BRAF V600E Gene Research Articles

The clinical significance of BRAFV600E mutations in pediatric papillary thyroid carcinomas

This study aimed to review the clinical significance of BRAFV600E mutations in pediatric papillary thyroid carcinoma (PTC). From 2018 to 2021, 392 pediatric thyroid operations were performed in the first affiliated Hospital of Zhengzhou University. Of these, 169 patients underwent their first operation in our hospital and were histopathologically diagnosed as papillary thyroid carcinoma. BRAFV600E gene mutation detection was performed in these 169 pediatric patients to investigate the correlation between BRAF gene mutations and clinicopathological features. Ninety-seven of our 169 patients had a BRAFV600E mutation, with a mutation rate of 57.4%. The incidence of BRAFV600E was higher in boys than in girls, and in the 13–18-year age group as compared with the 6–12-year age group (P < 0.05). The positivity rate of BRAFV600E in unilateral PTC (67.7%) was significantly higher than the ones in bilateral PTC (28.9%). The occurrence of diffuse microcalcification of the thyroid negatively correlated with the presence of BRAFV600E mutations. BRAFV600E mutations were found more frequently in patients with smaller tumor size, a lack of multifocality, lower TSH levels and central lymph node metastasis. During the follow-up time, 70 patients were treated with iodine-131. Eight patients required a second surgery (All had cervical lymph node recurrence). BRAFV600E mutations do not suggest a more aggressive course in papillary thyroid carcinoma in pediatric patients in the short term.

The fluorescence amplification strategy based on 3D DNA walker and CRISPR/Cas12a for the rapid detection of BRAF V600E.

Circulating tumor DNA (ctDNA) is a fragment of single- or double-stranded DNA originating from tumor or circulating tumor cells and provides accurate information regarding the molecular characteristics of tumors. Therefore, sensitive detection of ctDNA is of great significance to mutation analysis and clinical diagnosis. Among various ctDNAs, the BRAF V600E is related to aggressive behavior, disease recurrence, and disease-specific mortality in papillary thyroid carcinoma. Herein, we selected the BRAF V600E gene sequence as an in vitro biomarker, and established a fluorescence detection strategy combined 3D DNA walker with CRISPR/Cas12a. In the presence of the target ctDNA, 3D DNA walker could identify and bind it, and thus released a large amount of output DNAs through cyclic cleavage with the assistance of specific endonuclease (Nb.BbvCI). The output DNAs were specifically bound to crRNA and activated the non-specific trans-cleavage activity of Cas12a. Finally, the fluorescence signal was significantly enhanced. Notably, this method can detect the BRAF V600E in a range of 1 fM ~ 20nM with a detection limit of 0.37 fM without DNA polymerase. Due to the powerful amplification capability of 3D DNA walker and high specificity and programmability of CRISPR/Cas12a, the entire process took only a maximum of 70min. Furthermore, it can be potentially used for the detection of ctDNA in human serum. In summary, this method not only provides a platform for the rapid detection of ctDNA, but also shows good potential for early clinical diagnosis and biomedical research.

Pathological and Prognostic Characterization of Craniopharyngioma Based on the Expression of TrkA, β-Catenin, Cell Cycle Markers, and BRAF V600E Mutation.

We collected 61 craniopharyngioma (CP) specimens to investigate the expression of TrkA, β-catenin, BRAF gene mutation, and NTRK1 fusion in CP. There were 37 male and 24 female individuals with a median age of 34 years (range, 4–75 years). Histologically, there were 46 cases of adamantinomatous craniopharyngioma (ACP), 14 cases of papillary craniopharyngioma (PCP), and 1 case with a mixed adamantinomatous and papillary pattern. By immunohistochemistry, we found that moderate/high TrkA expression was detected in 47% (28/60) CP and was significantly higher in adult patients (p = 0.018). Interestingly, TrkA is more expressed in “whorled epithelium” cells in ACP, similar to the localization of abnormal β-catenin. The abnormal expression rate of β-catenin was 70% (43/61), and the medium/high cyclin D1 expression rate was 73% (44/60), both of which were significantly higher in ACP than in PCP. Of the CP, 41% (21/51) had a moderate/strong P16-positive signal; 58% (34/59) showed a high Ki-67 expression, and there was a significant correlation between high Ki-67 L.I. and high tumor recurrence (p = 0.021). NTRK1 fusion was not found in CP by fluorescence in situ hybridization (FISH). By PCR, 26% (15/58) CP showed BRAF V600E gene mutation, which mainly occurred in PCP (100%, 14/14) except one case of mixed CP. Moreover, TrkA expression was negatively correlated with Ki-67 index and positively correlated with P16 expression. There was a significantly negative correlation between BRAF V600E mutation and abnormal β-catenin expression. Our results demonstrate for the first time that TrkA expression might occur in CP, especially in adult CP patients, and suggest that cyclin D1 could be used for ACP histological classification in addition to β-catenin and BRAF V600E mutation, while Ki-67 could be used as a marker to predict CP recurrence.

