BRAF V600E Gene Mutation Research Articles

Cetuximab and vemurafenib plus liposomal irinotecan (II), leucovorin and fluorouracil for BRAF V600E -mutated advanced colorectal cancer (IMPROVEMENT2): A multicenter, open-label, randomized controlled trial.

TPS316 Background: Current first-line treatment regimen for advanced colorectal cancer with BRAF V600E gene mutation is chemotherapy combined with anti-angiogenic drug, but the efficacy is somewhat limited. Theoretically, targeting BRAF V600E mutation is an effective treatment strategy and has achieved success in lung cancer and melanoma. However, the objective response rate (ORR) is below 5% in colorectal cancer, suggesting that BRAF V600E mutation in colorectal cancer may have different feedback regulation mechanisms compared to other cancer types. Combining chemotherapy (such as 5-fluorouracil plus irinotecan) with BRAF/EGFR targeted therapy may potentially achieve good efficacy. Subsequently, we conducted the IMPROVEMENT (NCT03727763) study, which showed an objective response rate (ORR) of 85% and a disease control rate of 100% with this regimen, significantly higher than those with chemotherapy combined with anti-angiogenic drug. The recent BREAKWATER study showed similar trends. To further validate the efficacy and safety of this regimen, we designed a randomized controlled trial. Methods: IMPROVEMENT2 (NCT06603376) is a multicenter, open-label, randomized controlled trial in patients with histologically or cytologically confirmed advanced colorectal cancer. Adult patients who are previously untreated in the metastatic setting, have a confirmed BRAF V600E mutation, measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1 are eligible. Patients who received previous treatment in the adjuvant setting but experienced metastasis or recurrence within 12 months are permitted. A total of 75 eligible patients will be randomly assigned (2:1) to receive liposomal irinotecan(Ⅱ) 60 mg/m 2 , leucovorin 400 mg/m 2 , fluorouracil 2800 mg/m 2 , and cetuximab 500 mg/m 2 on day 1 of each 14-day cycle plus oral vemurafenib 720 mg twice daily, or liposomal irinotecan(Ⅱ) 60 mg/m 2 , leucovorin 400 mg/m 2 , fluorouracil 2800 mg/m 2 , and bevacizumab 5 mg/kg on day 1 of each 14-day cycle. Treatment will be continued until disease progression or unacceptable toxicity. The primary endpoint is ORR per RECIST 1.1 by blinded independent central review (BICR). Key secondary endpoints are depth of response, progression-free survival per RECIST 1.1 by BICR, overall survival, and safety. The study is actively enrolling patients. Clinical trial information: NCT06603376 .

An Autopsied Case of Erdheim-Chester Disease with Severe Cardiovascular Involvement

Erdheim-Chester disease (ECD) is a rare type of non-Langerhans cell histiocytosis, characterized by the infiltration of disease-specific foamy histiocytes, polymorphic granulomas, and fibrosis. Although cardiovascular involvement is observed radiologically in approximately half of ECD patients, only a few reports have described its pathological features. We herein report the autopsy of an ECD patient with pulmonary, cardiovascular, and retroperitoneal involvement that may have caused his death. Autopsy revealed the pathological association of coronary and renal arterial stenosis with the BRAFV600E gene mutation. BRAF mutations should be considered in patients with ECD, especially in those with arterial lesions.

Isolated Langerhans cell histiocytosis of the stomach in adults: An analysis of clinicopathologic characteristics and molecular genetics.

Isolated gastric Langerhans cell histiocytosis (LCH) occurs extremely rarely in adults. We characterized the clinicopathological and molecular genetics of this rare entity. We retrospectively analyzed the clinicopathologic and prognostic features of 3 patients with isolated gastric LCH during the past 10 years, with a review of an additional 20 patients from the literature. A total of 23 patients with isolated gastric LCH were included in this study. There were 15 males and 8 females, with a mean age of 44.5 (median, 48; range, 21-68) years. Stomach discomfort and abdominal pain were the most common presenting symptoms. The lesions were mainly concentrated in the gastric body and antrum (21/23). Gastroscopy often revealed an elevated lesion/polyp. Molecular tests showed that BRAF-V600E gene mutations were found in 10/11 (42%) patients, while none of the patients (0/5) harbored KRAS gene mutations. None of the 23 patients received further treatment. Twenty patients had follow-up results (from 4 to 66 months). One patient with atypical morphological features died of unknown cause 2 months after removal of the tumor. One patient was found to have secondary lesions in the skull and axillary region. The other 18 patients survived without any evidence of disease progression during the follow-up period. In the daily diagnosis of gastroscopic biopsy, it is necessary to be aware of the possibility of LCH in patients with lesions in the gastric body or antrum if endoscopy reveals bulge/polypoid changes and heavy microscopic inflammation. In addition, we should be alert to the possibility of LCH with malignant transformation if the histological morphology exhibits tumor cell nucleoli and mitotic figures or necrosis. The immunohistochemical marker CD56 may help differentiate between LCH and Langerhans cell sarcoma when the morphology is difficult to determine. Molecular detection has shown that the mutation rate of BRAF in gastric LCH is up to 90.9%; more work is needed as the number of cases is small. Current data show a good prognosis for isolated gastric LCH in adults, but long-term follow-up for early detection of disease progression or systemic involvement is necessary.

