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Introduction: In locally advanced gastric cancer (GC), FLOT represents the standard perioperative regimen and combination with immunotherapy is under investigation. However, the role of immune tumor microenvironment (TME) is poorly recognized in this setting. We aimed to study TME characteristics and dynamics during FLOT. Methods: Paired biopsy (PRE) and surgical (POST) samples of 25 patients treated with FLOT were prospectively analyzed. After collection of clinic-pathological data, NanoString analyses were performed. The primary objective of the study was to assess the changes induced by chemotherapy in POST compared to PRE samples. Results: The unsupervised hierarchical method analysis clearly distinguished PRE and POST samples, even though some cases showed high immune gene expression at baseline. When POST samples were compared with PRE, a differential expression in hyper-expressed gene sets related to cytotoxicity, T-cell functions, complement system, tumor necrosis factor superfamily, cell cycle, and regulation was recognized. Downstaging of the primary tumor (T-regression, measured by pathologic compared to clinical T stage) was the covariate most frequently associated with these changes. Using the immune cell profiling, cases with T-regression reported a significant increase of T, CD8+ T and B cells and a decrease in mast cells, while nonresponders demonstrated an increase of T, B, cytotoxic, and mast cells. Conclusion: Our analysis shows that FLOT significantly influences immune TME of GC. While relevant modifications preferentially occur in tumors showing primary tumor regression, response to treatment seems to be associated with a specific immune profile. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present study is to analyze thyroglossal duct cyst (TGDC) histopathological features, with focus on "arborization", in a cohort of pediatric patients who underwent surgical removal, and evaluate a possible correlation with clinical recurrences. Methods: A retrospective analysis of all patients who underwent surgical resection for TGDC at the division of Pediatric Surgery of the University of Pisa from 2015 to 2020 was performed; for each patient, the following data were recorded: age, sex, clinical presentation, localization, size of the lesion, diagnostic tools, histopathological features, perioperative complications, recurrence and follow-up. Results: With respect to arborization, following histopathological analysis 25/30 patients (83.3%) presented thyroglossal duct branching. After a median follow-up of 3.5 years, only 2 out of 30 patients (6.7%), one male and one female, respectively aged 4 y.o. and 6 y.o., presented recurrence within one year from first surgery. Conclusion: Surgery for TGDC remains a challenge for pediatric surgeons, while arborization was present in most of our cases which underwent surgery. With respect to the role of arborization, our study did not highlight sufficient conclusive data regarding their role in recurrence: instead, it showed wide resection as satisfactory, being the arborization present in most of the cases at histopathology. [ABSTRACT FROM AUTHOR]

Introduction: Mismatch repair (MMR) deficiency represents a biomarker and therapeutic target in various neoplasms, but its role in biliary tract cancers (BTCs) remains misunderstood. Methods: MMR status was retrospectively assessed using immunohistochemistry in 163-BTCs patients. We identified MMR proficiency (pMMR)/deficiency (dMMR) according to the loss of MMR proteins (MLH1, PMS2, MSH2, MSH6). The primary objective of the study was to assess the incidence of dMMR in BTCs; the secondary purpose was to explore its association with prognosis and clinical features. Results: dMMR was recorded in 9 patients, and it was strongly associated with mucinous histology (p < 0.01). Regarding the prognostic effect, in 122-radically resected patients, disease-free survival (DFS) resulted significantly shorter in dMMR patients compared to pMMR patients (10.7 vs. 31.3 months, p = 0.025) and so did nodal status (48.2 vs. 15.3 months in N0 vs. N+) (p < 0.01). Moreover, dMMR confirmed its prognostic role in terms of DFS at multivariate analysis (p = 0.03), together with nodal status (p = 0.01), and resection margin (p = 0.03). In 103 M+ patients (encompassing 41 metastatic de novo and 62 recurred after surgery patients) there were not differences between dMMR and pMMR regarding survival analyses. Conclusions: dMMR status is strongly correlated with mucinous histology and represents an independent prognostic factor in terms of disease relapse in patients with resected BTC. Implications for Practice: MMR may play an independent role in promoting an aggressive behaviour in patients with radically resected BTC. These results could be useful in improving the selection of patients after resection and, above all, should justify the evaluation of MMR status as a therapeutic target in BTC, especially in patients with atypical histology. [ABSTRACT FROM AUTHOR]

Background: The follicular variant (FV) of papillary thyroid cancer (PTC) is one of the most common variants of PTC. Clinically, non-infiltrative FVPTC is considered a low-risk variant of PTC, and the non-invasive encapsulated forms of FVPTC represent a group of thyroid tumors with a particularly good prognosis. Consequently, these neoplasms have been very recently reclassified as non-invasive follicular neoplasms with papillary-like nuclear features (NIFTP). From a molecular standpoint, NIFTP appears to be similar to follicular neoplasms. However, only limited data are currently available regarding their gene expression profile. Methods: The aim of this study was to identify specific molecular signatures of 26 NIFTPs compared to those of 19 follicular adenomas (FAs) and 18 infiltrative FVPTCs (IFVPTCs). A nanoString custom assay was used to perform mRNA expression analysis. All cases were also genotyped for BRAF, N-, H-, and K-RAS mutations. Samples were grouped on the basis of gene expression profiles by Pearson's correlation and non-negative matrix factorization clustering analysis. Finally, the uncorrelated shrunken centroid machine-learning algorithm was used to classify the samples. Results: The results revealed distinct expression profiles of FAs and IFVPTCs. NIFTP samples can exhibit different expression profiles, more similar to FAs (FA-like) or to IFVPTCs (IFVPTC-like), and these different expression profiles largely depend on the presence of different mutations ( RAS or BRAF). Conclusion: In conclusion, although further validation of the model is required by using a larger group of prospective cases, these data reinforce the hypothesis that IFVPTC-like NIFTPs might represent precursors of IFVPTC. [ABSTRACT FROM AUTHOR]

Noninvasive encapsulated follicular variants of papillary thyroid carcinomas have been recently reclassified as noninvasive follicular thyroid neoplasms with papillarylike nuclear features (NIFTPs). NIFTPs exhibit a behavior that is very close to that of follicular adenomas but different from the infiltrative and invasive follicular variants of papillary thyroid carcinomas (FVPTCs). The importance of miRNAs to carcinogenesis has been reported in recent years. miRNAs seem to be promising diagnostic and prognostic molecular markers for thyroid cancer, and the combination of miRNA expression and mutational status might improve cytological diagnosis. The aim of the present study was to evaluate the miRNA expression profile in wild-type, RAS- or BRAF-mutated NIFTPs, infiltrative and invasive FVPTCs, and follicular adenomas using the nCounter miRNA Expression assay (NanoString Technologies). To identify the significant Kyoto Encyclopedia of Genes and Genomes (KEGG) molecular pathways associated with deregulated miRNAs, we used the union of pathways option in DNA Intelligent Analysis (DIANA) miRPath software. We have shown that the miRNA expression profiles of wildtype and mutated NIFTPs could be different. The expression profile of wild-type NIFTPs seems comparable to that of follicular adenomas, whereas mutated NIFTPs have an expression profile similar to that of infiltrative and invasive FVPTCs. The upregulation of 4 miRNAs (miR-221-5p, miR-221-3p, miR-222-3p, miR-146b-5p) and the downregulation of 8 miRNAs (miR-181a-3p, miR-28-5p, miR-363-3p, miR-342-3p, miR-1285-5p, miR-152-3p, miR-25-3p, miR-30e-3) in mutated NIFTPs compared to wild-type ones suggest a potential invasive-like phenotype by deregulating the specific pathways involved in cell adhesion and cell migration (Hippo signaling pathway, ECM-receptor interaction, adherens junction, regulation of actin cytoskeleton, fatty acid biosynthesis and metabolism). [ABSTRACT FROM AUTHOR]