Comparison of diagnostic value of SWE, FNA and BRAF gene detection in ACR TI-RADS 4 and 5 thyroid nodules.

To compare the diagnostic value of shear wave elastography (SWE), fine needle aspiration (FNA) and BRAF gene detection (BRAFV600E gene mutation detection) in ACR TI-RADS 4 and 5 thyroid nodules. SWE images, FNA cytological results and BRAF detection results of ACR TI-RADS 4 and 5 thyroid nodules confirmed by pathology were analyzed retrospectively. The receiver operating characteristic (ROC) curve was drawn to determine the best cutoff value of SWE Emax. In the combined diagnosis of SWE, FNA and BRAF, firstly, the nodules with BRAF gene mutation were included in the positive ones, secondly, the nodules with benign and malignant FNA were included in the FNA + SWE or FNA + SWE + BRAF negative and positive ones respectively, finally, for FNA uncertain nodules: those whose SWE Emax were less than or equal to the cutoff value were included in FNA + SWE or FNA + SWE + BRAF negative ones, and those whose SWE Emax were greater than the cutoff value were included in positive ones. The diagnostic efficacy of SWE, FNA, SWE + FNA, FNA + BRAF and their combination in ACR TI-RADS 4 and 5 thyroid nodules were compared. The ROC curve showed that the best cutoff value of SWE Emax was 40.9 kpa, and the area under ROC curve (AUC) was 0.842 (0.800∼0.885). The sensitivity, specificity and accuracy of SWE were 76.3% (270/354), 75.5% (80/106) and 76.1% (350/460), respectively. The sensitivity, specificity and accuracy of FNA were 58.2% (206/354), 88.7% (94/106) and 65.2(300/460), respectively. The sensitivity, specificity and accuracy of FNA + BRAF were 95.5% (338/354), 88.7% (94/106) and 93.9% (432/460), respectively. The sensitivity, specificity and accuracy of SWE + FNA were 85.9% (304/354), 98.1% (104/106) and 88.7% (408/460), respectively. The sensitivity, specificity and accuracy of SWE + FNA + BRAF were 98.3% (348/354), 98.1% (104/106) and 98.3% (452/460), respectively. For the diagnostic accuracy, SWE + FNA + BRAF > FNA + BRAF > FNA + SWE > SWE > FNA, the difference was statistically significant (all P > 0.05). For ACR TI-RADS 4 and 5 thyroid nodules, SWE and FNA have high diagnostic efficiency. For the diagnostic accuracy, FNA + BRAF is better than FNA + SWE. FNA combination with BRAF gene detection further improves the diagnostic sensitivity and accuracy of FNA. The combined application of the three is the best.

Radiomic Model for Determining the Value of Elasticity and Grayscale Ultrasound Diagnoses for Predicting BRAFV600E Mutations in Papillary Thyroid Carcinoma.

BRAFV600E is the most common mutated gene in thyroid cancer and is most closely related to papillary thyroid carcinoma(PTC). We investigated the value of elasticity and grayscale ultrasonography for predicting BRAFV600E mutations in PTC.Methods138 patients with PTC who underwent preoperative ultrasound between January 2014 and 2021 were retrospectively examined. Patients were divided into BRAFV600E mutation-free group (n=75) and BRAFV600E mutation group (n=63). Patients were randomly divided into training (n=96) and test (n=42) groups. A total of 479 radiomic features were extracted from the grayscale and elasticity ultra-sonograms. Regression analysis was done to select the features that provided the most information. Then, 10-fold cross-validation was used to compare the performance of different classification algorithms. Logistic regression was used to predict BRAFV600E mutations.ResultsEight radiomics features were extracted from the grayscale ultrasonogram, and five radiomics features were extracted from the elasticity ultrasonogram. Three models were developed using these radiomic features. The models were derived from elasticity ultrasound, grayscale ultrasound, and a combination of grayscale and elasticity ultrasound, with areas under the curve (AUC) 0.952 [95% confidence interval (CI), 0.914−0.990], AUC 0.792 [95% CI, 0.703−0.882], and AUC 0.985 [95% CI, 0.965−1.000] in the training dataset, AUC 0.931 [95% CI, 0.841−1.000], AUC 0. 725 [95% CI, 0.569−0.880], and AUC 0.938 [95% CI, 0.851−1.000] in the test dataset, respectively.ConclusionThe radiomic model based on grayscale and elasticity ultrasound had a good predictive value for BRAFV600E gene mutations in patients with PTC.