The Combined Use of Fine-Needle Aspiration (FNA) and BRAF V600E Gene Testing: Can it Increase the Definitive Diagnosis Rate of Nodules Categorized as Bethesda III for Papillary Thyroid Carcinoma?

This study aimed to analyze the malignant probability of thyroid nodules diagnosed as indeterminate cytology, including atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), and investigate the diagnostic value of combining BRAF V600E gene testing within this classification. We conducted a retrospective analysis of 126 patients who underwent fine-needle aspiration (FNA) examination of thyroid nodules and subsequent surgical treatment at Beijing Haidian Hospital between October 2021 and November 2022. Among them, there were 22 male and 104 female patients, aged between 18 and 75years old. Surgical pathology results were considered the gold standard for diagnosing the nature of thyroid nodules, evaluating the malignant incidence of cytological results categorized as AUS/FLUS. Fisher's exact test and diagnostic test evaluation methods were used to analyze the discriminatory diagnostic efficacy of preoperative FNA combined with BRAF V600E gene testing for papillary thyroid carcinoma (PTC). Statistical analysis was performed using SPSS 22.0 software. In PTC patients, the BRAF V600E gene mutation rate was 87.93% (102/116). Within the category of FNA results as AUS/FLUS, the proportion of PTC was 60.00% (15/25). The specificity, sensitivity, positive predictive value, and negative predictive value of the BRAF V600E gene mutation in diagnosing PTC within the AUS/FLUS category were 10/10, 6/15, 6/6, and 10/19, respectively. The BRAF V600E gene mutation significantly increased the detection rate of PTC in patients classified under this cytology (P = 0.028, <0.05). Preoperative FNA combined with BRAF V600E gene mutation testing significantly enhances the malignant detection rate of thyroid nodules diagnosed cytologically as AUS/FLUS. This combined approach provides a potent tool to improve diagnostic accuracy in this indeterminate classification.

Clinicopathological features and prognosis of sporadic mismatch repair deficient colorectal cancer

Objective: To investigate the clinicopathological characteristics and prognostic factors of sporadic mismatch repair deficient (dMMR) colorectal cancer. Methods: A total of 120 cases of sporadic dMMR colorectal cancer from July 2015 to April 2021 were retrospectively collected in Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Patients with Lynch syndrome; synchronous multiple colorectal cancers; preoperative anti-tumor treatments such as chemotherapy and radiotherapy; and those with incomplete follow-up information were excluded based on family history and next-generation sequencing (NGS) test results. Immunohistochemical stains were used to detect the expression of mismatch repair proteins, methylation-specific PCR for methylation testing, and fluorescent PCR for BRAF V600E gene mutation detection. The clinical and pathological data, and gene mutation status were analyzed. Follow-up was done to assess survival and prognosis including progression-free survival and overall survival rate. Results: Sporadic dMMR colorectal cancer occurred more frequently in the right side of the colon, in females, and in the elderly. Morphologically, it was mostly moderately-differentiated, and most patients had low-grade tumor budding. In terms of immunohistochemical expression, MLH1 and PMS2 loss were dominant, and there were age and location-specificities in protein expression. MLH1 methylation was commonly detected in elderly female patients and rare in young male patients; while MLH1 and PMS2 deficiency, and BRAF V600E mutation occurred more often on the right side (P<0.05). The 3-year and 5-year progression-free survival rates were 90.7% and 88.7% respectively, and the 3-year and 5-year overall survival rates were 92.8% and 90.7% respectively. Tumor budding status was an independent risk factor affecting patient recurrence (hazard ratio=3.375, 95% confidence interval: 1.060-10.741, P=0.039), patients with low-grade tumor budding had better prognosis, and those with medium or high-grade tumor budding had poor prognosis. Conclusion: For dMMR colorectal cancer patients, tumor budding status is an independent risk factor for recurrence.

