The role of intraoperative neuromonitoring in preventing lesions of the spinal accessory nerve during functional neck dissection.

Intraoperative neuromonitoring (IONM) in thyroid surgery offers a valid aid to the operator in identifying the recurrent laryngeal nerve and preserving its function. Recently, IONM has also been used in other surgeries, such as spinal accessory nerve dissection, during lymphectomy of the II, III, IV, and V laterocervical lymph nodes. The goal is the preservation of the spinal accessory nerve, whose macroscopic integrity does not always indicate its functionality. A further difficulty is the anatomical variability of its course at the cervical level. The aim of our study is to assess whether the use of the IONM helps to reduce the incidence of transient and permanent paralysis of the spinal accessory nerve, compared to "de visu" identification by the surgeon alone. In our case series, the use of the IONM reduced the incidence of transient paralysis, and no permanent paralysis was recorded. In addition, if the IONM registers a reduction in nerve potential, compared to the baseline value during surgery, it could indicate the need for early rehabilitation treatment, increasing the patients' chances of regaining function and reducing the costs of prolonged physiotherapy treatment.

Utility of intraoperative neuromonitoring in detecting recurrent nerve's anatomical anomalies during thyroidectomy.

Anatomical variations such as a non-recurrent laryngeal nerve (NRLN) are very rare (reported rates within 0.6-1% to the right side and only four cases to the left side) but they can lead to serious risk of nerve lesion during thyroidectomy. It is known that to prevent inferior laryngeal nerve lesions, it is mandatory to obtain a correct and wide exposure of the nerve during all kind of thyroid surgeries but in case of laryngeal nerve position anomalies, it is hard to achieve a safe nerve identification. Continuous intraoperative neuromonitoring (C-IONM) technology can detect the presence of NRLN. In this study we present seven cases of NRLN incidentally found during our last 10-year experience, in a total of 1074 procedures, including total thyroidectomy and lobectomy. Three out of seven cases were identified with the help of C-IONM. On the other hand, the other four cases of non-recurrent laryngeal nerve were identified during an extensive dissection of the thyroid lodge. We registered no nerve palsy in the group of patients who underwent surgery with the help of C-IONM, while we had two nerve palsies (out of four cases) in the group of patients without the help of C-IONM. In our experience we also registered a reduction of surgery time when we used the C-IONM. In our opinion C-IONM is a safe method to discover anatomical anomalies such as a non-recurrent laryngeal nerve and may help to reduce nerve palsy rate.

Cancer Rate of the Indeterminate Lesions at Low or High Risk According to Italian System for Reporting of Thyroid FNA.

Background: Italian consensus for the classification and reporting of thyroid cytology (ICCRTC) has been used in almost all Italian institutions since 2014. High reliability of ICCRTC in classifying low and high risk indeterminate nodules (Tir 3A and Tir 3B, respectively) was demonstrated. Here we reviewed our casuistry of thyroid indeterminate lesions to analyze the histologic outcome. Methods: All lesions undergone FNA and final histology at S. Andrea Hospital of Rome after a cytologic assessment of Tir 3A and Tir 3B, according to ICCRTC, were included in the study. Results: A number of 157 indeterminate FNA was found after the introduction of ICCRTC. Of these, 75 undergone surgery and were finally included for the study. At histology we found a 33.3% of cancers and a 67.7% of benign lesions. Out of the overall series, 25 were classified as Tir 3A and 50 as Tir 3B. Cancer rate observed in Tir 3A (1/25, 4%) was significantly (p = 0.0002) lower than that of Tir 3B (24/50, 48%). No significant difference was found in age and size between the two subcategories. Conclusions: We confirm in our series that Italian consensus for the classification and reporting of thyroid cytology allows to discriminate indeterminate lesions at low and high risk of malignancy.

Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z.

Galectin-3 (Gal-3) regulates basic cellular functions such as cell-cell and cell-matrix interactions, growth, proliferation, differentiation, and inflammation. It is not surprising, therefore, that this protein is involved in the pathogenesis of many relevant human diseases, including cancer, fibrosis, chronic inflammation and scarring affecting many different tissues. The papers published in the literature have progressively increased in number during the last decades, testifying the great interest given to this protein by numerous researchers involved in many different clinical contexts. Considering the crucial role exerted by Gal-3 in many different clinical conditions, Gal-3 is emerging as a new diagnostic, prognostic biomarker and as a new promising therapeutic target. The current review aims to extensively examine the studies published so far on the role of Gal-3 in all the clinical conditions and diseases, listed in alphabetical order, where it was analyzed.

Comparative analysis of diagnostic performance, feasibility and cost of different test-methods for thyroid nodules with indeterminate cytology.

