Exosomes in breast cancer management: Where do we stand? A literature review.

BACKGROUND: Exosomes constitute cellular molecular fingertips that participate in intercellular communication both in health and disease states. Hence, exosomes emerge as critical mediators of cancer development and progression, as well as potential biomarkers and novel therapeutic targets. OBJECTIVE: To review literature data regarding applications of circulating exosomes in breast cancer management. METHODS: This is a literature review of relevant published studies until April 2020 in PubMed and Google Scholar databases. Original papers in the English language concerning exosome related studies were included. RESULTS: Exosomes represent molecular miniatures of their parent cells. Several homeostatic mechanisms control exosomal secretion and synthesis. Exosomal exchange among cells creates an intricate intercellular crosstalk orchestrating almost every tissue process, as well as carcinogenesis. Available data highlight exosomes as major mediators of cancer development and progression. The secretion of specific exosomal molecules, particularly miRNAs, correlates with the underlying processes and can be used as a means of tumor detection and prognostic assessment. CONCLUSIONS: Exosomal miRNAs expression profiles and levels closely relate to cancer extent, type and prognosis. Deep comprehension of such correlations and systematization of experimental outcomes will offer a novel approach in cancer detection and management.

A Strict Patient Selection Protocol Could Be the Key to Success for Transanal Minimally Invasive Surgery (TAMIS).

OBJECTIVES: In recent years, the local excision of benign rectal lesions or early-stage rectal cancers using minimally invasive surgical techniques has replaced radical interventions that caused impairment in patients' quality of life. The aim of the present study was to investigate the feasibility of transanal minimally invasive surgery (TAMIS), as well as its excision quality, its oncologic outcomes, and its impact on anorectal function. METHODS: Patients who underwent TAMIS at a single colorectal unit of a tertiary university hospital from 2015 until 2020 for benign rectal lesions or early-stage malignant rectal lesions, along with unsuitable patients for radical interventions, were included in the present study. RESULTS: Twenty-five patients underwent TAMIS for rectal lesions. Their median distance from the anal verge was 7 cm (range 4-12 cm) and their median size was 3.8 cm (range 2-6 cm). The median operative duration was 75 minutes (range 30-150 minutes) and the median hospitalization interval was 2 days (range 1-6 days). In addition, the negative resection rate was 100% and the recurrence rate was 4% during an average follow-up period of 30 months (range 3-36 months). Two patients (8%) presented short-term complications, and in 1 patient (4%) a hybrid technique was required. Seventeen patients (68%) reported moderate incontinence symptoms 6 weeks postoperatively that subsided in all patients 3 months postoperatively. CONCLUSIONS: TAMIS seemed to be a feasible technique with adequate oncologic outcomes and high excision quality, which preserved patients' quality of life. The impact of TAMIS on anorectal function after neoadjuvant chemoradiotherapy for rectal cancer should be further investigated, however.

Complex refractive index of freshly excised human breast tissue as a marker of disease.

We report differences in the refractive index of healthy and tumorous freshly excised human breast tissue as determined from reflectance profile measurements at five wavelengths (432 nm, 532 nm, 633 nm, 964 nm, 1551 nm) in the visible and near-infrared using a standard prism-coupling refractometer. These refractive index differences, particularly in the near-infrared, can be used to distinguish fibroadenomas and cancerous growths not only from normal breast tissue but also from each other.

Noxa upregulation and 5-gene apoptotic biomarker panel in colorectal cancer.