Base of tongue metastasis of cutaneous malignant melanoma masquerading as a pedunculated reactive lesion. Report of a case with rhabdoid and neuroendocrine features

<h3>Objectives</h3> Metastatic melanoma (ΜΜ) represents a highly aggressive malignancy associated with poor prognosis. ΜΜ has a propensity to microscopically resemble other neoplasms by displaying diverse morphologic variations. Herein, we present a case of cutaneous melanoma metastatic to the base of tongue clinically mimicking a reactive pedunculated lesion and histopathologically exhibiting unusual rhabdoid and neuroendocrine features. <h3>Findings</h3> A 63-year old male presented for evaluation of a painless tongue mass of 5 months duration. The patient had been surgically treated for cutaneous melanoma of the right chest 5 years ago. Clinically, a pedunculated, soft, partially ulcerated, hemorrhagic mass involving the left base of tongue was noted. With a provisional diagnosis of pyogenic granuloma or other reactive lesion, an excisional biopsy was performed. Histopathologic examination revealed invasion of the connective tissue by clusters of epithelioid and/or plasmacytoid neoplastic cells with prominent eosinophilic nucleoli and various degrees of cytoplasmic melanin pigmentation. Interestingly, a small subset of cells showed rhabdoid morphology. Most tumor cells expressed Melan-A, HMB-45, SOX-10, and S-100, while cells with rhabdoid morphology were positive for Myo-D1. Chromogranin and synaptophysin were also positive in a few scattered cells. A final diagnosis of ΜΜ with rhabdoid and neuroendocrine features was rendered. Molecular investigation revealed mutations for the BRAF V600E gene, while multiple brain metastatic foci were detected on further diagnostic work-up. <h3>Conclusions</h3> Divergent differentiation of melanoma cells may cause diagnostic pitfalls necessitating thorough immunohistochemical analysis. The presence of rhabdoid cells, although infrequent in primary melanomas, is relatively common in metastatic tumors. Furthermore, neuroendocrine differentiation in melanomas is very uncommon and its co-existence with rhabdoid features is exceedingly rare. Better characterization of such histopathologic variations in melanomas with evaluation of their potential biologic significance is warranted.

Combination of ultrasound with BRAF V600E gene detection for the evaluation of aggressive behavior of papillary thyroid microcarcinoma

Combination of ultrasound with BRAF V600E gene detection for the evaluation of aggressive behavior of papillary thyroid microcarcinoma

Clinical analysis for 15 patients with pulmonary Langerhans cell histiocytosis and literature review.

