tumour were observed in the Department of Surgical Sciences of "La Sapienza" University in Rome. Two hundred and thirty-nine patients with benign tumours and 65 with malignant tumours were analysed. As far as histological forms were concerned, the benign forms presented a prevalence of pleomorphic adenomas (55.2%) and of Warthin's tumours (36.4%). In the case of malignant tumours, the highest incidence was found for mucoepidermoid carcinomas (29.3%). In the case of benign neoplasms, the surgical strategy opted for was preneural parotidectomy performed in 148 cases (61.9%). Relapsing pleomorphic adenomas were observed in 11.65% of patients controlled, and relapsing Warthin's tumours in 8.7%. In malignant tumours, total parotidectomy was performed in principle, with possible enlargement modulated as a function of tumour stage; owing to causes related to the neoplasm, 18 patients (38.3%) died. In the treatment of benign parotid tumours, preneural parotidectomy is the preferred surgical strategy as it significantly reduces the relapse rate and, when performed by skilled surgeons, is characterized by a complication rate comparable to that of conservative surgery. In the treatment of malignant tumours, total parotidectomy is the basic procedure; extension of the action and the use of ancillary techniques are dependent on tumour stage.

The anatomy of the gonadal vein has been the subject of several studies relating particularly to the aetiology and therapy of varicocele and left ovarian vein syndrome. Venography shows the presence of valves, the collateral branches, the anastomoses between the left gonadal vein and the retroperitoneal venous networks and the effective pathways of venous reflux. The authors observed a particular congenital anomaly of the left gonadal vein in the dissection of a female cadaver, and studied the venographic pattern of a male patient with left idiopathic varicocele. The aim of this study was to investigate, with the aid of a review of the literature, the embryo-pathogenetic basis of congenital abnormalities of the left gonadic vein, stressing those factors most conducive to errors in the diagnosis and therapy of varicocele and left ovarian vein syndrome, particularly in the scleroembolisation therapy of idiopathic varicocele.

A variety of techniques for scrotal orchiopexy have been described in the literature, including those without suture fixation, such as the scrotal pouch. We perform a simple modified technique for bilateral testicular fixation in patients with bilateral and/or unilateral adult retractile testis and with symptoms characterised by chronic orchialgia due to testicular hypermobility or repeated funicular subtorsion.

Here we report a case of panhypopituitarism caused by pituitary Langerhans cell hystocitosis (LCH) in a 22-year-old woman affected by papillary thyroid carcinoma (PTC). Although several cases of the coexistence of PTC and LCH within thyroid tissue have been described in relative literature, in this case, the patient presented a unique suprasellar retrochiasmatic histocytosis localization which, to the best of our knowledge, had never been described before in association with PTC. Even if this aspect is not addressed in the present case report, it is worth noting that about 50% of the patients affected either by LCH or PTC are characterized by activating mutations of the proto-oncogene BRAF. This, along with other clinical studies, may warrant further biomolecular large-scale case study investigations in order to evaluate a possible connection between the 2 conditions and shed light on the etiology of these diseases, which are still largely unknown.