Relationship between BRAF V600E and some aggressive features in papillary thyroid carcinoma ≤1.5 cm

Objectives: Determine the association between BRAF V600E mutation in papillary thyroid microcarcinoma (PTMC), small papillary thyroid carcinoma (PTC 1-1.5 cm), with tumour-aggressive characteristics. Subjects and methods: Retrospective descriptive study of 104 patients with PTMC diagnosed by histopathology and with BRAF V600E gene mutation testing results. Study subjects were divided into 2 groups: PTMC (tumour size ≤1.0 cm) and PTC 1-1.5 cm (tumour size 1-1.5 cm) and evaluated aggressive features (macroscopic extrathyroidal invasion, lymph node metastasis, high-risk variants). Results: BRAF V600E gene mutation was detected in 72.8% of PTMC and 76.5% of PTC 1-1.5 cm. The proportion of tumours with aggressive features in PTMC with and without mutations was 66.7 and 52.63%, respectively (p=0.28). The proportion of tumours with aggressive features in PTC 1-1.5 cm with and without mutations was 80.7 and 100%, respectively (p=0.309). In the PTMC group, the rate of extrathyroidal invasion was higher in tumours with BRAF V600E mutation (p&lt;0.05). No association was found between BRAF V600E gene mutation and lymph node metastasis, high cell variation, and more than one aggressive feature in both PTMC and PTC 1-1.5 cm patient groups. Conclusions: In the PTMC group, the rate of extrathyroidal invasion was higher in patients with the BRAFV600E mutation. No association was found between BRAFV600E gene mutation and other aggressive features in patients with PTMC and PTC 1-1.5 cm.

Investigation of BRAF V600E Mutation in Breast Cancer Patients

The B-Raf is the essential protein in signal pathways inside cells which is affected by cell growth direction. The B-Raf protein encoded by the BRAF gene that is located at chromosome 7, BRAF gene is also pointed out as proto-oncogene. This study aimed to detect the substitution at codon 600 causing a change of valine to glutamic acid (V600E) mutation in Iraqi females to assist its role in initiating breast cancer. Sixty biopsies tissue from breast cancer Iraqi women and 20 women with benign lesions were enrolled in this study. DNA was extracted from breast cancer biopsies samples. PCR and DNA Sequencing techniques were used to screen the BRAF V600E gene mutation as it is an essential event in the initiation of cancer. The results revealed that none Iraqi breast cancer women had BRAF V600E mutation, The annotated BRAF gene has been deposited in DDBJ/GenBank under the accession number LC547435. In conclusion: The present data indicate no BRAF V600E mutation in Iraqi breast cancer females and may not possess a role in breast cancer initiation. The current results may be refer to ineffectiveness of Vemurafenib and Encorafenib therapies that specific for patients with the BRAF V600 mutation. Other studies with large numbers of patients are needed to confirm the result of this study, as the high prevalence of breast cancer among Iraqi women.

The clinicopathological features of adult thyroid tumors with DICER1 mutation

A total of 37 cases of thyroid tumors with pathological features suggestive of DICER1 gene mutation were selected to detect the DICER1 gene and BRAF gene using Sanger sequencing. A total of 10 patients (27.0%) exhibited DICER1 gene mutation all of whom were female with an age of [M(Q1, Q3)] 38.0 (30.5, 47.5) years. All patients had wild-type BRAFV600E gene. The ultrasound examination showed high-low echogenic well-demarcated intra-thyroidal nodules with abundant peripheral and internal blood flow signals in the DICER1 mutated thyroid tumor. The tumor was confined within the thyroid gland, with a diameter of (3.68±1.31) cm. The pathological features are as follows: the majority of tumors are encapsulated, which mainly composed of large follicles rich in colloid and some are small and micro follicles. The nucleus is round and deeply stained or slightly light stained, small to medium-sized, with occasional nuclear grooves and a lack of nuclear pseudoinclusion bodies within the nucleus. Immunohistochemical staining shows that Ki67 proliferation index of approximately 2%-10%. All cases were followed up for 11 to 18 months, and there was no recurrences or distant metastase. This study confirmed that the DICER1 gene mutation is mutually exclusive with the BRAFV600E gene mutation. The thyroid tumor with DICER1 mutation are in big size and are more common in young females with a good prognosis. Cases with the wild-type DICER1 gene may exhibit similar morphological features, and molecular testing is recommended. If somatic DICER1 mutation is confirmed, patients should undergo germline mutation testing to rule out DICER1 syndrome in order to define whether genetic counseling is necessary.