Since it is impossible to recognize malignancy at fine needle aspiration (FNA) cytology in indeterminate thyroid nodules, surgery is recommended for all of them. However, cancer rate at final histology is <30%. Many different test-methods have been proposed to increase diagnostic accuracy in such lesions, including Galectin-3-ICC (GAL-3-ICC), BRAF mutation analysis (BRAF), Gene Expression Classifier (GEC) alone and GEC+BRAF, mutation/fusion (M/F) panel, alone, M/F panel+miRNA GEC, and M/F panel by next generation sequencing (NGS), FDG-PET/CT, MIBI-Scan and TSHR mRNA blood assay.We performed systematic reviews and meta-analyses to compare their features, feasibility, diagnostic performance and cost. GEC, GEC+BRAF, M/F panel+miRNA GEC and M/F panel by NGS were the best in ruling-out malignancy (sensitivity = 90%, 89%, 89% and 90% respectively). BRAF and M/F panel alone and by NGS were the best in ruling-in malignancy (specificity = 100%, 93% and 93%). The M/F by NGS showed the highest accuracy (92%) and BRAF the highest diagnostic odds ratio (DOR) (247). GAL-3-ICC performed well as rule-out (sensitivity = 83%) and rule-in test (specificity = 85%), with good accuracy (84%) and high DOR (27) and is one of the cheapest (113 USD) and easiest one to be performed in different clinical settings.In conclusion, the more accurate molecular-based test-methods are still expensive and restricted to few, highly specialized and centralized laboratories. GAL-3-ICC, although limited by some false negatives, represents the most suitable screening test-method to be applied on a large-scale basis in the diagnostic algorithm of indeterminate thyroid lesions.

The electrophysiology of thyroid surgery: electrophysiologic and muscular responses with stimulation of the vagus nerve, recurrent laryngeal nerve, and external branch of the superior laryngeal nerve.

OBJECTIVES/HYPOTHESIS: Correlation of physiologically important electromyographic (EMG) waveforms with demonstrable muscle activation is important for the reliable interpretation of evoked waveforms during intraoperative neural monitoring (IONM) of the vagus nerve, recurrent laryngeal nerve (RLN), and external branch of the superior laryngeal nerve (EBSLN) in thyroid surgery. STUDY DESIGN: Retrospective chart review. METHODS: Data were reviewed retrospectively for thyroid surgery patients with laryngeal nerve IONM from January to December, 2015. EMG responses to monopolar stimulation of the vagus/RLN and EBSLN were recorded in bilateral vocalis, cricothyroid (CTM), and strap muscles using endotracheal tube-based surface and intramuscular hook electrodes, respectively. Target muscles for vagal/RLN and EBSLN stimulation were the ipsilateral vocalis and CTM, respectively. All other recording channels were nontarget muscles. RESULTS: Fifty surgical sides were identified in 37 subjects. All target muscle mean amplitudes were significantly higher than in nontarget muscles. With vagal/RLN stimulation, target ipsilateral vocalis mean amplitude was 1,095.7 µV (mean difference range = -814.1 to -1,078 µV, P < .0001). For EBSLN stimulation, target ipsilateral CTM mean amplitude was 6,379.3 µV (mean difference range = -6,222.6 to -6,362.3 µV, P < .0001). Target muscle large-amplitude EMG responses correlated with meaningful visual or palpable muscular responses, whereas nontarget EMG responses showed no meaningful muscle activation. CONCLUSIONS: Target and nontarget laryngeal muscles are differentiated based on divergence of EMG response directly correlating with presence or absence of visual and palpable muscle activation. Low-amplitude EMG waveforms in nontarget muscles with neural stimulation can be explained by the concept of far-field artifactual waveforms and do not correspond to a true muscular response. The surgeon should be aware of these nonphysiologic waveforms when interpreting and applying IONM during thyroid surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:764-771, 2017.

Combined clinical and ultrasound follow-up assists in malignancy detection in Galectin-3 negative Thy-3 thyroid nodules.