BACKGROUND: NOXA and MCL1 are involved in the intrinsic pathway of apoptosis, where Noxa selectively binds to MCL1 and prevents it from inhibiting apoptosis. Both factors are considered as potential tumour biomarkers, while MCL1 has attracted interest as target in cancer. The purpose of this study was to investigate the expression of NOXA and MCL1 in 160 CRC tumour samples, to investigate their significance, also in combination with IAPs, DR5 expression and KRAS gene mutations in CRC. MATERIALS AND METHODS: Fresh frozen colorectal tissue was obtained from patients undergoing surgery for CRC. Real-time quantitative PCR was performed for the determination of mRNA expression levels. Protein expression was determined immunohistochemically. Differences in the mRNA expression profile were evaluated with the nonparametric Wilcoxon signed ranks test. Statistical analysis was performed with the use of Mann-Whitney U test and receiver-operating characteristic (ROC) curve. RESULTS: NOXA was found to be overexpressed in CRC tumours (P < .0001), even from early stage. Moreover, NOXA/MCL1 mRNA expression was significantly elevated in tumour samples compared to normal pairs (P < .0001). ROC curve analysis showed that both NOXA expression and its combination with Mcl1 expression have fair discriminatory value between CRC and normal colorectal tissue. Combinatorial ROC analysis revealed the most significant discriminatory value of NOXA, MCL1 with cIAP1 and cIAP2 (AUC = 0.834, P < .0001) as a 5-gene panel of markers. CONCLUSION: Noxa, Mcl1, DR5, cIAP1 and cIAP2 mRNA expressions are significantly deregulated in CRC and could provide a panel of markers with significant discriminatory value between CRC and normal colorectal tissue.

Adrenocortical Cancer: A 20-Year Experience of a Single Referral Center in Prognosis and Outcomes.

Adrenocortical carcinoma (ACC) is a rare but very aggressive endocrine malignancy with poor survival. Histopathology is important for diagnosis, while in some cases immunohistochemical markers and gene profiling of the resected tumor may be superior to current staging systems to determine prognosis. We aimed to present the 20-year experience at a tertiary hospital in patients with ACCs and correlate the immunohistochemical characteristics of ACCs with the clinical and morphological characteristics of the tumors and the survival of the patients. Forty-five patients with ACC were included in the study. All the resections were R0. The tumor size and weight, the disease stage (ENSAT classification), Weiss score and Helsinki score were examined along with immunohistochemical expression of inhibin-A, melan A, calretinin, Ki67, synaptophysin, p53, vimentin, CKAE1/AE3. The male to female ratio was 1:1.37. The median age at diagnosis was 55.5 years (IQR 19-77). The median size of ACCs was 9 cm (IQR 3.5-22 cm) and the median weight 127 g (IQR 18-1400 g). The median follow up period was 18 months (IQR 1-96). Ki67 varied from<1% to 75% (median: 16.4%). The expression of melan-A and lower expression of Ki-67 (≤4) were independently associated with longer OS time (p=0.01 and p=0.04, respectively). In multivariable analysis, tumor volume>400 cm3 (p=0.046), Weiss score>5 (p=0.007) and overexpression of p53 (p=0.036) were independent risk factors for shorter survival. Adrenocortical carcinoma is a rare and very aggressive endocrine malignancy. The most important factors that determine long-term prognosis of ACC are the disease stage at diagnosis, the Weiss score, and the Ki67 index. Immunohistochemical markers such as melan A could also serve as prognostic factors.

A novel way of hook wire placement for surgical resection of suspicious breast lesions using the stereotactic vacuum assisted breast biopsy table.

Preoperative hook localization is a necessary procedure for targeting impalpable breast lesions. The aim of the current study is to introduce an alternative technique of wire placement by using the stereotactic biopsy device instead of the conventionally used mammography device. Fifty-one patients with impalpable mammographic lesions, graded BIRADS 4 or 5, were prospectively enrolled. Mean duration was 7 ± 1.5 minutes. Lesion-to-wire distance was <1 cm in 96% (51/53). Hook wire placement using the stereotactic biopsy device is considered as a safe, accurate, fast, and well-tolerable for the patient procedure.

Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis.

BACKGROUND: Hydrogen sulfide (H2S), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions. METHODS: Endothelial cell CSE knockout mice were generated, and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration, and monocyte adhesion). Mice were crossed onto the apolipoprotein E-deficient background, and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, H2S bioavailability, and amino acid profiling were also performed with human material. RESULTS: The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein human antigen R. CSE expression was upregulated in mice after partial carotid artery ligation and in atheromas from human subjects. Despite the increase in CSE protein, circulating and intraplaque H2S levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely resulting from increased interleukin-1ß. Consistent with the loss of H2S, human antigen R sulfhydration was attenuated in atherosclerosis and resulted in the stabilization of human antigen R-target mRNAs, for example, CD62E and cathepsin S, both of which are linked to endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed on treatment with a polysulfide donor. Finally, in mice and humans, plasma levels of the CSE substrate l-cystathionine negatively correlated with vascular reactivity and H2S levels, indicating its potential use as a biomarker for vascular disease. CONCLUSIONS: The constitutive S-sulfhydration of human antigen R (on Cys13) by CSE-derived H2S prevents its homodimerization and activity, which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation, the beneficial actions of CSE-derived H2S are lost owing to the phosphorylation and inhibition of the enzyme.