Erdheim-Chester disease initially discovered at extraskeletal locations: a clinicopathological analysis of four cases

Objective: To investigate the clinicopathological features of Erdheim-Chester disease (ECD) initially diagnosed at extraskeletal locations. Methods: Clinical and pathological data of four cases of ECD diagnosed initially in extraskeletal locations were collected at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2013 to June 2023. BRAF V600E gene was detected by reverse transcription polymerase chain reaction (RT-PCR). Pertinent literatures were reviewed. Results: Four ECD patients included two males and two females ranging in ages from 2 years 11 months to 69 years. The lesions located in the lung (two cases), central nervous system (one case), and the testicle (one case) were collected in the study. One patient had occasional fever at night, one had nausea and vomiting, and two were asymptomatic. Radiologically, the two pulmonary ECD showed diffuse ground-glass nodules in both lungs, and the lesions in central nervous system and testicle both showed solid masses. Microscopically, there were infiltration of foamy histiocyte-like cells and multinucleated giant cells in a fibrotic background, accompanied by varying amounts of lymphocytes and plasma cells. The infiltration of tumor cells in pulmonary ECD was mainly seen in the subpleural area, interlobular septa, and perivascular and peribronchiolar areas. The fibrosis was more pronounced in the pleura and interlobular septa, and less pronounced in the alveolar septa. Immunohistochemical staining showed that all tumor cells expressed CD68, CD163 and F􀃼a; one case showed S-100 expression; three cases were positive for BRAF V600E; all were negative for CD1α and Langerin. RT-PCR in all four cases showed BRAF V600E gene mutation. Conclusions: Extraskeletal ECD is often rare and occult, and could be easily misdiagnosed, requiring biopsy confirmation. The radiologic findings of pulmonary ECD is significantly different from other types of ECD, and the histopathological features of pronounced infiltration in the subpleura area, interlobular septa, perivascular and peribronchiolar areas can be helpful in the differential diagnosis from other pulmonary diseases. Detection of BRAF V600E gene mutation by RT-PCR and its expression by immunohistochemical staining are also helpful in the diagnosis.

Detection and Significance of Molecular Markers in Immunotherapy and Targeted Therapy of Colorectal Cancer in Tibet

Objective To study the expression of SWI/SNF-related,matrix-associated,actin-dependent regulator of chromatin,subfamily A,member 4(SMARCA4)/Brahma-related gene 1,V-raf murine sarcoma viral oncogene homolog B(BRAF),P53,programmed cell death protein-1(PD-1),and programmed death-ligand 1(PD-L1),and changes in the expression of BRAF and neurotrophic tyrosine receptor kinase(NTRK) in the patients with colorectal cancer in Tibet,thereby providing a basis for targeted therapy and immunotherapy for this disease in Tibet. Methods A total of 64 patients with colorectal cancer resected in the Tibet Autonomous Region People's Hospital from January 2015 to July 2021 were enrolled in this study.The expression of SMARCA4,BRAF,P53,PD-1,and PD-L1 was detected by immunohistochemical staining.The gene fusion involving NTRK1,NTRK2,and NTRK3 was detected by fluorescence in situ hybridization,and the BRAF V600E gene mutation by polymerase chain reaction. Results The 64 patients with colorectal cancer were at a male-to-female ratio of 1.21∶1,with the mean age of (56.59±13.27) years.The tumors were located in the colon in 46(71.88%) patients and in the rectum in 18(28.12%) patients.Sixty(93.75%) patients presented adenocarcinoma,and 4(6.25%) patients presented other types of tumors.The patients in T1/T2 and T3/T4 phases accounted for 17.19%(n=11) and 82.81%(n=53),respectively.Lymph node metastasis occurred in 24(37.50%) patients.The immunohistochemical staining results showed partially down-regulated or absent expression of SMARCA4 in 1(1.56%) patient,positive BRAF expression in 4(6.25%) patients,and mutant expression of P53 in 35(54.69%) patients.The PD-1-expressing tumor associated immune cell was proportion score<10% in 45(70.31%) patients and≥10% in 19(29.69%) patients.The PD-L1 combined positive score was<10 in 52(81.25%) patients and≥10 in 12(18.75%) patients.The gene fusion of NTRK1,NTRK2,and NTRK3 was negative in all the patients,and BRAF V600E gene mutation was positive in 4(6.25%) patients.The SMARCA4 gene alteration was not detected in the patient with partial expression missing of SMARCA4.The PD-L1 combine positive score was correlated with the deficient mismatch repair(dMMR)/microsatellite instability-high (MSI-H) and the PD-1 expression (χ2=10.223,P=0.001;χ2=11.979,P=0.001). Conclusions The down-regulated or absent SMARCA4 expression and NTRK gene fusion are rare in the patients with colorectal cancer in Tibet.A few patients present BRAF V600E gene mutations,and Pan-TRK and BRAF expression can be used for the primary screening of NTRK gene fusion and BRAF gene mutation.The patients with dMMR/MSI-H are prone to high expression of PD-L1 and expected to benefit from immunotherapy.No significant correlation exists between P53 mutation and PD-L1 expression.The high expression of PD-1 is positively correlated with the high expression of PD-L1.

