Nipple-Sparing Mastectomy Long-Term Outcomes: Early and Late Complications.

Background and Objectives: The surgical choice treatment of the breast cancer mostly depends on the stage of the disease. In the last years, breast cancer surgery has moved from being destructive to being more respectful of the anatomical and physiological integrity of the gland. The aim of the breast surgery should be finalized to obtain the best aesthetic and functional results, respecting the principles of oncologic radicality. The present study is a retrospective analysis aimed to evaluate the long-term outcomes of a conservative technique like the nipple-sparing mastectomy. Materials and Methods: We observed 894 patients with a median age of 47.5 years old, underwent nipple-sparing mastectomy between 2002-2017. The data acquired include population and tumor characteristics, patient reconstructive outcomes, including locoregional, regional, and distant metastases; other variables, among nipple-areola complex necrosis and infection were collected. Results: The complications detected were considered as "early" within 1 month later the nipple-sparing mastectomy or "late" after this time. The overall complications rate (early and late) and the overall survival and the relapses detected by this study were comparable with those reported in the literature. In order to identify factors that correlate with complications, either early or later, it has been processed an evaluation of the univariate analysis showing adjuvant chemotherapy as the only predictive factor for late complications, while we encountered no predictors for early complications. Conclusions: The present study adds to the data already present in literature, demonstrating that the nipple-sparing mastectomy is a safe procedure, providing good oncological and aesthetic results in patients carefully selected.

PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications.

The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.

A possible role for selenoprotein glutathione peroxidase (GPx1) and thioredoxin reductases (TrxR1) in thyroid cancer: our experience in thyroid surgery.

BACKGROUND: Oxidative stress is responsible for some alterations in the chemical structure and, consequently, in the function of proteins, lipids, and DNA. Recent studies have linked oxidative stress to cancers, particularly thyroid cancer, but the mechanisms remain unclear. Here, we further characterize the role of oxidative stress in thyroid cancer by analyzing the expression of two selenium antioxidant molecules, glutathione peroxidase (GPx1) and thioredoxin reductase (TrxR1) in thyroid cancer cells. METHODS: Samples of both healthy thyroid tissue and thyroid tumor were taken for analysis after total thyroidectomy. The expression of GPx1 and TrxR1 was revealed by Western blot analysis and quantified by densitometric analyses, while the evaluation of free radicals was performed by Electron Paramagnetic Resonance (EPR)-spin trapping technique. RESULTS: Our results show a decrease in the expression of GPx1 and TrxR1 (- 45.7 and - 43.2% respectively, p < 0.01) in the thyroid cancer cells compared to the healthy cells. In addition, the EPR technique shows an increase of free radicals in tumor tissue, significantly higher than that found in healthy thyroid tissue (+ 116.3%, p < 0.01). CONCLUSIONS: Our findings underscore the relationship between thyroid cancer and oxidative stress, showing the imbalance of the oxidant/antioxidant system in thyroid cancer tissue. These results suggest that either the inability to produce adequate antioxidant defense or an increased consumption of antioxidants, due to the hyper-production of free radicals, may play a crucial role in thyroid cancer.

Diagnosis and management of a mediastinal ectopic thyroid laying on the right bronchus: case report and review of literature.

BACKGROUND: The mediastinal ectopic thyroid is very rare, accounting for less than 1% of all cases of ectopic thyroid tissue. The differential diagnoses with other diseases such as lymphomas, thymic tumors and dermoid cysts is mandatory, in fact each one, needs different management and treatment. CASE PRESENTATION: Here, we discuss a rare case of mediastinal ectopic thyroid presenting with a paratracheal mass laying on the right bronchus without symptoms. A 63-year-old male presented with an abnormal well-defined mass along the right paratracheal side, detected by chest x-ray. The CT scan confirmed the presence of a 6 × 8 cm heterogeneously enhanced mass, located behind the superior vena cava and left brachiocephalic artery, reaching azygos vein and right bronchus, without a mass effect. Taking into account the clinical importance of a mediastinal mass, we removed it surgically, through a double surgical approach consisting in a classical transverse cervicotomy for the left thyroid lobe, followed then by a longitudinal sternal splitting to remove the mediastinal mass and complete the thyroidectomy. CONCLUSIONS: In case of mediastinal masses, the surgical excision is recommended, presenting the double advantage to clarify the diagnosis and to treat the pathology. As demonstrated in this case, a mediastinal ectopic thyroid should be taken into account in the differential diagnosis, considering its clinical importance.