Prognostic impact of stromal and intratumoral CD3, CD8 and FOXP3 in adjuvantly treated breast cancer: do they add information over stromal tumor-infiltrating lymphocyte density?

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and their subsets contribute to breast cancer prognosis. We investigated the prognostic impact of CD3+, CD8+ and FOXP3+ TILs in patients with early intermediate/high-risk breast cancer treated with adjuvant anthracycline-based chemotherapy within two randomized trials conducted by our Group. METHODS: We examined 1011 patients (median follow-up 130.9 months) and their tumors for total, stromal (s) and intratumoral (i) CD3, CD8 and FOXP3 lymphocyte density (counts/mm2) on tissue-microarray cores by immunohistochemistry. Morphological sTIL density on whole H&E-stained sections was also evaluated. RESULTS: The majority of TILs were CD3+. Total CD3 and CD8, sCD3 and sCD8, iCD3 and iCD8, sFOXP3 and iFOXP3 were strongly correlated (Spearman's rho values > 0.6). High individual lymphocytic subsets and sTIL density were strongly associated with high tumor grade, higher proliferation and HER2-positive and triple-negative tumors (all p values < 0.001). Higher sTIL density (10% increments), high density of almost each individual marker and all-high profiles conferred favorable prognosis. However, when adjusted for sTIL density, stromal and intratumoral lymphocytic subsets lost their prognostic significance, while higher sTIL density conferred up to 15% lower risk for relapse. Independently of sTIL density, higher total CD3+ and CD8+ TILs conferred 35% and 28% lower risk for relapse, respectively. CONCLUSIONS: Stromal and intratumoral CD3+, CD8+ and FOXP3+ TIL density do not seem to add prognostic information over the morphologically assessed sTIL density, which is worth introducing in routine histology reports.

Predictive factors for breast lesion excision system (BLES) accuracy and safety in stereotactic biopsy of suspicious calcifications.

AIM: To retrospectively assess the effectiveness and safety of BLES stereotactic biopsy of suspicious calcifications and investigate possible predictive factors for underestimation. METHODS AND MATERIALS: Between January 2014 and January 2016, 400 biopsies of suspicious calcifications were performed in our Department using the BLES stereotactic device. The mean age of our population was 58.5 years (range 39-78 years). The final surgical results were used as gold standard. The effectiveness of the method was statistically evaluated. Mammographic size, grade, molecular type, and presence of comedo type/necrosis were assessed as predictive factors. RESULTS: 90/400 (22.5%) cases were cancers (20% invasive cancers, 80% non-invasive cancers). 38/400 cases were atypical lesions (9.5%). No underestimation was found in atypical lesions that underwent surgery (29/38 cases). Downgrade was achieved in 45.5% of cases (with complete removal in 34.4%), concordance in 43.3%, and upgrade was found in 15.5% of the cases; the initial mammographic size and the grade of the cancers were found to be statistically significant predictive factors. The total complication rate was 8.75%. CONCLUSIONS: Breast lesion excision system is a highly accurate and safe stereotactic biopsy technique of suspicious calcifications with low underestimations and high downgrade/removal rates with the potential to alter the final surgical decision in selected cases.

How breast cancer treatments affect the quality of life of women with non-metastatic breast cancer one year after surgical treatment: a cross-sectional study in Greece.