Pulmonary Langerhans cell histiocytosis (PLCH) is a clonal disease, characterized by proliferation of Langerhans cells that derived from bone marrow infiltrating the lungs and other organs. Due to the rarity of the disease, the current understanding of the disease is insufficient, often misdiagnosed or missed diagnosis. This study aims to raise clinicians' awareness for this disease via summarizing the clinical characteristics, imaging features, and treatment of PLCH. We retrospectively analyzed clinical and follow-up data of 15 hospitalized cases of PLCH from September 2012 to June 2021 in the Second Xiangya Hospital of Central South University. The age of 15 patients (9 men and 6 women, with a sex ratio of 3 to 2) was 21-52 (median 33) years. Among them, 8 had a history of smoking and 5 suffered spontaneous pneumothorax during disease course. There were 3 patients with single system PLCH and 12 patients with multi-system PLCH, including 7 patients with pituitary involvement, 7 patients with lymph node involvement, 6 patients with bone involvement, 5 patients with liver involvement, 2 patients with skin involvement, 2 patients with thyroid involvement, and 1 patients with thymus involvement. The clinical manifestations were varied but non-specific. Respiratory symptoms mainly included dry cough, sputum expectoration, chest pain, etc. Constitutional symptoms included fever and weight loss. Patients with multi-system involvement experienced symptoms such as polyuria-polydipsia, bone pain, and skin rash. All patients were confirmed by pathology, including 6 by lung biopsy, 3 by bone biopsy, 2 by lymph node biopsy, and 4 by liver, skin, suprasternal fossa tumor, or pituitary stalk biopsy. The most common CT findings from this cohort of patients were nodules and/or cysts and nodular and cystic shadows were found in 7 patients. Three patients presented simple multiple cystic shadows, 3 patients presented multiple nodules, and 2 patients presented with single nodules and mass shadows. Pulmonary function tests were performed in 4 patients, ventilation dysfunction was showed in 2 patients at the first visit. Pulmonary diffusion function tests were performed in 4 patients and showed a decrease in 3 patients. Smoking cessation was recommended to PLCH patients with smoking history. Ten patients received chemotherapy while 2 patients received oral glucocorticoid therapy. Among the 11 patients with the long-term follow-up, 9 were in stable condition. PLCH is a neoplastic disease closely related to smoking. The clinical manifestations and laboratory examination are not specific. Pneumothorax could be the first symptom which is very suggestive of the disease. Definitive diagnosis relies on histology. There is no unified treatment plan for PLCH, and individualized treatment should be carried out according to organ involvement. Early smoking cessation is essential. Chemotherapy is the main treatment for rapidly progressing PLCH involved multiple organs. All diagnosed patients can be considered for the detection of BRAFV600E gene and relevant targeted therapies have been implemented recently.

Correlation between conventional ultrasound features and BRAFV600E gene mutation and central lymph node metastasis in thyroid papillary carcinoma

Objective:To investigate whether central lymph node metastasis（CLNM） in the central region of thyroid papillary carcinoma（PTC） is related to conventional ultrasound features of the primary lesion and BRAFV600E gene mutation. Methods:A total of 300 patients with PTC confirmed by surgical pathology and central lymph node dissection in the First Affiliated Hospital of Jinzhou Medical University from October 2019 to June 2021 were collected. The subjects were divided into the metastatic group and the non-metastatic group according to whether CLNM occurred. The correlation was determined by analyzing the conventional ultrasound characteristics and BRAFV600E gene test results of the two groups of patients. Results:Among 300 PTC patients, 120（40%） had CLNM. Univariate analysis showed that there were statistically significant differences between groups in gender, nodule maximum diameter line, number of lesions, boundaries, morphology, aspect ratio, proximity to the membrane, calcification and BRAFV600E gene mutation（P<0.05）. Logistic multivariate regression analysis showed that gender, maximum diameter line, aspect ratio, proximity to the membrane, microcalcification and BRAFV600E were the risk factors for CLNM in PTC patients（P<0.05）. ROC curve showed that when the maximum diameter was 8.5 mm, the Yooden index was the maximum. Conclusion:When the risk factors of male, maximum diameter ≥8.5 mm, aspect ratio ≥1, microcalcification, proximity to capsule and BRAFV600E（+） appear in PTC patients, high attention should be paid to preventive CLN dissection as soon as possible.

Different Threshold of Malignancy for RAS-like Thyroid Tumors Causes Significant Differences in Thyroid Nodule Practice.

Simple SummaryHistopathological diagnosis is prone to significant observer variation in the diagnosis of papillary thyroid carcinomas (PTCs) due to different thresholds of malignancy for RAS-like nuclear features (worrisome nuclear features of PTC). RAS-like PTCs in Western practice are differently classified by most Asian pathologists into follicular adenomas when they are not invasive, follicular carcinomas when they are invasive, and follicular variant PTCs when they have fully developed nuclear features. This commentary emphasizes that this observer variation in diagnosing RAS-like thyroid tumors among practices underlies several issues in thyroid nodule practice.Histopathological diagnosis of papillary thyroid carcinomas (PTCs) is prone to significant observer variation due to different thresholds of RAS-like nuclear changes among pathologists. This gap recently widened due to a defensive attitude by Western pathologists where malpractice litigation is significant. Cases with delicate RAS-like nuclear changes are follicular adenomas when they are noninvasive, follicular carcinomas when invasive, and follicular variant PTCs when they have fully developed PTC-type nuclear features in Asian practice. The different diagnostic threshold of PTC nuclear features resulted in a high (50–90%) incidence of BRAFV600E mutation of PTCs in most Asian countries, whereas it was low (35–50%) in most Western patient cohorts. The contamination of indolent RAS-like tumors in the malignant PTC category in Western patient cohorts explains why the BRAFV600E gene test identifies aggressive PTCs. However, the BRAFV600E test has no prognostic value for Asian PTC patients because most biologically benign or low-risk RAS-like tumors are excluded from PTC. All prognostic analyses of thyroid carcinomas before 2017 must be re-evaluated because most clinical guidelines were established based on data obtained from Western patient cohorts where a significant number of indolent RAS-like tumors were misclassified in the malignant category.