The use of galectin-3 ThyroTest in the preoperative evaluation of cytologically indeterminate (Thy-3) thyroid nodules has been largely validated by retrospective and prospective multicentre studies. Here we report the results of galectin-3 ThyroTest routinely applied in the management of Thy-3 nodules in combination with clinical and ultrasonography (US) examination, in which galectin-3 positive nodules were directly referred to surgery whereas galectin-3 negative lesions were considered for clinical and US long-term follow-up. A cohort of 331 patients, bearing 340 thyroid Thy-3 nodules, was enrolled and subjected to galectin-3 expression analysis. A total of 256 galectin-3 negative nodules were directed to periodical clinical and US examination, while 84 galectin-3 positive cases were referred to surgery. Excluding 63 dropout patients plus 15 patients that were operated because of clinical reasons the remaining 176 galectin-3 negative nodules were followed with clinical and US examination for an average period of 31 months. During the follow-up, the volume of galectin-3 negative nodules was unchanged in 85 cases (48 %), reduced in 47 (27 %), and increased in 44 (25 %). Based on combined clinical features and US follow-up results, a total of 36 out of 191 galectin-3 negative nodules (19 %) were referred to surgery, with a final histological finding of 28 benign lesions, three follicular tumor of uncertain malignant potential (FT-UMP), and five malignant lesions, corresponding to a 7 % false negative rate. In the group of 84 galectin-3 positive nodules, we detected 65 thyroid cancers with a prevalence of 77 %, 12 FT-UMPs, and 7 false positive lesions, corresponding to a 4 % false positive rate. A total of 150 patients were not operated and are still under clinical and US monitoring while surgery was performed in 118 patients with a final 70 thyroid cancers diagnosed, corresponding to a 59 % prevalence of malignancy detected at surgery and to a 26 % prevalence of malignancy among the entire Thy-3 nodule population. Galectin-3 ThyroTest is an easy and cheap diagnostic procedure that integrates conventional fine-needle-aspiration cytology, reduces the number of unnecessary thyroidectomies and increases the rate of malignancy at surgery. Clinical and US follow-up of galectin-3 negative lesions allows to further reduce false negative cases.

Minimally invasive video-assisted thyroidectomy: Ascending the learning curve.

BACKGROUND: Minimally invasive video-assisted thyroidectomy (MIVAT) is a technically demanding procedure and requires a surgical team skilled in both endocrine and endoscopic surgery. The aim of this report is to point out some aspects of the learning curve of the video-assisted thyroid surgery, through the analysis of our preliminary series of procedures. PATIENTS AND METHODS: Over a period of 8 months, we selected 36 patients for minimally invasive video-assisted surgery of the thyroid. The patients were considered eligible if they presented with a nodule not exceeding 35 mm and total thyroid volume <20 ml; presence of biochemical and ultrasound signs of thyroiditis and pre-operative diagnosis of cancer were exclusion criteria. We analysed surgical results, conversion rate, operating time, post-operative complications, hospital stay and cosmetic outcomes of the series. RESULTS: We performed 36 total thyroidectomy and in one case we performed a consensual parathyroidectomy. The procedure was successfully carried out in 33 out of 36 cases (conversion rate 8.3%). The mean operating time was 109 min (range: 80-241 min) and reached a plateau after 29 MIVAT. Post-operative complications included three transient recurrent nerve palsies and two transient hypocalcemias; no definitive hypoparathyroidism was registered. The cosmetic result was considered excellent by most patients. CONCLUSIONS: Advances in skills and technology allow surgeons to easily reproduce the standard open total thyroidectomy with video-assistance. Although the learning curve represents a time-consuming step, training remains a crucial point in gaining a reasonable confidence with video-assisted surgical technique.

Methodology and technical requirements of the galectin-3 test for the preoperative characterization of thyroid nodules.

In the last decade, the ß-galactosyl binding protein galectin-3 has been the object of extensive molecular, structural, and functional studies aimed to clarify its biological role in cancer. Multicenter studies also contributed to discover the potential clinical value of galectin-3 expression analysis in distinguishing, preoperatively, benign from malignant thyroid nodules. As a consequence galectin-3 is receiving significant attention as tumor marker for thyroid cancer diagnosis, but some conflicting results mostly owing to methodological problems have been published. The possibility to apply preoperatively a reliable galectin-3 test method on fine needle aspiration biopsy (FNA)-derived thyroid cells represents an important achievement. When correctly applied, the method reduces consistently the gray area of thyroid FNA cytology, contributing to avoid unnecessary thyroid surgery. Although the efficacy and reliability of the galectin-3 test method have been extensively proved in several studies, its translation in the clinical setting requires well-standardized reagents and procedures. After a decade of experimental work on galectin-3-related basic and translational research projects, the major methodological problems that may potentially impair the diagnostic performance of galectin-3 immunotargeting are highlighted and discussed in detail. A standardized protocol for a reliable galectin-3 expression analysis is finally provided. The aim of this contribution is to improve the clinical management of patients with thyroid nodules, promoting the preoperative use of a reliable galectin-3 test method as ancillary technique to conventional thyroid FNA cytology. The final goal is to decrease unnecessary thyroid surgery and its related social costs.

The loss of the p53 activator HIPK2 is responsible for galectin-3 overexpression in well differentiated thyroid carcinomas.

