Stefano Arcieri

Thyroid Imaging Reporting and Data System Score Combined with the New Italian Classification for Thyroid Cytology Improves the Clinical Management of Indeterminate Nodules

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.

The Role of Docosahexaenoic Acid (DHA) in the Control of Obesity and Metabolic Derangements in Breast Cancer

Obesity represents a major under-recognized preventable risk factor for cancer development and recurrence, including breast cancer (BC). Healthy diet and correct lifestyle play crucial role for the treatment of obesity and for the prevention of BC. Obesity is significantly prevalent in western countries and it contributes to almost 50% of BC in older women. Mechanisms underlying obesity, such as inflammation and insulin resistance, are also involved in BC development. Fatty acids are among the most extensively studied dietary factors, whose changes appear to be closely related with BC risk. Alterations of specific ω-3 polyunsaturated fatty acids (PUFAs), particularly low basal docosahexaenoic acid (DHA) levels, appear to be important in increasing cancer risk and its relapse, influencing its progression and prognosis and affecting the response to treatments. On the other hand, DHA supplementation increases the response to anticancer therapies and reduces the undesired side effects of anticancer therapies. Experimental and clinical evidence shows that higher fish consumption or intake of DHA reduces BC cell growth and its relapse risk. Controversy exists on the potential anticancer effects of marine ω-3 PUFAs and especially DHA, and larger clinical trials appear mandatory to clarify these aspects. The present review article is aimed at exploring the capacity of DHA in controlling obesity-related inflammation and in reducing insulin resistance in BC development, progression, and response to therapies.

Prevention of complications during reoperative thyroid surgery.

BACKGROUND Thyroidectomy performed by an experienced surgeon is associated with a low incidence of recurrent laryngeal nerve injury and permanent hypoparathyroidism. During reoperative thyroid surgery there is a higher technical risk because detection and preservation of the recurrent laryngeal nerves and parathyroid glands are more difficult than in the primary surgery. AIM Our retrospective cohort study was to assess short- and long-term complications associated with reoperative thyroid surgery in order to suggest a technical approach to lower the morbidity rate. MATERIALS AND METHODS From January 2005 to September 2013, 745 patients underwent surgery for thyroid disease. Before surgery all patients underwent clinical examination, laboratory blood tests, hormonal assays, neck ultrasound, chest radiography and indirect laryngoscopy. Patients were followed up at 1, 3, 6 months and then annually after operation with hormonal assays, blood tests and neck ultrasound. RESULTS Eighty (10.7%) out of 745 patients (mean-age= 52.5 years; age-range 18-80) underwent reoperative surgery for recurrent thyroid disease. The primary treatments were enucleoresection (11.2%), thyroid lobectomy(56,3%), thyroid lobectomy with isthmectomy(10%) and subtotal thyroidectomy (22,5%). In the reoperative surgery group (Group Re) the transient RLN complications were 1.3% compared to 0.2% in the primary surgery group (Group P) (p= 0.51). The incidence of temporary hypocalcemia was 45% in the reoperative surgery group vs. 42.7% in the primary surgery group (p=0.72). CONCLUSIONS Reoperative surgery should be reserved to experienced surgeons. However, even in this case, when surgical maneuvers reserved for primary surgery are applied, then this surgery is associated with a low complications rate.

Partial oesophagectomy for giant leiomyoma of the oesophagus: report of 7 cases

OBJECTIVES Oesophageal leiomyoma is the most common benign tumour of the oesophagus. The incidence of leiomyomas larger than 10 cm, defined as giant oesophageal leiomyomas (GELs), has been reported in 17% of all cases. Although computed tomographic scan and endoscopy are usually useful for diagnosis, big and symptomatic masses located in the lower mediastinum remain both a diagnostic and therapeutic challenge. METHODS We describe our experience in the management of 7 patients (4 males and 3 females, with a mean age of 41 years) with GEL treated in our department. Radical resection was performed in all cases with partial oesophagectomy in order to relieve symptoms and to obtain a definitive diagnosis. RESULTS There was no perioperative mortality. The minimum diameter of the tumours was 15 cm and the maximum was 30 cm. Definitive histological examination confirmed the diagnosis of leiomyoma in all cases without any sign of malignancy. No major postoperative complications developed. Minor complications included partial abdominal wound dehiscence in 1 case, and retention of secretions requiring bronchoscopy in 2. The mean length of hospital stay was 12 days (ranging between 9 and 14 days). After a mean follow-up of 5.4 years (ranging between 12 and 2 years), no sign of recurrence was observed. CONCLUSIONS Whereas removal of small oesophageal leiomyomas can be performed by simple enucleation by conventional thoracotomy or video-assisted thoracoscopy, partial oesophagectomy is often necessary for giant lesions. Since it is not possible preoperatively to distinguish GEL from leiomyosarcoma when metastases are absent, partial oesophageal resection is not to be considered an overtreatment and radical resection should always be planned. A gastric tube, in our experience employed as an oesophageal substitute, is effective and could reduce the risk of significant postoperative gastro-oesophageal reflux.