BACKGROUND: The continuously increasing survivorship of female breast cancer makes the monitoring and improvement of patients' quality of life ever so important. While globally there is a growing body of research on health-related quality of life 1 year after surgical treatment for non-metastatic breast cancer, up-to-date information regarding Greek patients is scarce. OBJECTIVE: To measure the level of QoL of non-metastatic BC survivors in Greece 1 year after surgery. METHODS: A sample of 200 female breast cancer survivors aged 18 to 75, who followed up as outpatients in five public hospitals were included in this cross-sectional study. All recruited patients agreed to participate in the study (100% response rate). Quality of life data were collected through the EORTC QLQ-C30 as well as BR23 questionnaires. RESULTS: Cronbach's alpha for all scales of the two questionnaires was from 0.551 to 0.936 indicating very good reliability. According to the Multiple Linear Regression, older patients showed a lower future perspective (p = .031), with those living in rural areas, which was associated with more financial difficulties (p = .001). Women with tertiary education and those who had been hospitalized in a university hospital recorded better on global health status (p = .003 and .000 respectively). Patients who underwent chemotherapy reported better scores in the emotional function sub-scale (p = .025). Women with reconstruction and at least one complication appeared to have significantly better scores in future perspective and social function (p = .005, .002 respectively). CONCLUSIONS: Breast cancer survivors were found to have an overall good quality of life, functioning/symptoms scores and were satisfied with the provided care.

Role of one-pass breast lesion excision system in complete excision of high-risk breast lesions with atypia expressed as clusters of microcalcifications.

PURPOSE: To assess the role of the breast lesion excision system (BLES) in complete removal of clusters of microcalcifications found on mammogram proved histologically to be high-risk lesions with cell atypia. METHODS AND MATERIALS: Three hundred ninety-four consecutive women (mean age 58.5 years, range 39-78 years) with 400 clusters of suspicious microcalcifications underwent stereotactic biopsy using the intact BLES device between January 2014 and January 2016. All cases proved histologically to be high-risk lesions were subsequently assessed for complete removal. The underestimation rate was also assessed. RESULTS: Thirty-eight out of 400 (9.5%) lesions were high-risk lesions with atypia with mean size 7.63 mm (st. dev. = 4.03 mm) which was within the size that the BLES needle can excise (20 mm). Four (10.5%) papillomas with atypia, 14 (36.8%) cases with flat epithelial atypia (FEA), 10 (26.3%) cases with lobular intraepithelial neoplasia (LIN-LIN 1, LIN 2), 8 (21.2%) with atypical ductal hyperplasia (ADH) and 2 (5.3%) cases with mucocele-like lesions (MLL) with atypia were found. Twenty-nine out of 38 lesions had subsequent surgery. Complete excision was achieved in 23/29 lesions (79.3%). No underestimation was found. Two-year mammographic stability was found in all lesions. Non-parametric statistical analysis showed no other significant predictive factor for complete excision apart from the distance of the lesions from the specimen margins (p = 0.031 Mann-Whitney test). CONCLUSION: One-pass BLES intact biopsy technique is a safe method of complete removal of high-risk atypical lesions with high accuracy rates for certain histologies and could be potentially used as an alternative excision method to diagnostic surgery in selected cases. KEY POINTS: • Breast lesion excision system (BLES) is an image-guided biopsy technique that uses radiofrequency to remove an intact piece of tissue including the target breast neoplasm. • Breast lesion excision system (BLES) under stereotactic guidance is able to accurately biopsy high-risk breast lesions expressed mammographically as clusters of suspicious microcalcifications. • BLES under stereotactic guidance is an accurate technique for en bloc excision of selected cases of small clusters of suspicious microcalcifications proved to be high-risk lesions with histopathologically disease-free margins of excision.

Variant hepatic arterial anatomy encountered during pancreatoduodenectomy does not influence postoperative outcomes or resection margin status: A matched pair analysis of 105 patients.