Clinical observation of Erdheim–Chester disease: diagnostic difficulties, treatment options

As is known, orphan diseases, which include histiocytosis, including Erdheim-Chester disease (ECD), occur under the guise of other diseases, which complicates timely diagnosis and treatment. The presence of various symptoms in patients with an unspecified diagnosis (weight loss, fever, chills, night sweats, malaise, shortness of breath, thirst, polyuria; pain in the muscles and joints, in the long tubular bones of the upper and lower extremities, in the lower back or abdomen due to kidney damage and/or retroperitoneal fibrosis; exophthalmos; rash, xanthomas; frequent infectious diseases; nystagmus, ataxia, dysarthria) requires doctors to be wary of BEC.The variety of symptoms is due to the involvement of many organs and systems (orbits, kidneys, skin, brain, including the pituitary gland; lungs; heart; blood vessels; tubular bones), which requires a thorough examination, including morphological verification of the pathological process. Histological examination of biopsy specimens for BEC is characterized by histiocytic infiltrates (so-called “foamy histiocytosis”) with signs of inflammation and the presence of Touton giant cells; Immunohistochemistry reveals positive staining of these giant cells for CD68 antigen and factor XIIIa. Bone scintigraphy reveals a pronounced symmetrical accumulation of radiopharmaceuticals in the affected bones; with radiography in places of ossalgia — significant symmetrical bilateral osteosclerosis of the periosteum; according to CT data - “hairy” kidneys, “lined” aorta as a result of infiltration with histiocytes. The BRAF V-600E gene mutation, detected in half of the cases, in combination with one or more clinical and morphological signs allows a correct diagnosis to be made. The treatment of this disease is quite complex due to the lack of multicenter international clinical studies due to the rare occurrence of this pathology. However, clinical studies are currently being conducted on the use of drugs of various groups in the treatment of BEC. There is no doubt that due to the rarity of the disease and the low awareness of doctors, our own clinical experience in managing such patients is of great interest.

Comparative efficiency of differential diagnostic methods for the identification of BRAF V600E gene mutation in papillary thyroid cancer (Review).

V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) encodes a serine-threonine kinase. The V600E point mutation in the BRAF gene is the most common mutation, predominantly occurring in melanoma, and colorectal, thyroid and non-small cell lung cancer. Particularly in the context of thyroid cancer research, it is routinely employed as a molecular biomarker to assist in diagnosing and predicting the prognosis of papillary thyroid cancer (PTC), and to formulate targeted therapeutic strategies. Currently, several methods are utilized in clinical settings to detect BRAF V600E mutations in patients with PTC. However, the sensitivity and specificity of various detection techniques vary significantly, resulting in diverse detection outcomes. The present review highlights the advantages and disadvantages of the methods currently employed in medical practice, with the aim of guiding clinicians and researchers in selecting the most suitable detection approach for its high sensitivity, reproducibility and potential to develop targeted therapeutic regimens for patients with BRAF gene mutation-associated PTC.

Update on current diagnosis and management of anaplastic thyroid carcinoma.