Expression and prognostic value of the cell polarity PAR complex members in thyroid cancer

Establishment and maintenance of the apical-basal cell polarity, required for proper replication, migration, specialized functions and tissue morphogenesis, relies on three evolutionary conserved complexes: PAR, CRUMBS and SCRIBBLE. Loss of cell polarity/cohesiveness (LOP/C) is implicated in cancer progression, and members of the polarity complex have been described as either oncogenes or oncosuppressors. However, no information on their role in thyroid cancer (TC) progression is available. In the present study, we evaluated the gene expression of the PAR complex members aPKCι, PARD3α/β and PARD6α/β/γ in 95 papillary TC (PTC), compared to their normal matched tissues and in 12 anaplastic TC (ATC). The mRNA and protein levels of investigated genes were altered in the majority of PTC and ATC tissues. In PTC, univariate analysis showed that reduced expression of aPKCι, PARD3β and PARD6γ mRNAs is associated with increased tumor size, and the reduced expression of PARD3β mRNA is associated also with recurrences. Multivariate analysis demonstrated that the presence of lymph node metastasis at diagnosis and the reduced expression of PARD3β are independent risk factors for recurrences, with hazard ratio, respectively, of 8.21 (p=0.006) and 3.04 (p=0.029). The latter result was confirmed by the Kaplan-Meier analysis, which evidenced the association between decreased PARD3β mRNA levels and shorter disease-free interval. In conclusion, we demonstrated that the expression of PAR complex components is deregulated in the majority of PTC and there is a general trend towards their reduction in ATC tissues. Moreover, a prognostic value for the PARD3β gene in PTCs is suggested.

Intraoperative enteroscopy by standard colonoscope with a minimal contamination technique

About 5% of occult gastrointestinal bleeding derives from small intestinal lesions. The intraoperative enteroscopy (IOE), although the development of double-balloon enteroscopy and capsule endoscopy reduced the indications, is still valid to locate the bleeding site in some selected cases. An 88-year-old woman presenting to the emergency department with a severe anemia underwent the laparotomic exploration and IOE. A 15-mm laparoscopy trocar with a sterile camera drape was adopted to introduce a standard colonscope through an enterotomy. The operation was safe and effective, without intraoperative morbidity and early complications related to surgery or endoscopy. We propose a technical solution during the IOE to minimize contamination of the surgical field. Although this technique is safe and feasible, further studies are needed to evaluate the method effectiveness.

Thyroid diseases and skin autoimmunity

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.

CTLA-4 and PD-1 Ligand Gene Expression in Epithelial Thyroid Cancers

The dysregulation of PD-1 ligands (PD-L1 and PD-L2) and CTLA-4 ligands (CD80 and CD86) represents a tumor strategy to escape the immune surveillance. Here, the expression of PD-L1, PD-L2, CD80, and CD86 was evaluated at the mRNA level in 94 patients affected by papillary thyroid carcinoma (PTC) and 11 patients affected by anaplastic thyroid carcinoma (ATC). Variations in the mRNAs in PTC patients were then correlated with clinicopathological features. The expression of all genes was deregulated in PTC and ATC tissues compared to normal tissues. In particular, the downregulation of CD80 was observed above all in ATC. In addition, the increased expression of CD80 associated with longer disease-free survival in PTC. Higher expression of PD-L1 associated with the classical histological variant and with the presence of BRAFV600E mutation in PTC. The increased PD-L2 expression correlated with BRAFV600E mutation and lymph node metastasis, while its lower expression correlated with the follicular PTC variant. The latter was also associated with the CD80 downregulation, which was also related to the absence of lymph node metastasis. In conclusion, we documented the overall dysregulation of PD-1 and CTLA-4 ligands in PTC and ATC tissues and a possible prognostic value for CD80 gene expression in PTC.

Aurora Kinases: New Molecular Targets for the Therapy of Aggressive Thyroid Cancers

Epithelial thyroid carcinomas (TC) account for more than 90% of all endocrine malignancies and represent one of the most frequent cancers in women. They include the well-differentiated TC (DTC), comprising the papillary (PTC) and follicular (FTC) histotypes, the poorly differentiated (PDTC), and the undifferentiated or anaplastic TC (ATC). Both PDTC and ATC are aggressive human neoplasms with a dire prognosis due to the absence of effective therapies, which makes mandatory the identification of novel therapeutic strategies. Intrinsic chromosomal instability (CIN, an increased rate of gain or losses of chromosomes during cell division) is a common feature of solid tumors and represents a major driving force in thyroid cancer progression, thought to be responsible for the acquisition by malignant cells of novel functional capabilities. Different mitotic kinases, whose expression or function has been found altered in human cancer tissues, are major drivers of thyroid tumor aneuploidy. Among these are the three members of the Aurora family (Aurora-A, Aurora-B and Aurora-C), serine/threonine kinases that regulate multiple aspects of chromosome segregation and cytokinesis. Over the last few years, several small molecule inhibitors targeting Aurora kinases were developed with promising antitumor effects in preclinical and clinical studies against different human cancers, including TC. Here, we will focus on the Aurora mitotic functions in normal cells; we shall then describe the main implications of their overexpression in the onset of genetic instability and aneuploidy. We will finally describe the consequences of Aurora kinase inhibition on TC cell growth and tumorigenicity.