Background: The forkhead transcription factor FoxP3 plays an important role in regulatory T cell (Treg) functions. Tregs are critical in maintaining immunologic tolerance. It has been shown that vaccination against FoxP3-expressing cells is associated with enhancement of tumor immunity. Tregs appear to be increased in blood and in the tumor microenvironment of patients with different cancer types. Tumor cells themselves can express FoxP3. The present study investigates the possible role of FoxP3 expression in a series of human papillary thyroid cancers with a mean follow-up time of 15 years. Methods: One hundred five cases of papillary thyroid carcinoma (PTC) were investigated, and FoxP3 expression was evaluated in both tumor cells and tumor-associated infiltrates. For all patients, clinical/pathologic features were considered and the results analyzed by statistical tests. Results: Of the 105 PTC cases, 45 (43%) scored FoxP3-positive and 60 (57%) were negative. FoxP3 staining was localized predominantly in the cytoplasm of tumor cells. In some cases, both nuclear and cytoplasmic staining was seen in infiltrating cells. FoxP3 expression in tumor cells was correlated with the presence of extrathyroid invasion ( p=0.04) and distant metastasis ( p=0.04), but not with overall survival. Interestingly, FoxP3 expression in neoplastic cells was significantly associated with a resistance phenotype to radioiodine treatment ( p=0.041). Conclusions: The data show an association of FoxP3 expression with features of PTC that seem to have a specific impact on radioiodine sensitivity. [ABSTRACT FROM AUTHOR]

Background: The prevalence of RET somatic mutations in sporadic medullary thyroid cancer (MTCs) is ∼40%-50%, and the most frequent somatic mutation is M918T. RET-positive MTCs have been demonstrated to have a more advanced stage at diagnosis and a worse outcome. Aims: The aim of the present work was to compare the prevalence of RET somatic mutations in sporadic microMTCs (<1 cm) and in larger MTCs. Patients: We analyzed the M918T RET point mutation in 160 sporadic MTC cases. Tumors were classified according to their size: group A, <1 cm; group B, >1 and <2 cm; group C, >2 and <3 cm; and group D, >3 cm. Results: The overall prevalence of the somatic M918T RET mutation was 19.4% (31/160). RET mutations were distributed differently among the four groups. The prevalence was 11.3% (6/53) in group A, 11.8% (8/68) in group B, 31.8% (7/22) in group C, and 58.8% (10/17) in group D, exhibiting an increase with increasing size of the tumor. When comparing the prevalence of mutations in the four groups, we found a lower prevalence in microMTCs ( p<0.0001). Conclusions: The overall prevalence of RET somatic mutations was lower than expected, and the prevalence of the somatic M918T RET mutation was significantly lower in microMTCs than in larger tumors. To explain this finding, we can hypothesize either that other oncogene(s) might be responsible for the majority of microMTC, thus identifying a tumor subset, or that the RET mutation might, or might not, occur later during tumor progression. [ABSTRACT FROM AUTHOR]

Background: In a number of human malignancies, the presence of lymphocytic infiltration in or around tumor tissue is commonly considered to be part of the host tumor immune response. An association between thyroid carcinoma and chronic inflammation has been described. This relationship is not fully understood, so we performed a systematic study on a follicular variant of papillary thyroid carcinoma (FVPTC), to evaluate the type and distribution of certain immunological cells and their relationship with prognostic factors. Methods: We selected 91 consecutive cases of FVPTC, in which we evaluated the presence of three different immunological cells: dendritic cells (DC), immature CD1a+ and mature DC-Lamp+; mast cells (MC), tryptase+; and macrophages (M), CD68+, in the intratumoral, peritumoral, and extratumoral areas. As a control we analyzed 44 cases of thyroid adenomas (A). Results: In the intratumoral and peritumoral areas, the expression of CD1a, tryptase, and CD68 was significantly higher in FVPTC than in adenomas. Expression of CD1a and tryptase was comparable in the extratumoral compartment, whereas CD68 expression in the extratumoral area was significantly higher in FVPTC than in adenoma ( p=0.0015). DC-Lamp expression was not significantly different among the intra-tumor, peri-tumor, and extra-tumor areas of FVPTC or adenoma. It was also very interesting that nonencapsulated FVPTC were more positive to tryptase. Conclusion: We highlight a higher presence of immunological cells in carcinomas than in adenomas. On this basis, it is possible to speculate that these inflammatory elements could be involved in tumor progression and invasion, as appears to be the case for MC and M. [ABSTRACT FROM AUTHOR]

Background: Reliability of mismatch repair proteins and microsatellite instability assessment is essential in order to define treatment strategy and identify candidates to immune checkpoint inhibitors in locally advanced gastroesophageal carcinoma. We evaluated the concordance of deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) status between endoscopic biopsies and surgical specimens. Methods: Consecutive patients with resectable gastric or gastroesophageal junction adenocarcinoma classified as MSI-H/dMMR by polymerase chain reaction (PCR) or immunohistochemistry (IHC) and operated at three referral Institutions were included. The primary endpoint was the rate of concordance between biopsy and surgical samples. If needed, central revision by IHC/PCR was performed by specialized pathologists from coordinating Institutions. Results: Thirteen (19.7%) out of 66 patients showed discordant MSI-H/dMMR results in the original pathology reports. In most cases (11, 16.7%) this was due to the diagnosis of proficient mismatch repair status on biopsies. Among the ten cases available for central review, four were due to sample issues, four were reclassified as dMMR, one case showed dMMR status but was classified as microsatellite stable by PCR, one was linked to misdiagnosis of endoscopic biopsy by the local pathologist. Heterogeneity of mismatch repair proteins staining was observed in two cases. Conclusions: Available methods can lead to conflicting results in MSI-H/dMMR evaluation between endoscopic biopsies and surgical samples of gastroesophageal adenocarcinoma. Strategies aiming to improve the reliability of assessment should be primarily focused on the optimization of tissue collection and management during endoscopy and adequate training of dedicated gastrointestinal pathologists within the multidisciplinary team. [ABSTRACT FROM AUTHOR]