BRAF V600E mutation and correlation with clinicopathologic features in radioactive iodine refractory papillary thyroid carcinoma

Objective: To define the rate of BRAF V600E mutation in radioactive iodine (RAI) refractory papillary thyroid carcinoma (PTC). The correlation BRAF V600E mutation with some clinicopathologic features in RAI refractory PTC. Subject and method: 92 patients with RAI refractory PTC were operated recurrent lesions at 108 Military Central Hospital from 9/2009 to 3/2018. Recurrent lesions were evaluated histopathological characteristics, immunohistochemical staining with BRAF V600E (Ventana, Roche), BRAF V600E gene test by real-time PCR. Evaluating the status of mutated BRAF V600E and correlate with some clinicopathologic features. Result: Average age: 47.1 ± 15.6 (12 - 81); the rate of BRAF V600E mutation accounted for 80.4%; the average age of unmutated BRAF V600E RAI refractory PTC group (40.2 ± 17.2) was lower than the group of BRAF V600E mutation (48.5 ± 14.9) (p=0.042); BRAF V600E mutation in early-stage disease (I - II) had a higher rate than ones in advanced disease (II-IV); similarly, this gene mutation occurred more frequent in the group received more than 600mCi cumulative dose of RAI compared with the group received less than 600mCi cumulative dose. There was no correlation of BRAF V600E mutation with age, tumor size, lymph node, distant metastasis. BRAF V600E mutation in tall cell variant of PTC was seen more frequently than other variants and it was also seen in cases of extracapsular lymph node invasion. There was no relationship between the existence of mutated BRAF V600E with vessel invasion and calcification. Conclusion: The rate of BRAF V600E mutation in RAI refractory PTC is high, accounting for 80.4%. It correlates with some clinicopathologic characteristics such as disease stage, cumulative dose of radioactive iodine, tall cell variant of PTC; no correlation of BRAF V600E mutation with age, tumor size, lymph node and distant metastasis, extracapsular lymph node invasion

Implementation of molecular genetic tests in the diagnostics of thyroid cancer: own research

Aim — to investigate the significance of BRAFV600E, NRAS, KRAS, HRAS, RET/PTC (RET/PTC1 and RER/PTC3), PAX8/PPARg mutations for the development and course of thyroid cancer with the determination of a significant predictor mutation. Materials and methods. The analysis included 63 selected case histories of patients who, at the preoperative stage, underwent molecular genetic testing (MHT) of the thyroid gland (TG) masses and subsequently underwent surgical treatment in the surgical department of the Ukrainian Scientific and Practical Center for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues. The average age of the patients was 41.0 ± 1.8 years; from them 7men and56women. All patients underwent fine-needle aspiration puncture biopsy(FNAB) of thyroid nodules according to the standard method followed by a cytological conclusion in accordance with the Bethesda system.The Bethesda III category was revealed in 3 patients (4.8 %), Bethesda IV — 13 patients (20.6 %), Bethesda V — 12 patients (19.0 %), Bethesda VI in 35 (55.6 %) patients. The pathogenic mutations were detected in 47 (74.6 %) patients (group 1), among them two mutations were simultaneously found in two subjects. In 16 cases (25.4 %), no pathogenic mutation was found at all (group 2). Results. The genes that occurred most often were BRAFV600E — in 35 patients (55.6 %), NRAS — in 11 patients (17.5 %), KRAS — in 3 patients (4.8 %). In case of thyroid cancerdiagnosis, pathogenic mutations were found in 38 (79.1 %) subjects. The BRAFV600E gene mutation was observed when establishing a cytological conclusion classified as Bethesda III—V in 28.9 %, and in Bethesda V and in 77.1 %. Accordingly, the sensitivity of the test was low — 0.646, specificity — 0.733. The high prognostic significance of a positive result(PPV) value (from 0.784 to 0.943) indicated the likelihood of detecting thyroid cancer. This assumption confirms the calculation of the c-square criterion with the Yates correction, which is 5.207 (p = 0.023). The use of this test for the presence of the NRAS gene to detect thyroid cancer was ineffective, the value of the c -square criterion with Yates correction = 0.009 (p = 0.927). The incidence of thyroid cancer in group 1 in the cytological class Bethesda III—V was higher than in group 2, but it did not differ significantly between the groups. The aggressiveness of thyroid cancer in patients of group 1 with a positive MHT result did not have significant differences compared with the results obtained in group 2 (39.5 % and 33.3 %, respectively). Conclusions. The use of the kit for the determination of MHTmade it possible to identify pathogenic mutations in the genes BRAFV600E, NRAS, KRAS in 79.1 % of cases. The presence of these genes in combination with the analysis of cytomorphological findings classified according to the Bethesda III—V system did not increase the detection of thyroid cancer in the studied patients. The BRAFV600E gene, which was observed in 64.6 % of cases (PPV from 0.784 to 0.943), was a significant predictor among the studied candidate genes for establishing the diagnosis of thyroid cancer. Detection of a pathogenic mutation in patients with thyroid cancer did not indicate in favour of its aggressive course.&#x0D;

