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Intratumoral heterogeneity (ITH) refers to a subclonal genetic diversity observed within a tumor. ITH is the consequence of genetic instability and accumulation of genetic alterations, two mechanisms involved in the progression from an early tumor stage to a more aggressive cancer. While this process is widely accepted, the ITH of early stage papillary thyroid carcinoma (PTC) is debated. By different genetic analysis, several authors reported the frequent occurrence of PTCs composed of both tumor cells with and without RET/PTC or BRAFV600E genetic alterations. While these data, and the report of discrepancies in the genetic pattern between metastases and the primary tumor, demonstrate the existence of ITH in PTC, its extension and biological significance is debated. The ITH takes on a great significance when involves oncogenes, such as RET rearrangements and BRAFV600E as it calls into question their role of driver genes. ITH is also predicted to play a major clinical role as it could have a significant impact on prognosis and on the response to targeted therapy. In this review, we analyzed several data indicating that ITH is not a marginal event, occurring in PTC at any step of development, and suggesting the existence of unknown genetic or epigenetic alterations that still need to be identified.

Background Neuroendocrine neoplasms (NENs) represent a heterogeneous class of rare tumors with increasing incidence. They are characterized by the ability to secrete peptide hormones and biogenic amines but other reliable biomarkers are lacking, making diagnosis and identification of the primary site very challenging. While in some NENs, such as the pancreatic ones, next generation sequencing technologies allowed the identification of new molecular hallmarks, our knowledge of the molecular profile of NENs from other anatomical sites is still poor. Methods Starting from the concept that NENs from different organs may be clinically and genetically correlated, we applied a multi-omics approach by combining multigene panel testing, CGH-array, transcriptome and miRNome profiling and computational analyses, with the aim to highlight common molecular and functional signatures of gastroenteropancreatic (GEP)-NENs and medullary thyroid carcinomas (MTCs) that could aid diagnosis, prognosis and therapy. Results By comparing genomic and transcriptional profiles, ATM-dependent signaling emerged among the most significant pathways at multiple levels, involving gene variations and miRNA-mediated regulation, thus representing a novel putative druggable pathway in these cancer types. Moreover, a set of circulating miRNAs was also selected as possible diagnostic/prognostic biomarkers useful for clinical management of NENs. Conclusions These findings depict a complex molecular and functional landscape of NENs, shedding light on novel therapeutic targets and disease biomarkers to be exploited.

Medullary thyroid carcinoma (MTC) is a rare thyroid cancer arising from parafollicular C cells belonging to the heterogeneous class of neuroendocrine neoplasms. Mutations in the RET and RAS genes are detected in approximately 50% to 80% of sporadic MTCs, while other genetic alterations are relatively uncommon. Only a few transcriptomic studies of this neoplasia have been performed, and the biology and the molecular mechanisms underlying its progression remain largely unknown. In this study, we performed transcriptome profiling of a cohort comprising 72 MTC specimens from patients with different genetic backgrounds. The presented data highlighted the molecular heterogeneity of MTCs and the need for personalized treatment strategies. For this reason, the obtained profiles could offer novel perspectives into the molecular landscape of this neoplasm within the scientific community.

Thyroid nodules are detected in up to 60% of people by ultrasound examination. Most of them are benign nodules requiring only follow up, while about 4% are carcinomas and require surgery. Malignant nodules can be diagnosed by the fine-needle aspiration cytology (FNAC), which however yields an indeterminate result in about 30% of the cases. Testing for RAS mutations has been proposed to refine indeterminate cytology. However, the new entity of non-invasive follicular thyroid neoplasm, considered as having a benign evolution and frequently carrying RAS mutations, is expected to lower the specificity of this mutation. The aggressive behavior of thyroid cancer with RAS mutations, initially reported, has been overturned by the recent finding of the cooperative role of TERT mutations. Although some animal models support the carcinogenic role of RAS mutations in the thyroid, evidence that adenomas harboring these mutations evolve in carcinomas is lacking. Their poor specificity and sensitivity make the clinical impact of RAS mutations on the management of thyroid nodules with indeterminate cytology unsatisfactory. Evidence suggests that RAS mutation-positive benign nodules demand a conservative treatment. To have a clinical impact, RAS mutations in thyroid malignancies need not to be considered alone but rather together with other genetic abnormalities in a more general context.