Objective: Despite an increase in thyroid fine needle aspiration (FNA) and advances in whole slide imaging (WSI) adoption, digital pathology is still considered inadequate for primary diagnosis of these cases. Herein, we aim to validate the utility of WSI in thyroid FNAs employing the Delphi method strategy. Methods: A panel of experts from seven reference cytology centres was recruited. The study consisted of two consecutive rounds: (1) an open‐ended, free‐response questionnaire generating a list of survey items; and (2) a consensus analysis of 80 selected shared WSIs from 80 cases by six investigators answering six morphological questions utilising a 1 to 5 Likert scale. Results: High consensus was achieved for all parameters, with an overall average score of 4.27. The broad majority of items (84%) were ranked either 4 or 5 by each physician. Two badly scanned cases were responsible for more than half of the low‐ranked (≤2) values (57%). Good to excellent (≥3) diagnostic confidence was reached in more than 95.2% of cases. For most cases (78%) WSI assessment was not limited by technical issues linked to the image acquisition process. Conclusion: This systematic Delphi study indicates broad consensus among participating physicians on the application of DP to thyroid cytopathology, supporting expert opinion that WSI is reliable and safe for primary diagnostic purposes. [ABSTRACT FROM AUTHOR]

2nd-line target therapy outperforms chemotherapy in patients with BRAFV600E-mut mCRC regardless of RNF43 status. PURPOSE: Target therapy (TT) with encorafenib plus cetuximab is a standard option in patients with BRAFV600E -mutated (mut) pretreated metastatic colorectal cancer (mCRC). Recently, mutations in RNF43 , encoding a negative regulator of the WNT pathway, were associated with longer progression-free survival (PFS) and overall survival (OS) in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) BRAFV600E -mut mCRC treated with TT. Here, we explored the effect of RNF43 mutations on the efficacy of second-line TT versus standard chemotherapy (CT). METHODS: A retrospective cohort of patients with pMMR/MSS BRAFV600E -mut tumors, available RNF43 mutational status, and treated with second-line TT or oxaliplatin- and/or irinotecan-based CT was analyzed. RESULTS: One hundred thirty-two patients with pMMR/MSS BRAFV600E -mut mCRC were included. RNF43 was found mut in 34 (26%) cases. Among RNF43 mutants, TT was associated with longer PFS (7.7 v 3.0 months; P =.002) and higher overall response rate (ORR; 45% v 0%; P =.009) compared with CT. Conversely, among RNF43 wild-type (wt) patients, only a trend for longer PFS (4.5 v 3.7 months; P =.064) favoring TT, with no differences in ORR (P =.14), was observed. After excluding 36 patients receiving TT in third line or beyond, a longer OS (19.4 v 10.1 months; P =.022) and a numerically OS advantage (10.6 v 6.6 months; P =.068) were reported for TT both in the RNF43 -mut and in the RNF43 wt groups. However, no interaction effect was reported between RNF43 mutational status and treatment in ORR (P interaction =.96), PFS (P interaction =.13), and OS (P interaction =.44). CONCLUSION: Patients with pMMR/MSS BRAFV600E -mut mCRC achieve benefit from TT versus CT independently of RNF43 mutational status, although a higher magnitude of benefit from TT is observed in RNF43 -mut tumors. These findings deserve confirmation in concluded and ongoing randomized trials. [ABSTRACT FROM AUTHOR]

Salivary gland tumors (SGTs) are rare tumors of the head and neck with different clinical behavior. Preoperative diagnosis, based on instrumental and cytologic examinations, is crucial for their correct management. The identification of molecular markers might improve the accuracy of pre-surgical diagnosis helping to plan the proper treatment especially when a definitive diagnosis based only on cytomorphology cannot be achieved. miRNAs appear to be new promising biomarkers in the diagnosis and prognosis of cancer. Studies concerning the useful of miRNA expression in clinical decision-making regarding SGTs remain limited and controversial.The expression of a panel of 798 miRNAs was investigated using Nanostring technology in 14 patients with malignant SGTs (6 mucoepidermoid carcinomas, 4 adenoid cystic carcinomas, 1 acinic cell carcinoma, 1 ductal carcinoma, 1 cystadenocarcinoma and 1 adenocarcinoma) and in 10 patients with benign SGTs (pleomorphic adenomas). The DNA Intelligent Analysis (DIANA)-miRPath v3.0 software was used to determinate the miRNA regulatory roles and to identify the controlled significant Kyoto Encyclopedia of Genes and Genomes (KEGG) molecular pathways. Forty six miRNAs were differentially expressed (False Discovery Rate—FDR<0.05) between malignant and benign SGTs. DIANA miRPath software revealed enriched pathways involved in cancer processes as well as tumorigenesis, cell proliferation, cell growth and survival, tumor suppressor expression, angiogenesis and tumor progression. Interestingly, clustering analysis showed that this signature of 46 miRNAs is able to differentiate the two analyzed groups. We found a correlation between histological diagnosis (benign or malignant) and miRNA expression profile.The molecular signature identified in this study might become an important preoperative diagnostic tool. [ABSTRACT FROM AUTHOR]

Somatic copy number alterations (SCNA) involving either a whole chromosome or just one of the arms, or even smaller parts, have been described in about 88% of human tumors. This study investigated the SCNA profile in 40 well-characterized sporadic medullary thyroid carcinomas by comparative genomic hybridization array. We found that 26/40 (65%) cases had at least one SCNA. The prevalence of SCNA, and in particular of chromosome 3 and 10, was significantly higher in cases with a RET somatic mutation. Similarly, SCNA of chromosomes 3, 9, 10 and 16 were more frequent in cases with a worse outcome and an advanced disease. By the pathway enrichment analysis, we found a mutually exclusive distribution of biological pathways in metastatic, biochemically persistent and cured patients. In particular, we found gain of regions involved in the intracellular signaling and loss of regions involved in DNA repair and TP53 pathways in the group of metastatic patients. Gain of regions involved in the cell cycle and senescence were observed in patients with biochemical disease. Finally, gain of regions associated with the immune system and loss of regions involved in the apoptosis pathway were observed in cured patients suggesting a role of specific SCNA and corresponding altered pathways in the outcome of sporadic MTC. [ABSTRACT FROM AUTHOR]

The relevance of thyroid autoimmunity to the prognosis of papillary thyroid carcinoma is still unsettled. We decided to investigate the impact of thyroid autoimmunity on the prognosis of papillary thyroid carcinoma and the handling of TgAbs. We evaluated the clinical course of a large group of patients according to the presence (PTC-LT) or absence (PTC) of lymphocytic thyroiditis at histology. We studied 194 consecutive patients with a diagnosis of PTC and treated them with total thyroidectomy plus 131I ablation between 2007 and 2009. Median follow-up (with 25th-75th percentiles) was 84.0 (56.4-118.0) months. The remission criteria were: basal Tg < 0.2 ng/mL (or stimulated Tg: < 1), TgAbs < 8 IU/mL (otherwise 'decreasing TgAb trend', a decline of ≤20% in sequential TgAb measurements) and unremarkable imaging. PTC-LT and PTC patients had comparable treatment. TgAbs were detectable in 72.5% of PTC-LT and 16.5% of PTC patients. Time to remission was longer in the detectable than in the undetectable TgAb cohort (28.5 vs· 7.5 months (median); HR: 0.54, CI: 0.35-0.83, P = 0.005). When comparing PTC-LT to PTC patients, the difference was maintained in the detectable TgAb (29.3 vs 13.0 months; HR: 0.38, CI: 0.18-0.80; P = 0.01) but not in the undetectable TgAb cohort (7.7 vs 7.3 months; HR: 0.90, CI: 0.55-1.47; P = 0.68). Using the decreasing TgAb trend, the influence of detectable TgAbs on time to remission was abolished. Thyroid autoimmunity does not influence the prognosis of papillary thyroid carcinoma. A decreasing TgAb trend seems an appropriate criterion to establish the remission of papillary thyroid carcinoma. [ABSTRACT FROM AUTHOR]