BACKGROUND/AIM: Anatomic vascular abnormalities of the hepatic arteries are frequent. The aim of the study was to analyze the influence of hepatic arterial variations on postoperative morbidity and resection margin status after pancreatoduodenectomy (PD). MATERIALS/METHODS: Patients who underwent PD over a 7-year period (2010-2017) were included in the study. Patients with variant hepatic arterial anatomy were matched 1:2 for age, sex, ASA score, and histology. RESULTS: A total of 232 patients underwent PD. Variant hepatic arterial anatomy was found in 35 (15.1% of the total patient population). The most common variation was an accessory right hepatic artery (8.19%) and a replaced right hepatic artery (5.60%) arising from the superior mesenteric artery. These 35 patients were compared with 70 patients with no hepatic artery variations. Postoperative surgical complications occurred in 12.1% and 26.5% (P = 0.08) and in-hospital mortality was 6% and 5.4% ( P = 0.99) between patients with and without variant hepatic arteries. There was no difference in positive resection margins (R1) (18.2% vs 20.5%, P = 0.99) between the two groups. CONCLUSIONS: An aberrant hepatic artery does not increase morbidity or R1 resection in patients undergoing PD.

Praxagoras of Cos (4th Century BC) and His Innovative Method of a Diverting Enterocutaneous Fistula to Relieve Small Bowel Obstruction.

Born in an island with huge medical tradition in ancient Greece, Praxagoras of Cos became an esteemed medico-philosopher and surgeon. The evolution made by the Hippocratic School of Medicine further boosted his talent and helped him perform surgical operations, which were believed impossible for his era. Praxagoras introduced an innovative surgical technique to confront small bowel obstruction, by creating an enterocutaneous fistula. This historical review connects all available data to present the life and work of an important medical figure of the ancient Hellenic School.

Experimental Hemorrhagic Shock Protocol in Swine Models: The Effects of 21-Aminosteroid on the Small Intestine.

BACKGROUND: The protective potential of lazaroids has been reported in previous studies on ischemia/reperfusion and induced hemorrhagic shock protocols. OBJECTIVES: The present study is the first experimental protocol on the effects of the antioxidant factor U-74389G on the small intestine of swine models in a hemorrhagic shock protocol and resuscitation with 3 different types of fluids. METHODS: The study included 49 Landrace breed swine that were divided into groups of 7 each. Hemorrhage was provoked 45 minutes after starting the surgical protocol (0 minutes), followed by resuscitation starting 30 minutes after haemorrhage ceased by using 3 different fluids. Three groups (Group A, resuscitation using blood; Group B, resuscitation with Ringer's lactate solution; and Group C, resuscitation with hypertonic saline solution) underwent resuscitation with fluid alone, and another 3 groups (named A', B,' and C') were administered lazaroid U-74389G in addition to fluid. Control Group S underwent all the surgical procedures without hemorrhagic shock. Vital signs, complete blood count, and biochemical markers were analyzed, and tissue samples of the small intestine were collected from all animals. Further, malondialdehyde, tumor necrosis factor-α, and levels of inflammation in the tissue sample were measured. RESULTS: In Group S-A-A' and Group S-C-C', the analysis did not show statistically significant differences in the percentage changes of histopathology, malondialdehyde, and tumor necrosis factor-α through time. In Group S-B-B', the malondialdehyde levels in the small intestine were reduced in both the B and B' groups, without lazaroid (Group B) (P = 0.038) and lazaroid (Group B') (P = 0.011), compared with Group S (control), but the group without lazaroid (Group B) had greater reduction in malondialdehyde levels than the group treated with lazaroid (Group B'). With regard to the biochemistry results, 24% reduction was observed for alkaline phosphatase (P = 0.022) in Group A' treated with lazaroid compared with that in the untreated group. Lastly, for the complete blood count parameters, a 14% reduction in white blood cells was observed in Group B', which was treated with lazaroid in all phases (P = 0.015) (absolute value = 6.23) compared with Group B (absolute value = 13.74). CONCLUSIONS: Despite few initial findings of this study suggesting that administration of lazaroid U-74389G may have some potential in attenuation of the effects of hemorrhagic shock in the small intestine of swine models, no differences remained after correction for multiple comparisons was made. Therefore, further research is required to investigate this result thoroughly.

Le "canceur des fumeurs" in 19th century: the contribution of the French surgeon Étienne-Frédéric Bouisson (1813-1884).