Spider surgical system versus multiport laparoscopic surgery: performance comparison on a surgical simulator.

BACKGROUND: The rising interest towards minimally invasive surgery has led to the introduction of laparo-endoscopic single site (LESS) surgery as the natural evolution of conventional multiport laparoscopy. However, this new surgical approach is hampered with peculiar technical difficulties. The SPIDER surgical system has been developed in the attempt to overcome some of these challenges. Our study aimed to compare standard laparoscopy and SPIDER technical performance on a surgical simulator, using standardized tasks from the Fundamentals of Laparoscopic Surgery (FLS). METHODS: Twenty participants were divided into two groups based on their surgical laparoscopic experience: 10 PGY1 residents were included in the inexperienced group and 10 laparoscopists in the experienced group. Participants performed the FLS pegboard transfers task and pattern cutting task on a laparoscopic box trainer. Objective task scores and subjective questionnaire rating scales were used to compare conventional laparoscopy and SPIDER surgical system. RESULTS: Both groups performed significantly better in the FLS scores on the standard laparoscopic simulator compared to the SPIDER. Inexperienced group: Task 1 scores (median 252.5 vs. 228.5; p = 0.007); Task 2 scores (median 270.5 vs. 219.0; p = 0.005). Experienced group: Task 1 scores (median 411.5 vs. 309.5; p = 0.005); Task 2 scores (median 418.0 vs. 331.5; p = 0.007). Same aspects were highlighted for the subjective evaluations, except for the inexperienced surgeons who found both devices equivalent in terms of ease of use only in the peg transfer task. CONCLUSIONS: Even though the SPIDER is an innovative and promising device, our study proved that it is more challenging than conventional laparoscopy in a population with different degrees of surgical experience. We presume that a possible way to overcome such challenges could be the development of tailored training programs through simulation methods. This may represent an effective way to deliver training, achieve mastery and skills and prepare surgeons for their future clinical experience.

Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis.

Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Since tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA. Our results suggest a possible effect of anti-TNF drugs on ADMA serum levels; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA.

Serum levels of asymmetric dimethylarginine and apelin as potential markers of vascular endothelial dysfunction in early rheumatoid arthritis.

OBJECTIVES: Impaired endothelial function represents the early stage of atherosclerosis, which is typically associated with systemic inflammatory diseases like rheumatoid arthritis (RA). As modulators of endothelial nitric oxide synthase expression, asymmetric-dimethylarginine (ADMA) and apelin might be measured in the blood of RA patients to detect early atherosclerotic changes. We conducted a prospective, case-control study to investigate serum ADMA and apelin profiles of patients with early-stage RA (ERA) before and after disease-modifying antirheumatic drug (DMARD) therapy. METHODS: We enrolled 20 consecutively diagnosed, treatment-naïve patients with ERA and 20 matched healthy controls. Serum ADMA and apelin levels and the 28-joint disease activity scores (DAS28) were assessed before and after 12 months of DMARDs treatment. All patients underwent ultrasonographic assessment for intima-media tickness (IMT) evaluation. RESULTS: In the ERA group, ADMA serum levels were significantly higher than controls at baseline (P = 0.007) and significantly decreased after treatment (P = 0.012 versus controls). Baseline serum apelin levels were significantly decreased in this group (P = 0.0001 versus controls), but they were not significantly altered by treatment. IMT did not show significant changes. CONCLUSIONS: ERA is associated with alterations of serum ADMA and apelin levels, which might be used as biomarkers to detect early endothelial dysfunction in these patients.