Objective: About 20% of sporadic medullary thyroid carcinomas (MTC) have no RET/RAS somatic alterations or other known gene alterations. The aim of this study was to investigate RET/RAS-negative MTC for the presence of NF1 alterations. Methods: We studied 18 sporadic RET/RAS-negative MTC cases. Next-generation sequencing (NGS) of tumoral and blood DNA was performed using a custom panel including the entire coding region of the NF1 gene. The effect of NF1 alterations on the transcripts was characterized by reverse transcriptase-polymerase chain reaction (RT-PCR), and the loss of heterozygosity (LOH) of the other NF1 allele was investigated with Multiplex Ligation-dependent Probe Amplification (MLPA). Results: Two cases showed biallelic inactivation of NF1 with a prevalence of about 11% of RET/RAS-negative cases. In a patient affected by neurofibromatosis, there was a somatic intronic point mutation determining the transcript alteration in 1 allele and a germline LOH in the other. In a second patient, we described that both the point mutation and the LOH were somatic events; this latter finding shows, for the first time, a driver role of NF1 inactivation in MTC independent of RET/RAS alterations and the presence of neurofibromatosis. Conclusions: About 11% of our series of sporadic RET/RAS-negative MTC harbor biallelic inactivation of the NF1 suppressor gene also regardless of neurofibromatosis status. According to our results, NF1 alterations should be searched in all RET/RAS-negative MTC as possible drivers. Moreover, this finding reduces the number of negative sporadic MTC and may have important clinical implications in the management of these tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: This is the largest mono-institutional study addressing the debated issue about the impact of tall-cell areas on papillary thyroid carcinoma (PTC) prognosis correlated with patient age. The results of this series confirm that the tall-cell morphology alone in PTCs does not have the same negative prognostic significance in the younger population as in the older population. The tall-cell variant of papillary thyroid carcinoma (TCPTC) is the most common aggressive variant of papillary thyroid carcinoma (PTC) and typically occurs in older patients. In this study, we analyzed retrospectively the largest mono-institutional series of PTCs with tall-cell features (989 patients) over a 17-year period, re-evaluating tumors based on age at presentation and outcomes in different age groups. We divided patients into three age groups following different criteria (the criterion from the American Joint Committee on Cancer Tumor Node Metastasis (AJCC TNM) guidelines, criterion for the statistical division into tertiles and adolescent/post-adolescent criterion) to analyze the clinicopathological characteristics in different age groups, especially in terms of recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). We obtained three main results: 1. the population is distributed among the different age groups, and therefore, this type of cancer is not exclusively found among those of an older age; 2. in the RFS analysis, we can see a higher probability of local recurrence in the younger and older groups and, unexpectedly, a lower probability of local recurrence in the "median age" group; and 3. in the DRFS analysis, we can observe a higher probability of distant recurrence in older patients. From a molecular perspective, no significant differences in the mutational status of BRAF were detected according to different age groups, while mutations in the TERT promoter were exclusively present in older patients of all age groups, highlighting the potential prognostic implications of TERT promoter mutations in PTCs. In conclusion, the results of this series confirm that TC morphology alone in PTCs does not have the same negative prognostic significance in the younger population as in the older population. The reason for these different outcomes remains unclear and needs further studies. [ABSTRACT FROM AUTHOR]

BRAF mutations represent the most common genetic alteration in papillary thyroid carcinoma (PTC). The p.V600E mutation is specific for the classic and tall-cell variants of PTC and has been associated with a more aggressive biologic behavior. On the other hand, the p.K601E mutation is peculiar to the follicular variant of PTC, and seems to be a favorable prognostic indicator. A 12-year-old boy presented with a 10-mm left-sided thyroid nodule. Fine-needle aspiration cytology reported the lesion as suspicious for a follicular neoplasm (Bethesda category IV). The patient underwent lobectomy, and histopathology revealed a follicular adenoma with normal surrounding tissue. The cytological smear was found to be positive for BRAF p.K601E mutation, and this was later confirmed on the corresponding paraffin block. This case was independently revised by 4 expert pathologists, all of whom confirmed the benign nature of the thyroid lesion. This article describes the presence of a BRAF mutation in a benign thyroid lesion. To the authors' knowledge, this is the fourth case of follicular adenoma carrying BRAFK601E reported in literature to date. BRAFK601E mutation can occur in benign thyroid lesions. This finding, in the context of the current literature and the recently proposed reclassification of the noninvasive encapsulated follicular variant of papillary thyroid carcinoma into a benign lesion, confirms the importance of preoperative BRAF p.K601E testing in offering patients a tailored treatment plan and avoiding overtreatment. [ABSTRACT FROM AUTHOR]

Background: Trop-2 and Nectin-4 are transmembrane proteins overexpressed in many tumours and targets of antibody–drug conjugates (ADC). In metastatic colorectal cancer (mCRC), the role of Trop-2 and Nectin-4 has been poorly investigated. Methods: Tumour samples of patients randomised in the phase III TRIBE2 were assessed for Trop-2 and Nectin-4 expression. Results: Three hundred eighty-six tumours were assessed for Trop-2 expression. 90 (23%), 115 (30%) and 181 (47%) were Trop-2 high, medium and low, respectively. Patients with low Trop-2 tumours achieved longer PFS (12 versus 9.9 months, p = 0.047) and OS (27.3 versus 21.3 months, p = 0.015) than those with high/medium Trop-2 tumours. These findings were confirmed in multivariate analysis (p = 0.022 and p = 0.023, respectively). A greater OS benefit from treatment intensification with FOLFOXIRI/bevacizumab was observed in patients with high/medium Trop-2 tumours (p-for-interaction = 0.041). Two hundred fifty-one tumours were assessed for Nectin-4 expression. Fourteen (5%), 67 (27%) and 170 (68%) were high, medium and low, respectively. No prognostic impact was observed based on Nectin-4 expression and no interaction effect was reported between Nectin-4 expression groups and treatment arm. Conclusions: In mCRC, expression levels of Trop-2 and Nectin-4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin-4 ADCs. Medium/high Trop-2 expression is associated with worse prognosis and higher benefit from chemotherapy intensification. [ABSTRACT FROM AUTHOR]