Correlation of conventional ultrasound features and related factors with BRAFV600E gene mutation in papillary thyroid carcinoma

Objective:To investigate the correlation of conventional ultrasound features and related factors with BRAFV600E gene mutation in papillary thyroid carcinoma（PTC）. Methods:A total of 266 nodules in 208 patients with PTC confirmed by operation and pathology in First Affiliated Hospital of Jinzhou Medical University from October 2019 to March 2021 were selected. BRAFV600E gene was detected by real-time fluorescence PCR quantitative technique after operation. According to the results of gene detection, the patients were divided into gene mutation positive group and gene mutation negative group. The routine ultrasound features and clinical data of the patients were collected, and the correlation with BRAFV600E gene mutation was analyzed. Results:Among the 266 samples, 188 cases（70.7%） had gene mutation. Univariate analysis showed that there were significant differences in age, nodular edge, capsule boundary, microcalcification and abnormal cervical lymph nodes between the two groups（P<0.05）. The results of Logistic multivariate regression analysis showed that age, nodular margin and abnormal cervical lymph nodes were independent influencing factors of BRAFV600E gene mutation in patients with PTC. ROC curve showed that when the age was 46.5 years old, the Youden index was the highest. Conclusion:BRAFV600E gene mutation is associated with age≤46.5 years old, uneven edge of nodules and abnormal lymph nodes in neck in patients with PTC. The above characteristics can be used to evaluate BRAFV600E gene mutation and have certain guiding significance for clinical diagnosis, treatment and prognosis.

DIAGNOSIS OF PLEOMORPHIC XANTHOASTROCYTOMA

Introduction. Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic cancer of the central nervous system that is classified as grade II according to the WHO score. It accounts for 1% of primary brain tumors. It is mainly located in the temporal lobe and belongs to a group of tumors called long-term epilepsy associated tumors. Surgical tumor resection is the treatment of choice.&#x0D; Brief description of the state of knowledge. The non-invasive method of PXA diagnostics is neuroimaging, which is based on computer tomography (CT) and magnetic resonance imaging (MRI). In the image, PXA presents as a solid tumor undergoing contrast enhancement, located supratentorial, with frequent peripheral cystic components.&#x0D; The characteristic histologic picture for PXA is the presence of highly pleomorphic, fusiform or round, large astrocytes with single or multiple cell nuclei. Lymphoplasmic infiltrates are visible within the tumor. The most common mutations associated with the occurrence of this cancer are mutations in the BRAF V600E gene.&#x0D; Conclusions. PXA is a very rare tumor of the central nervous system (CNS) that can recur and spread throughout the CNS. Imaging tests, i.e. CT and MRI, allow for precise imaging of the lesion, however, it is necessary to perform a histopathological examination to make a final diagnosis. The rarity of this cancer assimilates diagnostic problems. Therefore, further molecular research is needed to develop more efficient diagnostics.