PTH after Thyroidectomy as a Predictor of Post-Operative Hypocalcemia.

Post-thyroidectomy hypocalcemia is a frequent complication with significant morbidity, and has been shown to increase hospital stay and readmission rates. The evaluation of serum parathyroid hormone (PTH) levels after thyroidectomy represents a reliable method to predict post-thyroidectomy hypocalcemia, but it remains infrequently used. This retrospective study investigates serum PTH values 3 h after thyroidectomy as a predictor of hypocalcemia. In this study, we enrolled 141 patients aged between 27 and 71 years eligible for total thyroidectomy who presented with multinodular goiter, suspicious nodule on cytological examination, Graves' disease, or toxic multinodular goiter. Three hours after total thyroidectomy, 53 patients (37.6%) showed a reduction in serum PTH. Of these patients 75.5% developed hypocalcemia by 24 h after surgery and 100% were hypocalcemic after 48 h (p < 0.001). There was no significant difference attributable to the different thyroid diseases, nor to the age of the patients. PTH at 3 h after total thyroidectomy accurately predicts post-operative hypocalcemia. The early detection of patients at risk of developing post-operative hypocalcemia allows for prompt supplementation of calcium and Vitamin D in order to prevent symptoms and allows for a safe and timely discharge.

Poorly Differentiated Thyroid Carcinoma: Single Centre Experience and Review of the Literature.

There is controversy in the literature regarding a distinct subset of thyroid carcinoma whose histologically classification falls between well-differentiated and anaplastic carcinomas, previously identified as 'poorly differentiated thyroid carcinoma' (PDTC), or 'insular carcinoma', in view of the peculiar morphological characteristics of the cell groupings. The correct diagnosis and treatment of this entity have important prognostic and therapeutic significance. In this review, we describe the epidemiology, diagnosis, and management of PDTC and report our single centre experience to add to the limited evidence existing in the literature.

Preoperative Ultrasonography in the Evaluation of Suspected Familial Non-Medullary Thyroid Cancer: Are We Able to Predict Multifocality and Extrathyroidal Extension?

Family history of thyroid cancer increases the risk of harboring thyroid malignancies that end up having extrathyroidal extension (ETE) and multifocality on histology; some authors suggest a more aggressive surgical approach. Their pre-operative identification could allow more conservative surgical procedures if none of these features are suspected. Our aim was to assess if neck ultrasonography could identify or exclude multifocality or ETE in these patients to tailor the extent of surgery. This retrospective study included patients with previous thyroid surgery, ≥1 first-grade relative with thyroid cancer, and who had undergone pre-surgical ultrasound. ETE was suspected in the case of thyroid border interruption or gross invasion of perithyroidal tissues. Multiple suspicious nodules were defined as suspicion of multifocal cancer. The cohort consisted of 45 patients (median age 49 years, 40 with thyroid cancer, 30 females). The positive predictive value of ultrasonography in predicting multifocality and ETE was 57.14% (25.25-84.03) and 41.67% (21.5-65.1%), respectively, while the negative predictive values were 63.2% (56.4-69.4%) and 72.7% (63.3-80.5%). Pre-operative ultrasound examination is unable to reliably identify or exclude multifocal disease or extrathyroidal extension. In patients scheduled for surgery and with a first-degree relative affected by DTC, a "negative" pre-operative US report does not exclude the potential finding of multifocality and ETE at final histopathology.

Oxidative stress and defective platelet apoptosis in naïve patients with Kawasaki disease.