At the beginning of the 19th century, the alarming rise in tobacco consumption and its consequences in health preoccupied physicians. Several medical authors pointed out the harmful effects of smoking, enumerating related disorders. In 1821, the hygienist Alexandre Parent du Châtelet (1790-1835) and the chemist Félix d'Arcet (1814-1847), studied the effects of tobacco in health and concluded that it was a relatively healthy habit providing also a kind of immunity from contagious diseases. The tobacco controversy opened up and continued for almost 40 years. In 1861, the professor of surgery and politician Étienne-Frédéric Bouisson (1813-1884) in his work entitled: "Tribut à la chirurgie ou mémoires sur divers sujets de cette science" (Tribute to surgery or dissertations on various topics of this science) related for the first time tobacco consumption to oral cancer, applying medical statistics and analyzing meticulously all the available data.

Health-related quality of life of young women with breast cancer. Review of the literature.

PURPOSE: The purpose of the present article was to investigate the health related quality of life (QoL) of young women with breast cancer. METHODS: For the purposes of this article, we reviewed the literature via the electronic databases Pubmed, Scopus and Google Scholar. Key words used were breast cancer, young women, health related quality of life, and quality of life. RESULTS: Young women reported fatigue, pain in the breast and hand problems with lymphedema as the most frequent physical effects of treatment. Other physical problems were the not periodic and painful menses, vaginal dryness and loss of libido. Many young women had depressive symptoms such as depressed mood, helplessness, hopelessness, sleep loss, psychomotor retardation and disorders of appetite. There were often concerns about the health monitoring and self-image, while they were anxious if they will have a baby in the future or if they can nurture the existing ones. Many problems arose in the career of young women. They faced discrimination in the labor supply and/or layoff because they were considered unable to do their job effectively. In addition, they reported isolation problems and feeling different from other women of similar age. CONCLUSIONS: Young women consider that their healthrelated QoL is worse compared with older women. Young women worry about their future, with particular reference to their role as mothers and especially to children-bearing. The free screening and non-exclusion of young women is particularly important for breast cancer prevention and women's well-being.

RANKL, OPG, TRAIL, KRas, and c-Fos expression in relation to central lymph node metastases in papillary thyroid carcinoma.

PURPOSE: RANKL, OPG and TRAIL have long been pursued in cancer. Mutated KRas proteins and c-Fos overexpression - well-recognized oncogenic events - have been conceived as coordinators of RANKL, OPG and TRAIL pathways. Considering the paucity in the relevant literature, the purpose of the present study was to investigate whether the expression of these molecules configures a distinct papillary thyroid carcinoma (PTC) subgroup with adverse clinicopathological characteristics. METHODS: RANKL, OPG, TRAIL, KRas, and c-Fos immunohistochemical expression in relation to clinicopathological characteristics of PTC was assessed retrospectively in paraffin-embedded PTC specimens from 114 patients who underwent total thyroidectomy with simultaneous central lymph node dissection (CLND). RESULTS: Expression of RANKL, OPG, TRAIL, Kras and c- Fos was revealed in 78.6, 63.2, 61.4, 47.4, and 73.7% of PTC, respectively. As predominant KRas-expressing PTC histotype emerged the classical PTC (cPTC), comprising 66.7% of PTC. A significant correlation was demonstrated of RANKL, OPG, and TRAIL expression with central lymph node metastasis CLNM (p=0.007, p<0.001, and p=0.002, respectively), concerning especially cPTC as regards to RANKL (p=0.027) and OPG (p=0.006), and both cPTC (p=0.043) and follicular variant of PTC (FVPTC) (p=0.049) with regard to TRAIL. OPG expression associated significantly with multifocality (p=0.045). Multivariable-adjusted logistic regression models characterized TRAIL as independent predictor of CLNM (OR=10.335, 95% CI: 1.23-86.87). CLNM correlated significantly with six pairs of coexpressions: TRAIL-KRas (p=0.011), TRAIL-c-Fos (p=0.006), OPG-c-Fos (p=0.024), RANKL-TRAIL (p<0.001), RANKL-OPG (p<0.001), TRAIL- OPG (p<0.001). CONCLUSION: The present study suggested for the first time that OPG, RANKL, TRAIL expressions, either alone or in concert involving c-Fos and KRas expression, are related to CLNM. Further research is warranted to elucidate whether the examined molecules can be endorsed as indicators of aggressive PTC behavior and guide a personalized therapeutic intervention.