The effect of Hashimoto's thyroiditis on the diagnostic efficacy of ultrasound-guided fine needle aspiration cytology for thyroid nodules ≥ 1 cm

Objective:To explore the diagnostic efficacy of ultrasound-guided fine needle aspiration cytology（US-FNAC） for thyroid nodules ≥1 cm, and the effect of Hashimoto's thyroiditis（HT） on it. Methods:The clinical data of 1027 cases of thyroid nodules ≥ 1 cm were retrospectively analyzed. Two-dimensional ultrasound, US-FNAC and BRAFV600E gene testing were performed. The postoperative pathological results were used as the criterion. The two dimensional ultrasound examination, clinical characteristics, follow-up results, and BRAFV600E were used to diagnosis for unoperated patients. The diagnostic efficiency of US-FNAC in HT（+） group and HT（-） group was compared, and the factors affecting the diagnostic efficiency were analyzed. Results:Of the 1027 nodules, the cytological results were nondiagnostic/unsatisfactory in 73 nodules（7.1%）, benign in 282（27.5%）, atypia of undetermined significance/follicular lesion of undetermined significance in 230（22.4%）, follicular neoplasm/suspicious for a follicular neoplasm in 20（1.9%）, suspicious for malignancy in 120（11.7%）, and malignant in 302（29.4%）. 515 cases underwent surgery. Among them, 495 were malignant and 20 were benign. 512 cases continued to be followed up without surgery, and the BRAFV600E of them were wild type. Combined with the two dimensional ultrasound examination, clinical features, and follow-up results, they were judged to be benign. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, false positive rate and the false negative rate the of US-FNAC were 98.7%, 98.4%, 99.3%, 99.5%, 97.5%, 0.7% and 1.6%, respectively. The accuracy, sensitivity and negative predictive value of the HT（+） group were 95.5%, 95.4% and 82.8%, respectively, which were lower than that of HT（-） group （99.5%, 99.4%, 99.2% ）（P=0.001, 0.018, P<0.001）. The false negative rate of the HT（+） group was 4.6%, higher than 0.6% of the HT（-） group（P=0.018）, and HT was an risk factor for increased FNR（OR=7.596, 95%CI: 1.452-39.740）. Conclusion:US-FNAC is an effective method for the diagnosis of thyroid nodules and it has high sensitivity and specificity in ≥ 1 cm nodules. However, the combination of HT reduces the diagnostic accuracy and HT is a risk factor for increased false negative rate.

Multiple Primary Intracranial and Spinal Juvenile Xanthogranuloma: A Case Report

Juvenile Xanthogranuloma (JXG) is a rare histiocytic disorder that belongs to the non-Langerhans cell histiocytosis family. It commonly occurs in the skin of young children, particularly the head and neck region. Occasional cases with extracutaneous involvement have been described. However, involvement of the central nervous system without cutaneous lesions is extremely rare. We present a case of an 11-year-old male child with multiple intracranial and spinal JXGs. At 30 months follow up, after administration of chemotherapy, the patient had passed away. The broad clinical spectrum of JXG and the morphological resemblance to other histiocytic lesions prompt a cautious approach for the diagnosis. Immunohistochemically, those lesions were positive for CD68 and negative for S100 and CD1a. A revised classification for histiocytosis was recently proposed, based on the underlying molecular characteristics. The diagnosis of extracutaneous or disseminated JXG with MAPK-activating mutation or ALK translocations was considered as Erdheim-Chester disease. However, our study did not fit into the proposed classification due to the absence of BRAF-V600E gene mutation and ALK gene rearrangement. Chemotherapy with or without radiotherapy has been suggested as treatment options for unresectable central nervous system lesions.

Encorafenib (Braftovi) in Combination With Binimetinib (Mektovi)

&#x0D; CADTH recommends that Braftovi in combination with Mektovi should be reimbursed by public drug plans for the treatment of unresectable or metastatic melanoma with a BRAF V600 mutation if certain conditions are met.&#x0D; Braftovi and Mektovi should only be reimbursed if used in combination and prescribed and monitored by clinicians with expertise in diagnosis and management of melanoma who are familiar with the toxicity profile associated with the Braftovi with Mektovi regimen and if it does not cost more than the least costly BRAF inhibitor and MEK inhibitor (BRAFi/MEKi) combination treatment.&#x0D; Braftovi with Mektovi should only be covered to treat adult patients with advanced or metastatic melanoma who have a BRAF V600 gene mutation that has been identified through a validated test. Patients who have not received previous treatment and patients whose disease has progressed after first-line immunotherapy are eligible for coverage.&#x0D;

A new molecular-genetic panel in the algorithm of diagnosis and treatment in patients with tiroid nodules