• Sarcina Ventriculi is mainly isolated in the gastrointestinal tract. • Upper endoscopy could lead to SV diagnosis and rule out gastric perforations • Antibiotic therapy may eradicate the infection and prevent complications. • Emergency surgery is required in case of source control. This study is aimed to report a case of SV -related gastritis and the results of a systematic literature review of SV infections. Following a case presentation, we systematically searched different databases (MEDLINE, PubMed, Scopus, Web of Science, EMBASE, google scholar) for the items " sarcina, " " ventriculi, " " clostridium " with AND/OR. A total of 55 articles reporting 65 cases of Sarcina Ventriculi were found. Thus, 66 patients, including our case, were reviewed. The median age was 51 years (IQR: 0-87 years). Females accounted for 51% of cases. 68% of patients had one or more comorbidities. SV was isolated in the gastrointestinal tract (88%), respiratory (5%), urine (4%), and bloodstream (3%) systems. Upper endoscopy was performed in 52 patients (79%). Biopsies were obtained in all 52 cases and were normal in 23%. Surgery was warranted in 15 patients (23%), and specific antimicrobial therapy was delivered in 34 (52%) patients. Mortality was 14%. At follow-up, 88% of patients showed complete eradication of the SV infection. Upper gastrointestinal biopsy positive for SV should prompt an evaluation of the clinical conditions, considering the risk of gastric perforation is not negligible. Antibiotic therapy may eradicate the infection and prevent complications. Emergency surgery is required in case of source control. [ABSTRACT FROM AUTHOR]

A decade after nearly all surgical disciplines developed minimally invasive techniques, the first report of a single case of minimally invasive thyroidectomy was published. Minimally invasive video-assisted thyroidectomy (MIVAT) is now considered the most widely practiced and most easily reproducible minimally invasive procedure for thyroidectomy. The aim of this review was to analyze the treatment of benign thyroid diseases by MIVAT. A systematic evidence-based literature review focusing on three questions was carried out. Additional data were obtained on the basis of our personal experience. (1) Are minimally invasive procedures indicated in the treatment of thyroid diseases? (2) Is MIVAT a safe technique and what are the demonstrated advantages? (3) Since different thyroid diseases may be treated by MIVAT, is it of any value in the treatment of benign thyroid diseases? MIVAT can be considered an appropriate treatment of some thyroid diseases; it represents a safe procedure with the same incidence of complications as traditional surgery, and also has advantages in terms of both cosmetic result and postoperative distress. In spite of an increasing trend toward performing more extensive procedures other than thyroidectomy alone during videoscopic procedures, the current literature seems to reaffirm that the main and safest indication for MIVAT is benign disease. [ABSTRACT FROM AUTHOR]

Total thyroidectomy (TT) remains the treatment of choice for differentiated thyroid carcinomas (DTCs), but a limited approach can be proposed when tumors are at an early stage and limited to a single lobe. The aim of this study was to analyze the pathologic and clinical aspects of a retrospective series of DTCs in an attempt to determine whether these features might prove useful for limiting the surgical strategy in selected cases. From 2000 to 2005, a total of 2798 patients (637 males, 2161 females; mean age 44.6 years) underwent TT for papillary thyroid carcinoma in our department. The histologic features considered were size, histologic subtype and capsule of the tumor, its multifocality/bilaterality, infiltration of the thyroid capsule, and the presence of nodal metastases. Statistical analysis revealed that among tumors ≤ 1 cm the presence of the tumor capsule, infiltration of the thyroid capsule, bilaterality, and the presence of node metastases were all significantly lower when the tumor size was ≤ 0.5 cm ( p < 0.0001). Furthermore, patients with bilateral carcinomas demonstrated a significantly higher presence of a tumor capsule ( p = 0.012), infiltration of the thyroid capsule ( p < 0.0001), and node metastases ( p < 0.0001) and a higher incidence of the “tall-cells” variant ( p < 0.0001) when compared to the unilateral population. Based on these data it is suggested that tumors ≤ 1 cm cannot be considered a homogeneous class of DTCs. Nevertheless, in tumors ≤ 0.5 cm the absence of a “tall-cells” variant and the absence of infiltration of the thyroid capsule might be useful for avoiding an unnecessary completion thyroidectomy after lobectomy. [ABSTRACT FROM AUTHOR]

Background: Thyroid dysfunctions have been reported after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. However, the biological mechanisms behind these conditions remain unexplored. Herein, we report on changes of the immune transcriptome in autoptic thyroid tissues of people who have died from coronavirus disease 2019 (COVID-19). Methods: Twenty-five autoptic thyroid specimens of subjects dying from COVID-19 were investigated. Eleven autoptic thyroid specimens of subjects dying from causes other than infectious conditions served as controls. RNA transcripts of 770 immune-related genes together with RNA genomes of multiple coronavirus types were measured by the nCounter system. Reverse transcription–polymerase chain reaction for two SARS-CoV-2 genes was used to assess virus positivity. Results were validated by immunohistochemistry. Results: The SARS-CoV-2 genome and antigens were detected in 9 of 25 (36%) thyroid specimens from the COVID-19 cohort. Virus-negative thyroid tissues from COVID-19 subject did not show changes of gene transcription nor significant numbers of infiltrating immune cells. Conversely, SARS-CoV-2-positive thyroid specimens showed marked upregulation of immune genes, especially those proper of the type I and type II interferon (IFN) pathways. In infected tissues, infiltrates of innate immune cells (macrophages and polymorphonuclear neutrophils) were prevalent. Conclusions: The thyroid gland can be directly infected by the SARS-CoV-2. Infection strongly activates IFN pathways. The direct viral insult combined with an intense immune response may trigger or worsen thyroid conditions in predisposed individuals. [ABSTRACT FROM AUTHOR]

We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors. Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS). TMB was defined as low, intermediate, or high if <7, 7–16, or ≥17 mutations/megabase (mut/Mb) were found. The performance of TMB to predict MSI status was tested by receiver operating characteristic (ROC) curve. Actionable alterations included BRAF V600E, KRAS G12C, POLE mutations, HER2 amplification and mutations, and MSI-H. Of 216 paired cases, concordance between MMR-IHC and MSI-NGS was 98.6%. Among 11 TMB-high tumours, eight (73%) were MSI-H and three (27%) were microsatellite stable and harboured POLE or MSH6 mutations. High TMB had a trend for a better outcome than low/intermediate TMB (hazard ratio for overall survival 0.45, 95% confidence interval 0.28–1.33; P = 0.106). No interaction effect between TMB and treatment arm was observed. Seventeen mut/Mb was identified as the optimal threshold of TMB for predicting MSI status. Actionable alterations were found in 62 (21%) of 296 patients. Genomic profiling provides an overview of the genomic landscape of mCRC in a single analysis, including actionable targets and markers of immune sensitivity. • Microsatellite testing by next-generation sequencing is higly concordant with immunohistochemistry. • High tumour mutational burden (TMB) defines a clinical and molecular subtype of mCRC. • Alterations in DNA damage repair are rare in microsatellite stable mCRC with high TMB. • Potentially actionable alterations are detectable in a small percentage of mCRC. • Molecular characterisation of mCRC is helpful in adopting personalised treatments. [ABSTRACT FROM AUTHOR]

Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF -mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study. Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy. Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001). Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment. • A restricted panel of 44 genes discerns BM1/BM2 subtypes of BRAF mut mCRC. • AXIN2 expression distinguishes LI versus LD Wnt pathway activation of BRAF mut mCRC. • No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. • No predictive effect of both BM1/BM2 and LI/LD subtypes was shown for FOLFOXIRI/bev. • ECOG-PS >0 and left-sidedness seem associated with no benefit from FOLFOXIRI/bev. [ABSTRACT FROM AUTHOR]

Claudin-18.2 (CLDN18.2) is a member of the tight junction protein family and is a highly selective biomarker with frequent abnormal expression during the occurrence and development of various primary malignant tumors, including gastric cancer (GC) and esophago-gastric junction adenocarcinomas (EGJA). For these reasons, CLDN18.2 has been investigated as a therapeutic target for GC/EGJA malignancies. Recently, zolbetuximab has been proposed as a new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced and metastatic GC/EGJA. The use of CLDN18 IHC assays to select patients who might benefit from anti-CLDN18.2 therapy is currently entering clinical practice. In this setting, pathologists play a central role in therapeutic decision-making. Accurate biomarker assessment is essential to ensure the best therapeutic option for patients. In the present review, we provide a comprehensive overview of available evidence on CLDN18.2 testing and its impact on the therapeutic management of patients with GC/EGJA, as well as some practical suggestions for CLDN18.2 staining interpretation and potential pitfalls in the real-world setting. [ABSTRACT FROM AUTHOR]

Background. Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by RET proto-oncogene mutation. Two different clinical variants of MEN2 are known (MEN2A and MEN2B): medullary thyroid carcinoma (MTC) almost always present and associated with pheochromocytoma (Pheo), and primary hyperparathyroidism (HPTH) in MEN2A and with Pheo and other nonendocrine diseases in MEN2B. Case Report. A 7-year-old girl, previously treated for a pelvic plexiform neurofibroma, arrived at our observation with a peculiar MEN2B syndrome and with HPTH. The neck ultrasound showed bilateral thyroid nodules, local lymph node lesions, and a suspicious left hyperplastic parathyroid. The CT scan showed a megacolon and described the persistence of the pelvic tumor. A new RET germline deletion in exon 11 (c.1892_1899delCGAGCT; p.Glu632_Leu633del) was found. She underwent total thyroidectomy, central compartment and latero-cervical lymph node dissection, and neck exploration for primary HPTH. The histology confirmed bilateral MTC, multiple lymph node metastases, a hyperplastic parathyroid, and a parathyroid adenoma. Conclusions. This is the first case of a complex syndrome characterized by peculiar features of MEN2B, without Pheo but with a pelvic plexiform neurofibroma and with HPTH, which is typical of MEN2A. A "de novo" new germline RET deletion located in exon 11 was found. [ABSTRACT FROM AUTHOR]

Background: HER2 is the only validated predictive biomarker in gastro-oesophageal carcinoma (GOC). However, several factors, such as heterogeneity in protein expression, shortage of evaluable tumour tissue and need for quick target assessment, underline the usefulness of a pre-screening tool in order to anticipate HER2 status.Methods: Data from 723 consecutive GOC analysed for HER2 at four Italian Institutions were collected. HER2 positivity was defined as 3+ by immunohistochemistry (IHC) or 2+ with gene amplification by in situ hybridisation (ISH). A multivariate logistic regression model was built using data from 413 cases, whereas 310 patients served as validation cohort. C-index, visual inspection of the calibration plot, Brier score and Spiegelhalter z-test were used to assess the performance of the nomogram.Results: HER2 positive rate was 17.4%. Four variables were retained after adjustment in the final model: grading, Lauren's histotype, pathologic material analysed (surgical specimen/biopsy) and site of tissue collection (primary tumour/metastases). Visual inspection of the calibration plot revealed a very good overlap between predicted and observed probabilities, with a Brier score of 0.101 and a non-significant Spiegelhalter z-test (P = 0.319). C-index resulted in 0.827 (95%CI 0.741-0.913).Conclusion: A simple nomogram based on always-available pathologic information accurately predicts the probability of HER2 positivity in GOC. [ABSTRACT FROM AUTHOR]

Anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) are very aggressive cancers whose histological diagnosis is not always straightforward. Clinical, pathological and genetic features may be useful to improve the identification of these rare histotypes. In the present study the clinical, pathological and genetic features of two groups of ATC (n=21) and PDTC (n=21) patients were analyzed. Clinical data were retrieved from a computerized database. The oncogenic profiles were studied using the Sanger sequencing method of a selected series of oncogenes and/or tumor suppressor genes known to be altered in these tumors. The presence of macrophages in both series of tissues was evaluated by immunohistochemistry. Patients with ATC were older and affected by a more advanced disease at diagnosis than those with PDTC. The median survival was significantly shorter in ATC compared with PDTC patients (P=0.0014). ATC showed a higher prevalence of TP53 and TERT mutations (10/21, 47.6% and 9/21, 42.8%, respectively) while TERT and BRAF mutations were the most prevalent in the PDTC group (7/21, 33.3% and 4/23, 19% respectively). Genetic heterogeneity (i.e., >2 mutations) was more frequent in ATC (10/21, 28.6%) compared with in PDTC (3/21, 4.7%) (P=0.03). Macrophages were more frequently present in ATC, particularly in those cases with TP53 mutations. In conclusion, these data indicate that ATC and PDTC may be characterized by different clinical, pathological and genetic profiles. In particular ATC, but not PDTC, were positive for TP53 and PTEN alterations. Complex mutations were also found in ATC but not in PDTC. Moreover, genetic heterogeneity was more frequent in ATC than PDTC. Finally, TP53 mutation and the accumulation of several mutations correlated with a shorter survival time. [ABSTRACT FROM AUTHOR]

Krukenberg tumours are rare metastatic tumours of the ovaries characterized by the presence of mucin-producing neoplastic Signet Ring Cell Carcinoma (SRCC). At first glance, this tumour may be confused with a primary ovarian tumour. Surgery and chemotherapy combination have led to improvement in prognosis, but it still remains severe. We report the case of a 60-year-old woman with a Krukenberg tumour rising from a low differentiated gastric adenocarcinoma. The patient was clinically stable for 26 months after surgery until she experienced a prompt decline and died of cerebral haemorrhage within two weeks. The aim of this article was to give an overview of the Krukenberg tumour starting from our case report and comparing it with clinicopathological characteristics of this pathology derived from a review of recent literature. [ABSTRACT FROM AUTHOR]