Kawasaki disease (KD) is a rare and often undiagnosed disease, at least in the western countries. It is characterized by an inflammatory acute febrile vasculitis of medium sized arteries with a propensity to damage the coronary arteries. It normally occurs in the early childhood and the diagnosis is based on clinical symptoms. During the progression of the disease thrombocytosis is usually detected. This can exert a pathogenetic role in the cardiovascular complications occurring in KD. In the present work peripheral blood plasma and platelets from twelve naïve patients with KD were analyzed in order to detect possible pathogenetic determinants or progression markers. Morphological, biochemical and flow cytometrical methods have been used. With respect to age-matched healthy donors, we found an increase of platelet activation markers, i.e. degranulation, phosphatidylserine (PS) externalization and leukocyte-red cell-platelet aggregates. Some significant alterations that could represent suitable diagnostic determinants have also been detected in patient plasma: (i) decreased antioxidant power, (ii) decreased levels of asymmetric dymethylarginine (ADMA), a naturally occurring chemical interfering with the production of nitric oxide, and (iii) increased levels of soluble P-Selectin and soluble annexin V. Since PS externalizing platelets are known to exert a pro-coagulant activity, our data suggest the hypothesis that increased risk of vascular complications in KD could depend on platelet stimulation and defective apoptosis probably related to nitrosative stress.

Factors Influencing Epigenetic Mechanisms: Is There A Role for Bariatric Surgery?

Epigenetics is the interaction between the genome and environmental stimuli capable of influencing gene expression during development and aging. A large number of studies have shown that metabolic diseases are highly associated with epigenetic alterations, suggesting that epigenetic factors may play a central role in obesity. To investigate these relationships, we focus our attention on the most common epigenetic modifications that occur in obesity, including DNA methylation and post-translational modifications of histones. We also consider bariatric surgery as an epigenetic factor, evaluating how the anatomic and physiologic modifications induced by these surgical techniques can change gene expression. Here we discuss the importance of epigenetic mechanisms in chronic disease and cancer, and the role of epigenetic disturbances in obesity, with a focus on the role of bariatric surgery.

The Effect of Sleeve Gastrectomy on Oxidative Stress in Obesity.

High concentrations of free radicals are present in the blood of obese patients. Free radicals are associated with endothelial dysfunction, diabetes, and neoplastic transformation, all conditions that are closely related to obesity. The purpose of our study was to determine whether bariatric surgery modifies the production of free radicals in obese patients. In total, 20 patients with morbid obesity, who were candidates for laparoscopic sleeve gastrectomy (SG), and 18 controls were enrolled in the study. Oxidative stress was studied in obese subjects before and after sleeve gastrectomy. The evaluation of oxidative stress was carried out on blood samples using electron paramagnetic resonance, a refined spectroscopic technique used to identify and quantify the major free radicals, such as •OH, O2•, ONOO-, and NO. Oxidative stress was higher in subjects with morbid obesity prior to surgery, compared to the controls (CP• 9.9 ± 0.3 µM vs. 5.8 ± 0.2 µM). After SG, values decreased to levels comparable to those of controls (CP• 5.4 ± 0.2 µM). Further analysis identified O2• as the main free radical responsible for the oxidative stress. Obesity is associated with an increased blood concentration of free radicals. The normalization of free radicals after sleeve gastrectomy highlights another important benefit of this bariatric surgery technique.

Metabolomic Reprogramming Detected by 1H-NMR Spectroscopy in Human Thyroid Cancer Tissues.

Thyroid cancer cells demonstrate an increase in oxidative stress and decreased antioxidant action, but the effects of this increased oxidative stress on cell function remain unknown. We aimed to identify changes in the metabolism of thyroid cancer cells caused by oxidative stress, using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Samples of thyroid cancer and healthy thyroid tissue were collected from patients undergoing thyroidectomy and analyzed with 1H-NMR spectroscopy for a wide array of metabolites. We found a significant increase in lactate content in thyroid cancer tissue compared to healthy tissue. Metabolomic analysis demonstrated significant differences between cancer tissue and healthy tissue, including an increase in aromatic amino acids, and an average decrease in citrate in thyroid cancer tissue. We hypothesize that these changes in metabolism may be due to an oxidative stress-related decrease in activity of the Krebs cycle, and a shift towards glycolysis in cancer tissue. Thus, thyroid cancer cells are able to reprogram their metabolic activity to survive in conditions of high oxidative stress and with a compromised antioxidant system. Our findings, for the first time, suggested a connection between oxidative stress and the alteration of the metabolic profile in thyroid tumors.