Specific complications after thyroid surgery, such as recurrent laryngeal nerve injury (RLN) or hypoparathyroidism, are feared because they may give rise to a lifelong disability for the patient. The aim of this study was to evaluate the possible association between the types of device used (bipolar vs ultrasound-based harmonic scalpel defined Harmonic Focus) and major postoperative complications. During a 1-year period, between October 2010 and October 2011, Italian Endocrine Surgery Units affiliated with the Italian Endocrine Surgery Units Association collected data on all consecutive patients older than 18 years who had undergone primary total thyroidectomy, near total thyroidectomy, and completion thyroidectomy. The data were included in a dataset, listing demographic variables, details on the surgical procedure, and 2 major complications of the thyroid surgery: postoperative RLN palsy/hypomobility and hypocalcemia. Our population comprised 1,846 subjects (78.6% women, median age 52 years). Six hundred four (32.7%) subjects underwent thyroidectomy by bipolar forceps and 1,242 (67.3%) by ultrasonic device. The risk of hypocalcemia in subjects undergoing thyroidectomy by ultrasonic device was similar to those undergoing thyroidectomy by bipolar after adjusting for sex, type of thyroidectomy, and central lymphadenectomy (odds ratio .94, 95% confidence interval .76 to 1.17). Subjects who underwent thyroidectomy by ultrasonic device had a lower risk of RLN paralysis compared with those undergoing thyroidectomy by bipolar forceps also after adjusting for central lymphadenectomy (odds ratio .39, 95% confidence interval .2 to .7). This multicenter study acknowledges the value of the ultrasonic device as a protective factor only for RLN palsy, confirming nodal dissection as a risk factor for postoperative hypocalcemia and vocal folds disorders. •The study involve 1,846 subjects submitted to thyroidectomy performed by ultrasonic/bipolar forceps.•RLN paralysis is lower when an ultrasonic device is employed compared with the bipolar forceps.•Patients are at greater risk of developing hypocalcemia if a central neck dissection is performed.•Finally, these results may aim about which devices to use in thyroid surgery.

Alpha B-crystallin (CRYAB, HSPB5) belongs to the small heat shock protein (HSP) family and is highly expressed in various human cancers, suggesting a crucial role in tumor progression. However, few studies have examined CRYAB expression in colorectal cancer (CRC). In the present study, we investigated the relationship between CRYAB expression and the clinicopathological features of CRC samples. We comparatively analyzed CRYAB protein expression in 111 CRC tissues and normal adjacent colonic tissue, observing that it was significantly lower in CRC tissues than in corresponding non-cancerous tissues. Moreover, immunohistochemical analysis showed a significant correlation between CRYAB expression and high histological grade G3 (p = 0.033). In summary, our results point to its possible application as a prognostic biomarker in CRC patients.

PurposeThe Covid-19 pandemic represents an extraordinary and unpredictable event influencing the whole economy and society. Using a case study approach, the authors explored how big companies operating in Italy were able to respond to the crisis to ensure business continuity. Therefore, the authors discussed different business disruptions caused by Covid-19; in addition, they developed an integrated policy framework in which they proposed specific strategic responses for increasing the level of organizational resilience. The aim of the paper is to discuss and reflect on the ability of specific companies to increase their level of organizational resilience when unexpected events happen.Design/methodology/approachThe authors conducted semi-structured interviews with target CEOs of four major companies operating in Italy in different industries. Especially, the authors focused on multiutilities, media and communications, investment banking and mobile telecommunications. The interviews were based on questions dealing with Covid-19 implications and strategic responses to navigate this complex scenario.FindingsBased on the CEOs' contributions, the authors presented short-term actions and long-term strategies planned and implemented by each Italian company. In particular, the authors emphasized similarities and dissimilarities in terms of strategic responses and future business development.Originality/valueThe analysis of practical cases was helpful for increasing their knowledge on organizational resilience and for providing the managerial community with a policy framework to navigate unexpected events like the Covid-19 pandemic.