Objective Medullary thyroid carcinoma ( MTC) is a rare disease that can be inherited or sporadic; its pathogenesis is related to activating mutations in the RET gene. Design This study describes our 20-year experience regarding RET genetic screening in MTC. Patients and methods We performed RET genetic screening in 1556 subjects, 1007 with an apparently sporadic MTC, 95 with a familial form and 454 relatives of RET-positive patients with MTC. Results A germline RET mutation was found in 68 of 1007 (6·7%) patients with sporadic MTC, while 939 patients with MTC were negative for germline RET mutations. We then identified a total of 137 gene carriers ( GC). These subjects initiated a clinical evaluation for the diagnosis of MEN 2. A total of 139 MEN 2 families have been followed: 94 FMTC, 33 MEN 2A and 12 MEN 2B. Thirty-three different germline RET mutations were identified. Codon 804 was the most frequently altered codon particularly in FMTC (32/94, 34%), while codon 634 was the most frequently altered codon in MEN 2A (31/33, 94%); MEN 2B cases were exclusively associated with an M918T mutation at exon 16. Conclusions Our 20-year study demonstrated that RET genetic screening is highly specific and sensitive, and it allows the reclassification as hereditary of apparently sporadic cases and the identification of GC who require an adequate follow-up. We confirmed that FMTC is the most prevalent MEN 2 syndrome and that it is strongly correlated with noncysteine RET mutations. According to these findings, a new paradigm of follow-up of hereditary MTC cases might be considered in the next future. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular thyroid neoplasm with an indolent clinical behaviour. In this study, we evaluated a retrospective series of 451 NIFTPs, of which 197 (43.7%) presented in coexistence with collateral thyroid tumours. Unifocal and multifocal NIFTPs did not show peculiar ultrasound, cytological, molecular, and histo-pathological characteristics. Considering the high rate of coexisting carcinomas, NIFTP patients might benefit from monitoring of the contralateral lobe. Background: Non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs) were introduced in thyroid pathology in 2016. NIFTPs are a group of follicular neoplasm with an indolent behaviour. In this study, we gathered a large retrospective cohort of NIFTPs and compared those presenting as solitary lesions and NIFTPs found in multifocal setting. Methods: A retrospective search of NIFTPs was performed, and the clinico-pathological features were recorded. For a subgroup of patients, pre-surgical ultrasound (US) evaluation, cytological diagnosis, and molecular analysis were available. Results: We collected 451 NIFTPs; 254 (56.3%) were truly solitary tumours, while 197 coexisted with one or more NIFTP/cancer. Contrasting unifocal and multifocal settings, NIFTPs size was the only significantly different parameter. Preoperatively, NIFTP nodules mostly showed low-risk US characteristics, indeterminate cytology and a RAS-like molecular profile. Conclusion: NIFTPs often coexist with collateral thyroid tumours. However, no clinical-pathological differences can be observed between solitary and "multifocal" NIFTPs. Despite the well-established clinical indolence of NIFTP, a careful monitoring of the contralateral lobe should not be excluded. [ABSTRACT FROM AUTHOR]

Background: Approximately 60% of sporadic medullary thyroid carcinomas (sMTC) remain orphan of a recognized genetic cause. Recently, a high percentage of RAS point mutations have been described in RET-negative sMTC. The aim of this study was to assess the prevalence of RAS point mutations in a large series of MTC collected in four Italian centers. Methods: For this purpose, we studied codons 12, 13, and 61 of H-, K-, and N- RAS genes in 188 MTC samples, either hereditary or sporadic, by direct sequencing. Correlations between the RAS mutational status and the clinical-pathological features of MTC patients as well as a meta-analysis of all published data were performed. Results: The prevalence of RAS mutations in the present series of MTC was 10.1%, and 17.6% when considering only RET-negative cases. RAS mutations were found in MTC tumoral tissue, but not in peripheral blood indicating their somatic origin. A novel mutation in codon 72 (M72I) was found, but with a low or null transforming potential. No association was found between the presence of RAS mutations and the clinical-pathological features of the patients. Although not statistically significant, a positive association between the presence of RAS mutations and a better outcome was observed. The meta-analysis of all published studies confirmed a prevalence of 8.8% for RAS mutations in MTC. Conclusions: The prevalence of RAS mutations in our MTC series was relatively low and consistent with the meta-analysis data. Only somatic RAS mutations were found and only in RET-negative sMTC. Likewise, MTCs that harbor a RAS mutation identify a subgroup of tumors with less aggressive behavior. To our knowledge, this is the largest series of MTCs studied for the presence of mutations in RAS genes and the first meta-analysis on this specific topic. [ABSTRACT FROM AUTHOR]

For an identification of novel candidate genes in thyroid tumourigenesis, we have investigated gene copy number changes in a Trk-T1 transgenic mouse model of thyroid neoplasia. For this aim, 30 thyroid tumours from Trk-T1 transgenics were investigated by comparative genomic hybridisation. Recurrent gene copy number alterations were identified and genes located in the altered chromosomal regions were analysed by Gene Ontology term enrichment analysis in order to reveal gene functions potentially associated with thyroid tumourigenesis. In thyroid neoplasms from Trk-T1 mice, a recurrent gain on chromosomal bands 1C4-E2.3 (10.0% of cases), and losses on 3H1-H3 (13.3%), 4D2.3-E2 (43.3%) and 14E4-E5 (6.7%) were identified. The genes Twist2, Ptma, Pde6d, Bmpr1b, Pdlim5, Unc5c, Srm, Trp73, Ythdf2, Taf12 and Slitrk5 are located in these chromosomal bands. Copy number changes of these genes were studied by fluorescence in situ hybridisation on 30 human papillary thyroid carcinoma (PTC) samples and altered gene expression was studied by qRT-PCR analyses in 67 human PTC. Copy number gains were detected in 83% of cases for TWIST2 and in 100% of cases for PTMA and PDE6D. DNA losses of SLITRK1 and SLITRK5 were observed in 21% of cases and of SLITRK6 in 16% of cases. Gene expression was significantly up-regulated for UNC5C and TP73 and significantly down-regulated for SLITRK5 in tumours compared with normal tissue. In conclusion, a global genomic copy number analysis of thyroid tumours from Trk-T1 transgenic mice revealed a number of novel gene alterations in thyroid tumourigenesis that are also prevalent in human PTCs. [ABSTRACT FROM AUTHOR]

Background: The first report of minimally invasive video-assisted thyroidectomy (MIVAT) was published in 1999, and the indications were progressively implemented: from cytologically undetermined thyroid nodules to intermediate-risk differentiated thyroid cancers. The aim of this study was to review the entire series of patients who underwent a MIVAT, critically analyzing its indications and contraindications and trying to figure out how the indications might be extended. Methods: From 1998 to 2009, a total of 1,946 patients (1,659 females, 287 males; mean age = 40.2 years) underwent MIVAT in our department. Inclusion criteria were benign thyroid nodules <35 mm, malignant nodules <20 mm, and an ultrasonographically estimated thyroid volume (ETV) <25 cc. The presence of suspicious or metastatic lymph nodes and the presence of severe thyroiditis were considered a contraindication for MIVAT. Results: A total thyroidectomy was performed in 1,435 patients (72.3%). A total lobectomy was performed in 511 cases (26.3%), and a central neck node sampling was associated with total thyroidectomy in 104 cases. Final histology revealed benign disease in 979 cases (51.5%) and a malignancy was diagnosed in 915 cases (48.5%). Unexpected thyroiditis was found on final histology in 17.9% of the patients with benign disease and 30.9% of patients with malignancy. The incidence of thyroiditis was significantly different in these two populations ( p < 0.0001). Conclusion: Our data confirm the validity of the traditional indications for MIVAT: low-risk differentiated thyroid cancer (DTC), cytologically undetermined nodules, and small-volume benign thyroid disease. The indications may be further and safely extended to those patients with associated thyroiditis and those with intermediate-risk DTC. MIVAT can be proposed on a much larger scale than it was at its onset and cannot be considered an option for only a limited number of patients. [ABSTRACT FROM AUTHOR]