Peroxynitrite signaling in human erythrocytes: synergistic role of hemoglobin oxidation and band 3 tyrosine phosphorylation.

Peroxynitrite crosses the red blood cell (RBC) membrane and reacts with hemoglobin (Hb) producing mainly metHb, which is reduced back to ferrousHb by NADH- and NADPH-dependent reductases. Peroxynitrite also induces band 3 (B3) tyrosine phosphorylation, a signaling pathway believed to activate glucose metabolism. This study was aimed to decipher the relationship between these two peroxynitrite-dependent processes. Peroxynitrite induced a burst of the hexose monophosphate shunt (HMS), revealed by NMR studies, and a burst of the glycolytic pathway, measured by lactate production. The HMS plays a prominent role in membrane signaling, as demonstrated by B3 phosphotyrosine inhibition by the glycolytic pathway inhibitor 2-deoxy-glucose (2DG) and activation by dehydroepiandrosterone (DHEA), an inhibitor of HMS. Peroxynitrite-induced B3 tyrosine phosphorylation was paralleled by the inhibition of membrane-associated phosphotyrosine phosphatase (PTP) activity, which was protected by 2DG but not DHEA. Interestingly, heme poisoning with CO inhibited peroxynitrite-dependent Hb oxidation and lactate production but did not affect PTP down regulation. These results suggest two distinct and concurrent effects of peroxynitrite: one mediated by Hb which, likely in its oxidized state, binds more strongly to B3, and another mediated by PTP-dependent B3 phosphorylation. Both effects are directed towards a surge in glucose utilization.

The surgical management of locally advanced well-differentiated thyroid carcinoma: changes over the years according to the AJCC 8th edition Cancer Staging Manual.

BACKGROUND: Well-differentiated thyroid carcinoma is defined as locally advanced in the presence of an extra thyroid extension, e.g., when the surrounding structures such as the trachea, larynx, esophagus and main blood vessels are invaded by cancer. The 8th edition AJCC Cancer Staging Manual states that this is the main characteristic to evaluate for the staging and consequently for the prognosis in patients over 55 years old. MAIN BODY: Distinguishing different forms of locally advanced thyroid cancer is essential, and the various anatomical structures and the clinical and therapeutic consequences must be taken into account. An accurate diagnosis of the organs invaded by thyroid cancer is necessary for the planning of surgical treatment, and both aspects are crucial to improving the patients' survival. Patients affected by thyroid cancer with extra thyroid extension have a poor prognosis and the removal of the entire neoplasm represents a key factor for better disease-free survival. CONCLUSIONS: We discuss the changes introduced by the 8th edition AJCC Cancer Staging Manual, in terms of the diagnostic and surgical management of extra thyroid extension, in patients affected by papillary and follicular thyroid cancer.

Red blood cells as a model to differentiate between direct and indirect oxidation pathways of peroxynitrite.

Red blood cells are the major physiological scavengers of reactive nitrogen species and have been proposed as real-time biomarkers of some vascular-related diseases. This chapter proposes that the erythrocyte is a suitable cell model for studying the modifications induced by peroxynitrite. Peroxynitrite decays both extra- and intracellularly as a function of cell density and CO(2) concentration, inducing the appearance of distinct cellular biomarkers, as well as the modulation of signaling and metabolism. Intracellular oxidations are due mostly to direct reactions of peroxynitrite with hemoglobin but also lead to the appearance of apoptotic biomarkers. Surface/membrane oxidations are due principally to indirect radical reactions generated by CO(2)-catalyzed peroxynitrite homolysis.

Automated classification of focal breast lesions according to S-detect: validation and role as a clinical and teaching tool.