The role of endoscopic evaluation in ulcerative colitis (UC) is well recognized, but a universally accepted gold standard for endoscopic activity evaluation is still lacking, and many scores have been proposed to this purpose. Among these, the Mayo Endoscopic Score (MES) and the Ulcerative Colitis Endoscopic Index (UCEIS) are currently the most used in trials and clinical practice. The aim of the study is to evaluate feasibility and performance of MES and UCEIS among expert endoscopists with no specific expertise in inflammatory bowel diseases (IBD), in a single hospital center. Two minutes video recordings, from colonoscopy of 12 UC patients, were observed and scored, according to MES and UCEIS, by seven hospital gastroenterologists with experience in digestive endoscopy and no particular expertise in IBD. Knowledge and utilization of the two scores were investigated. Inter-observer agreement and agreement with an IBD-expert gastroenterologist of the same center (central reader), and correlation between the two scores, was calculated. Among the endoscopists, MES was much more known and currently used than UCEIS. Both the scores displayed a similar good performance. Agreement with central reader was moderate for MES and UCEIS, and interobserver agreement was good, for both MES and UCEIS. Correlation between the two scores was very good both for central reader and for the hospital endoscopists. This single center study confirmed potential feasibility and usefulness of MES and UCEIS for assessment of endoscopic activity in UC patients in a real-life setting.

Background Malignant tumours of minor salivary glands are uncommon, representing only 2-4% of all head and neck cancers. In the larynx, minor salivary gland tumours rarely occur and constitute less than 1% of laryngeal neoplasm. Most of the minor salivary gland tumours arise in the subglottis; however, they can also occur in the supraglottis, in the false vocal cords, aryepiglottic folds and caudal portion of the epiglottis. The most common type of malignant minor salivary gland tumour is adenoid cystic carcinoma. Methods We present a unusual case of adenoid cystic carcinoma of glottic-subglottic region in a 61-year-old woman. Follow-up endoscopy and laryngeal magnetic resonance imaging (MRI) at three years after treatment showed no recurrence of the tumour. Results The diagnosis of glottic-subglottic adenoid cystic carcinoma should be considered in patients who are characterized by dyspnea, cough and stridor, but do not respond to pharmacologic approach. Conclusions Adenoid cystic carcinoma is usually a very slow growing cancer, invested by an apparently normal laryngeal mucosa, so that it can show no clear symptoms for a long time. For these reasons the increasing number of diagnostic mistakes or late diagnosis that may be fatal in some cases.

Papillary thyroid carcinoma (PTC), while often having a favorable prognosis, can progress to aggressive forms. Matrix metalloproteinases (MMPs) are crucial in extracellular matrix remodeling and are implicated in tumor invasion and metastasis. This study investigated MMP expression and activity in PTC and the efficacy of two selective MMP inhibitors in suppressing PTC cell migration and invasion. The analysis of RNA-seq data from the TCGA-THCA dataset highlighted the overexpression of MMP-14 in PTC, a key upstream activator of several MMPs, including MMP-2 and, indirectly, MMP-9. This elevation correlated with disease status and recurrence risk. Validation in a cell model, using PTC lines (K1 and BCPAP) and non-tumoral thyroid cells (Nthy-ori 3-1), showed markedly increased MMP-14 activity in PTC lines (6-fold in K1; 11-fold in BCPAP). MMP-9 activity was also substantially elevated (386-fold in K1; 131-fold in BCPAP), along with increased MMP-2 activity. We then tested selective inhibitors. NSC405020, an MMP-14 inhibitor, reduced K1 cell migration by 56.52% and invasion by 67.3%. Gallic acid, an MMP-2 and MMP-9 inhibitor, reduced K1 cell migration to 60.3% and invasion to 33.3% relative to the controls. These findings suggest that elevated MMP activity is a hallmark of aggressive PTC, underscoring MMPs’ role in cancer progression. Targeting MMPs, particularly with agents like NSC405020 and gallic acid, presents a promising therapeutic strategy to disrupt PTC tumor progression.