Abstract: About 30% of hereditary Medullary Thyroid Carcinoma (MTC) have been demonstrated to harbour imbalance between mutant and wild-type RET alleles. We studied the RET copy number alterations (RET CNA) in 65 MTC and their correlation with RET mutation and patients’ outcome. Fluorescence in situ Hybridization and Real-time PCR revealed RET CNA in 27.7% MTC but only in a variable percentage of cells. In sporadic MTC, RET CNA were represented by chromosome 10 aneuploidy while in hereditary MTC by RET amplification. A significant higher prevalence of RET CNA was observed in RET mutated MTC (P =0.003). RET CNA was also associated to a poorer outcome (P =0.005). However, the multivariate analysis revealed that only RET mutation and advanced clinical stage correlated with the worst outcome. In conclusion, 30% MTC harbour RET CNA in variable percentage of cells suggesting cell heterogeneity. RET CNA can be considered a poor prognostic factor potentiating the poor prognostic role of RET mutation. [Copyright &y& Elsevier]

Abstract: Proton pump inhibitors promote ulcer repair in nonsteroidal anti-inflammatory drug (NSAID)-treated patients with ongoing NSAID-induced gastric toxicity, although the underlying mechanisms remain unclear. We examined the healing mechanisms of esomeprazole on NSAID-induced gastric ulcerations in the presence of a continued NSAID treatment. Ulcerations were induced in rats by oral indomethacin (6μmol/kg/day) for 14 days. Indomethacin administration was continued, alone or combined with equivalent acid inhibitory doses of esomeprazole (5μmol/kg/day), lansoprazole (15μmol/kg/day) or famotidine (20μmol/kg/day), for additional 7 days. Stomachs were then processed for: histomorphometric analysis of mucosal injury; mucosal levels of prostaglandin E2 (PGE2) and malondialdehyde (MDA); expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), caspase-3, and cyclooxygenase-2 (COX-2) (Western blot); expression of Ki-67 (immunohistochemistry). Indomethacin for 14 days elicited mucosal damage, reduced PGE2 levels and increased MDA. After additional 7 days, indomethacin induced the following effects: further enhancement of mucosal damage and MDA content; decrease in PGE2 levels; increase in COX-2 and activated caspase-3 expression; decrease in VEGF, PCNA and Ki-67 expression. In the presence of indomethacin, esomeprazole and lansoprazole were more effective than famotidine in promoting resolution of mucosal damage. Concomitantly, esomeprazole and lansoprazole, but not famotidine, restored PCNA and Ki-67 expression, and normalized MDA levels. Moreover, esomeprazole, lansoprazole and famotidine partly counteracted caspase-3 activation, without affecting VEGF expression. The healing activity of esomeprazole on indomethacin-induced gastric ulcerations can be ascribed to two mechanisms: (1) acid-dependent reduction of pro-apoptotic signalling; (2) acid-independent restoration of proliferating/repairing pathways. [Copyright &y& Elsevier]

Simple Summary: Papillary thyroid carcinoma (PTC) in pediatric patients shows different characteristics compared with PTC in adults. In this large mono-institutional cohort of pediatric PTCs, tumor tissue samples have been analyzed for point mutations and fusions. Overall, molecular alterations were detected in 131 out of 163 PTCs (80%). Fusion-driven PTCs showed more aggressive clinico-pathological features compared to mutation-driven and wild-type cases. These results highlight the importance of testing pediatric PTCs for gene rearrangement in routine characterization of tumors. Papillary thyroid carcinoma (PTC) presents distinct clinico-pathological and molecular differences in children compared with adult patients. Whether the presence of rearrangements or point mutations is associated with aggressive PTC clinical presentation is still controversial. In this study, PTCs diagnosed in patients aged less than 18 years were retrospectively searched from the institutional archive and tumor tissue was tested for point mutations in BRAF and RAS genes and for rearrangements in RET, NTRK1, NTRK3, ALK, PPARG, BRAF and THADA. A total of 163 PTCs were analyzed. Point mutations were found in 83 (51%) and gene fusions in 48 cases (30%). The most frequent alteration was the BRAFV600E mutation (36.8%), followed by NTRK3 fusion (11%), NRAS mutation (10.4%) and RET fusion (10.4%). Fusion-driven PTCs showed more frequently infiltrative growth, larger tumors, extrathyroidal extension and N1b disease. PTCs showing solid growth pattern were significantly enriched in gene fusions. This is one of the largest cohorts of pediatric PTCs. Fusion-driven tumors most frequently show aggressive pathological features; the search for rearrangements, especially in tumors with solid areas, could improve the characterization of pediatric PTCs and offer possible therapeutic options. [ABSTRACT FROM AUTHOR]

Simple Summary: Thyroid tumors that derive from follicular cells are not a homogeneous entity, showing variable morphological appearance and different degrees of differentiation. Molecular markers are useful for both diagnostic purposes and prognostic stratification of patients. In presurgical setting, molecular testing of indeterminate thyroid nodules on aspirates provides useful diagnostic information; the molecular analysis on tumor tissues can also reveal the presence of genetic alterations related to patients' prognosis. In recent years, the molecular characterization of these tumors has acquired even more importance thanks to the introduction of targeted drugs. This review summarizes the current literature on the molecular landscape of follicular-derived thyroid tumors. Thyroid cancer is the most common type of endocrine-related malignancy, whose incidence rates have increased dramatically in the last few decades. Neoplasms of follicular origin generally have excellent prognosis, with the exception of less differentiated tumors. Follicular-derived thyroid cancer can manifest as a variety of morphologically distinct entities, characterized by various degrees of differentiation and invasiveness. Histological evaluation is thus crucial for the definition of patients' prognosis. However, within each histological subtype, tumor behavior can be highly variable, and, in this respect, molecular characterization can provide insightful information to refine the risk stratification of tumors. In addition to the importance of its prognostic role, molecular testing can be used to support the differential diagnosis of thyroid nodules in the absence of marked cyto-morphological aberrations. Finally, with the advent of targeted drugs, the presence of molecular alterations will guide the therapeutic strategies for patients with advanced tumors who do not respond to standard treatment. This review aims to describe the genetic landscape of follicular-derived thyroid tumors also highlighting differences across histological subtypes. [ABSTRACT FROM AUTHOR]