BACKGROUND: Galectin-3 (Gal-3) is an anti-apoptotic molecule involved in thyroid cells transformation. It is specifically overexpressed in thyroid tumour cells and is currently used as a preoperative diagnostic marker of thyroid malignancy. Gal-3 expression is downregulated by wt-p53 at the transcriptional level. In well-differentiated thyroid carcinomas (WDTCs) there is an unexplained paradoxical concomitant expression of Gal-3 and wt-p53. HIPK2 is a co-regulator of different transcription factors, and modulates basic cellular processes mainly through the activation of wt-p53. Since we demonstrated that HIPK2 is involved in p53-mediated Gal-3 downregulation, we asked whether HIPK2 deficiency might be responsible for such paradoxical Gal-3 overexpression in WDTC. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed HIPK2 protein and mRNA levels, as well as loss of heterozygosity (LOH) at the HIPK2 locus (7q32-34), in thyroid tissue samples. HIPK2 protein levels were high in all follicular hyperplasias (FHs) analyzed. Conversely, HIPK2 was undetectable in 91.7% of papillary thyroid carcinomas (PTCs) and in 60.0% of follicular thyroid carcinomas (FTCs). HIPK2 mRNA levels were upregulated in FH compared to normal thyroid tissue (NTT), while PTC showed mean HIPK2 mRNA levels lower than FH and, in 61.5% of cases, also lower than NTT. We found LOH at HIPK-2 gene locus in 37.5% of PTCs, 14.3% of FTCs and 18.2% of follicular adenomas. To causally link these data with Gal-3 upregulation, we performed in vitro experiments, using the PTC-derived K1 cells, in which HIPK2 expression was manipulated by RNA interference (RNAi) or plasmid-mediated overexpression. HIPK2 RNAi was associated with Gal-3 upregulation, while HIPK2 overexpression with Gal-3 downregulation. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HIPK2 expression and function are impaired in WDTCs, in particular in PTCs, and that this event explains Gal-3 overexpression typically observed in these types of tumours. Therefore, HIPK2 can be considered as a new tumour suppressor gene for thyroid cancers.

Retroperitoneal mesenchymal chondrosarcoma mimicking a large retroperitoneal sacral schwannoma.

We report a case of retroperitoneal chondrosarcoma in which preoperative radiological study induced to a possible diagnosis of sacral schwannoma. A 25-year-old woman was admitted to our neurosurgical institute for a progressive sciatic pain with gait difficulties with a sudden radicular deficit with right positive Lasegue's sign at 30 degrees, loss of Achilles reflex, sensory deficit on right S1 dermatome, and complete motor deficit of right plantar flexion. We performed an en bloc removal of the lesion via an anterior retroperitoneal approach. We believe that the treatment of choice is radical surgical excision of the tumor with complete en-bloc removal of the lesion; postoperative radiotherapy and chemotherapy should be valuated case by case.

Molecular characterisation of JC virus strains detected in human brain tumours.

AIMS: The aim of this study was to evaluate the presence and significance of JC virus (JCV) in human brain tumours. METHODS: Histology, immunohistochemistry (IHC) and molecular biology techniques were employed to examine specimens of tumour tissue, peripheral blood and cerebrospinal fluid taken from 22 patients with primary neuro-epithelial tumours. Furthermore, the coding viral protein (VP1) region and non-coding transcription control region (TCR) of JCV genome isolated from the tumours were submitted to sequence analysis in order to detect viral rearrangements or mutations. RESULTS: JCV genome was found in nine of the 22 tumour specimens (40.9%), including eight astrocyte-derived tumours (seven glioblastomas and one astrocytoma) and one oligodendroglioma, and in two of the 15 cerebrospinal fluid specimens (13.3%) with positive tumour tissue (one glioblastoma and one astrocytoma). Sequence analysis of JCV VP1, which was amplified in seven tissue samples and the two cerebrospinal fluid samples, revealed only genotype 1 (four 1a and three 1b), whereas TCR was amplified in six tissue samples and only one cerebrospinal fluid sample. TCR sequence analysis was possible in four cases and identified three Mad-4 and one type II sequences; the TCR genomic structures of JCV isolated from cerebrospinal fluid were the same as those sequenced from corresponding tumour tissue, thus indicating a possible cerebrospinal fluid dissemination of neoplastic cells carrying viral DNA. CONCLUSIONS: Our results suggest a possible role of JCV in the induction of brain tumours, especially in those originating from brain cells normally targeted by JCV infection.

The management of retrorectal congenital tumors.

Although retrorectal congenital tumors are still rare, the number of the observed ones is destined to increase, as methods by imaging become routinely used in the clinical practice. By presenting three clinical cases the authors describe the surgical technique of the anterior route they performed for the management of such formations. The abdominal approach had no postoperative complications, short hospital stay, no neurological consequences and good long-term results. There has been no evidence of recurrence thus far. Once diagnosed, the removal of retrorectal lesions should be mandatory. A precise definition of the extent of the tumors and of their relationships with the surrounding tissue and organs is necessary to perform maneuvers of total excision. For this reason an abdominal approach is recommended.