The increase in the number of patients with thyroid nodules requires the development of the most effective methods of preoperative diagnosis, allowing timely detection and differentiation of follicular neoplasia and highly differentiated cancer. A comprehensive study was carried out, which made it possible to optimize the diagnosis and choice of therapeutic tactics in patients of this category through the use of a new molecular genetic panel. Results of examination and surgical treatment of 60 patients suffering from benign and malignant thyroid gland formations are analyzed, pre-operative diagnosis of which was supplemented by immunocytochemical and molecular genetic methods of studying cellular material obtained during fine-needle aspiration biopsy. The threshold value of the Galektin-3 expression level for the differential diagnosis of follicular neoplasia in the direction of adenomas or well-differentiated thyroid cancer was determined. The significance of the BRAF V600E gene mutation in the detection of papillary thyroid cancer, the features of its clinical course and the determination of rational surgical tactics was proved. The limit value of the sodium-iodide symporter for predicting the resistance of thyroid cancer to radioactive iodine therapy, which determines the need to expand the scope of surgical intervention, has been established. The place of these molecular genetic markers in the algorithm of diagnosis and treatment in patients with thyroid nodules was determined.

A Pedigree Analysis and Clonal Correlations of the Coexistence of B-Cell Lymphoma and Histiocytic/Dendritic Cell Tumor.

Histiocytic/dendritic cell tumors are rare in clinical practice. It is postulated that they originate from bone marrow stem cells. Accumulating evidence has established the existence of immunoglobulin gene and T-cell receptor gene rearrangements in these tumors. Cases of transdifferentiation across lineages from follicular lymphoma to histiocytic/dendritic cell tumors have also been reported. Herein, we report 2 adult males with histiocytic neoplasms coexisting with B-cell lymphoma. Laser capture microdissection and capillary electrophoresis polymerase chain reaction analysis revealed comparable immunoglobulin gene rearrangement in both patients. In one case, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Langerhans cell sarcoma, and histiocytic sarcoma coexisted in the lymph nodes. 11q22 deletion often present in CLL/SLL and expression of the BRAF V600E gene was detected in all the 3 components. In the other case, there diffuse large B-cell lymphoma and histiocytic sarcoma coexisted in the spleen. Forty-seven mutated genes commonly found in B-cell lymphoma were detected by next-generation sequencing. In the same line, DTX1, IRF8, KMT2D, MAP2K1, and TET2 genes were found to have similar mutation sites. The results of this study will contribute in providing new ideas for targeted treatment of these diseases.

DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN CHILDREN: MR CHARACTERISTICS, CLINICAL FEATURES AND OUTCOME. FOUR CLINICAL CASES

Background. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare entity first officially recognized in 2016 WHO classification of tumors of the central nervous system. Magnetic resonance imaging (MRI) of this tumor usually visualizes diffuse meningeal infiltration with contrast enhancement, with the presence of multiple small contrast‑negative cysts, visible mainly in the T2 images. The main molecular markers of DLGNTs include the KIAA1549-BRAF fusion gene, BRAF V600E substitution is less common.The aim of this work is to describe the manifestation of DLGNT, its neuroimaging and molecular genetic characteristics, the experience of using anti‑BRAF and anti‑MEK therapy.Materials and methods. In this article are described four cases of DLGNT. The first patient with the presence of the KIAA1549-BRAF fusion in the tumor tissue received a full course of SIOP‑LGG / 2004 chemotherapy (carbo‑ platin and vincristine), the stabilization of the disease on the MRI remains for 4 years after completion of treatment. Second patient with KIAA1549-BRAF fusion gene in tumour tissue received MEK inhibitor trametinib as first line of treatment with the stabilization of the disease on control MRI which last for 2 years. A third patient with a mutation in the BRAF V600E gene. After disease progression on standard chemotherapy (carboplatin and vincristine) according to the SIOP‑LGG / 2004 protocol, anti‑BRAF therapy with vemurafenib was prescribed. After 10 months on MRI a complete response was recorded, which persists during the drug intake for 2.5 years. In the fourth patient, no molecular genetic aberrations were detected; a refractory / progressive course of the dis‑ ease was noted. To date, the stabilization of the disease is recorded on the fourth line of chemotherapy (everoli‑ mus and temozolomide).Conclusion. Given the rarity of this tumor and the lack of consensus about therapy, despite the limited number of observations, our experience allows us to recommend molecular testing of DLGNT to detect activating events in the BRAF gene, as well as consideration of anti‑BRAF / MEK therapy if either the BRAF V600E mutation is de‑ tected or KIAA1549-BRAF fusion.