PURPOSE: To assess the diagnostic performance and the potential as a teaching tool of S-detect in the assessment of focal breast lesions. METHODS: 61 patients (age 21-84 years) with benign breast lesions in follow-up or candidate to pathological sampling or with suspicious lesions candidate to biopsy were enrolled. The study was based on a prospective and on a retrospective phase. In the prospective phase, after completion of baseline US by an experienced breast radiologist and S-detect assessment, 5 operators with different experience and dedication to breast radiology performed elastographic exams. In the retrospective phase, the 5 operators performed a retrospective assessment and categorized lesions with BI-RADS 2013 lexicon. Integration of S-detect to in-training operators evaluations was performed by giving priority to S-detect analysis in case of disagreement. 2 × 2 contingency tables and ROC analysis were used to assess the diagnostic performances; inter-rater agreement was measured with Cohen's k; Bonferroni's test was used to compare performances. A significance threshold of p = 0.05 was adopted. RESULTS: All operators showed sensitivity > 90% and varying specificity (50-75%); S-detect showed sensitivity > 90 and 70.8% specificity, with inter-rater agreement ranging from moderate to good. Lower specificities were improved by the addition of S-detect. The addition of elastography did not lead to any improvement of the diagnostic performance. CONCLUSIONS: S-detect is a feasible tool for the characterization of breast lesions; it has a potential as a teaching tool for the less experienced operators.

Two different pathways are involved in peroxynitrite-induced senescence and apoptosis of human erythrocytes.

CO(2) changes the biochemistry of peroxynitrite basically in two ways: (i) nitrating species is the CO(3)(-) / ()NO(2) radical pair, and (ii) peroxynitrite diffusion distance is significantly reduced. For peroxynitrite generated extracellularly this last effect is particularly dramatic at low cell density because CO(3)(-) and ()NO(2) are short-lived and decay mostly in the extracellular space or at the cell surface/membrane. This study was aimed to distinguish between peroxynitrite-induced extra- and intracellular modifications of red blood cells (RBC). Our results show that at low cell density and in the presence of CO(2) peroxynitrite induced the oxidation of surface thiols, the formation of 3-nitrotyrosine and DMPO-RBC adducts, and the down-regulation of glycophorins A and C (biomarkers of senescence). Reactivation of glycolysis reversed only the oxidation of surface thiols. Without CO(2) peroxynitrite also induced the oxidation of hemoglobin and glutathione, the accumulation of lactate, a decrease in ATP, the clustering of band 3, the externalization of phosphatidylserine, and the activation of caspases 8 and 3 (biomarkers of apoptosis). The latter biomarkers were all reversed by reactivation of glycolysis. We hypothesize that cell senescence could (generally) be derived by irreversible radical-mediated oxidation of membrane targets, while the appearance of apoptotic biomarkers could be bolstered by oxidation of intracellular targets. These results suggest that, depending on extracellular homolysis or diffusion to the intracellular space, peroxynitrite prompts RBCs toward either senescence or apoptosis through different oxidation mechanisms.

Salivary uric acid at the acidic pH of the stomach is the principal defense against nitrite-derived reactive species: sparing effects of chlorogenic acid and serum albumin.

A complex antioxidant system is present in human saliva, with uric acid being the most concentrated component. Ascorbic acid, present at low concentrations in saliva, is actively secreted into the gastric lumen. We report that ascorbic acid added to human saliva at pH 2 was consumed within a few minutes, regenerating HNO(2), whereas uric acid was consumed relatively slowly in a nitrite-dependent manner. The consumption of uric acid was (i) rapid under normoxic conditions and slower at low oxygen tensions, (ii) coupled to *NO release, (iii) linked to the decrease in nitrite consumption and in nitrate formation, and (iv) unaffected by the nitrosation catalyst thiocyanate. Both chlorogenic acid and bovine serum albumin, representative of a phenol- and a protein-rich meal, respectively, were able to spare uric acid, although chlorogenic acid increased, whereas bovine serum albumin inhibited, *NO release. We hypothesize that the major role of uric acid in saliva at pH 2 could be to preserve the stomach from the formation of toxic nitrogen species and that low levels of uric acid, together with ascorbic acid consumption, may contribute to the high occurrence of tumors at the gastroesophageal junction and cardia. The sparing effects of dietary compounds may therefore be an important not fully appreciated effect.