Circulating thyroid cancer biomarkers: Current limitations and future prospects.

Differentiated thyroid cancer (DTC) is the most common malignancy of the endocrine system. There has been a significant increase in its incidence over the past two decades attributable mainly to the use of more sensitive diagnostic modalities. Ultrasound-guided fine needle aspiration cytology is the mainstay of diagnosis of benign disorders and malignancy. However, approximately 20% of lesions cannot be adequately categorized as benign or malignant. In the postoperative setting, monitoring of thyroglobulin (Tg) levels has been employed for the detection of disease recurrence. Unfortunately, Tg antibodies are common and interfere with Tg measurement in this subset of patients. Despite this limitation, Tg remains the sole widely used thyroid cancer biomarker in the clinical setting. In an attempt to bypass antibody interference, research has focused mainly on mRNA targets thought to be exclusively expressed in thyroid cells. Tg and thyroid stimulating hormone receptor (TSHR) mRNA have been extensively studied both for discerning between benign disease and malignancy and in postoperative disease surveillance. However, results among reports have been inconsistent probably reflecting considerable differences in methodology. Recently, microRNA (miRNA) targets are being investigated as potential biomarkers in DTC. MiRNAs are more stable molecules and theoretically are not as vulnerable as mRNA during manipulation. Initial results have been encouraging but large-scale studies are warranted to verify and elucidate their potential application in diagnosis and postoperative surveillance of thyroid cancer. Several other novel targets, primarily mutations and circulating cells, are currently emerging as promising thyroid cancer circulating biomarkers. Although interesting and intriguing, data are limited and derive from small-scale studies in specific patient cohorts. Further research findings demonstrating their value are awaited with anticipation.

Assessment of the vulnerable carotid atherosclerotic plaque using contrast-enhanced ultrasonography.

Carotid atherosclerosis represents a primary cause for cerebrovascular ischemic events and its contemporary management includes surgical revascularization for moderate to severe symptomatic stenoses. However, the role of invasive therapy seems to be questioned lately for asymptomatic cases. Numerous reports have suggested that the presence of neovessels within the atherosclerotic plaque remains a significant vulnerability factor and over the last decade imaging modalities have been used to identify intraplaque neovascularization in an attempt to risk-stratify patients and offer management guidance. Contrast-enhanced ultrasonography of the carotid artery is a relatively novel diagnostic tool that exploits resonated ultrasound waves from circulating microbubbles. This property permits vascular visualization by producing superior angiography-like images, and allows the identification of vasa vasorum and intraplaque microvessels. Moreover, plaque neovascularization has been associated with plaque vulnerability and ischemic symptoms lately as well. At the same time, attempts have been made to quantify contrast-enhanced ultrasonography signal using sophisticated software packages and algorithms, and to correlate it with intraplaque microvascular density. The aim of this review was to collect all recent data on the characteristics, performance, and prognostic role of contrast-enhanced ultrasonography regarding carotid stenosis management, and to produce useful conclusions for clinical practice.

Hallmarks in history of esophageal carcinoma.

Esophageal cancer is one of the deadliest cancers due to its aggressive behavior and poor survival. It was mentioned in the works of ancient Chinese and Arabo-islamic physicians, centuries before the recognition of high incidence in the Asian esophageal cancer belt. Till the 19th century the disease was considered incurable and the main goal of the proposed treatments was to alleviate dysphagia and pain. The introduction of esophagoscope in 1868 by Adolf Kussmaul (1822-1902) contributed to the observation of the living esophagus and to the diagnosis of esophageal pathologies, paving the way for new therapeutic approaches. In 1877, Vincenz Czerny (1842-1916) performed the first successful resection of the cervical esophagus for carcinoma, followed by Franz Torek (1861-1938) who carried out in 1913 the first successful subtotal thoracic esophagectomy and Tohru Ohsawa (1882-1984) who performed the world's first esophagectomy with an intrathoracic esophagogastric anastomosis. Nowadays, despite the advent of biomedical technology and the development of operation techniques, the surgical treatment of esophagus still remains a challenge.