Well-differentiated thyroid carcinoma has a favorable prognosis with a 5-year survival rate of over 95%. However, the undifferentiated or anaplastic type accounting for < 0.2%, usually in elderly individuals, exhibits a dismal prognosis with rapid growth and disappointing outcomes. It is the most aggressive form of thyroid carcinoma, with a median survival of 5 mo and poor quality of life (airway obstruction, dysphagia, hoarseness, persistent pain). Early diagnosis and staging are crucial. Diagnostic tools include biopsy (fine needle aspiration, core needle, open surgery), high-resolution ultrasound, computed tomography, magnetic resonance imaging, [(18)F]fluoro-D-glucose positron emission tomo-graphy/computed tomography, liquid biopsy and microRNAs. The BRAF gene (BRAF-V600E and BRAF wild type) is the most often found molecular factor. Others include the genes RET, KRAS, HRAS, and NRAS. Recent management policy is based on surgery, even debulking, chemotherapy (cisplatin or doxorubicin), radiotherapy (adjuvant or definitive), targeted biological agents and immunotherapy. The last two options constitute novel hopeful management modalities improving the overall survival in these otherwise condemned patients. Anti-programmed death-ligand 1 antibody immunotherapy, stem cell targeted therapies, nanotechnology achievements and artificial intelligence imple-mentation provide novel promising alternatives. Genetic mutations determine molecular pathways, thus indicating novel treatment strategies such as anti-BRAF, anti-vascular endothelial growth factor-A, and anti-epidermal growth factor receptor. Treatment with the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has been approved by the Food and Drug Administration in cases with BRAF-V600E gene mutations and is currently the standard care. This neoadjuvant treatment followed by surgery ensures a two-year overall survival of 80%. Prognostic factors for improved outcomes have been found to be younger age, earlier tumor stage and radiation therapy. A multidisciplinary approach is necessary, and the therapeutic plan should be individualized based on surveillance and epidemiology end results.

Relationship of Recurrence Rate with some Characteristics in Patients with Thyroid Carcinoma.

Determining the clinical and subclinical characteristics related to the recurrence status in patients with a thyroid carcinoma has great significance for prognosis, prediction of recurrence and monitoring of treatment outcomes. This study aimed to determine the association between recurrence rate and some characteristics in patients with thyroid carcinoma. The study was conducted by descriptive method with longitudinal follow-up on 102 thyroid carcinoma patients at 103 Military Hospital, Hanoi, Vietnam, from July 2013 to December 2016. Univariate analysis showed that there was a relationship between the recurrence characteristics in the studied patients and the characteristics of lymph node metastasis (P = 0.026; OR = 15; 95% CI = 1.4-163.2) and BRAF V600E mutation status (P = 0.01; OR = 3.41; 95% CI = 1.31-8.88). When analysing the multivariable Logistic regression model, there was a positive correlation between the occurrence of BRAF V600E gene mutation (P = 0.032; OR = 17.649; 95% CI = 1.290-241.523) and male sex (P = 0.036; OR = 12.788; 95% CI = 1.185-137.961) and the occurrence of recurrence in study patients. The mean time to relapse was earlier in male patients than in female patients (P = 0.02). The mean time to relapse in patients with the BRAF V600E mutation (31.81 ± 1.14 months) was shorter than the mean time to relapse in the group without the mutation (57.82 ± 2.08 months) (P = 0.01). The group of patients with mutations in the BRAF V600E gene increased the risk of recurrence compared with the group without the mutation (HR = 9.14, P = 0.04). There is a positive correlation between recurrence and masculinity, lymph node metastasis and the occurrence of BRAF V600E mutations in thyroid carcinoma patients.

Single BRAFV600E mutation is not associated with aggressive biological behavior in adolescent and pediatric papillary thyroid carcinoma.

Papillary thyroid carcinoma is more likely to show aggressive biological behaviors in the majority of pediatric patients than in adult patients. The aim of this study was to investigate the mutation rate of the BRAFV600E gene in adolescents and children with papillary thyroid carcinoma and to analyze the association between BRAFV600E gene mutation and tumor-aggressive pathological factors. A total of 42 pediatric patients with papillary thyroid carcinoma who underwent thyroid surgery from 2017 to 2022 were studied retrospectively. Whether the BRAFV600E gene mutation in papillary thyroid carcinoma was related to aggressive biological behavior was analyzed. Among the 42 pediatric patients with papillary thyroid carcinoma, the median patient age was 15.71±2.51years (mean±SD) and the median tumor diameter was 24.95±12.29mm (mean±SD). Among all enrolled patients, the mutation rate of the BRAFV600E gene was 54.76% (23 of 42). There were 33 patients with classic papillary thyroid carcinoma, and 22 (66.67%) with classic subtypes were BRAFV600E positive. The BRAFV600E mutation was associated with lower distant metastasis (p=.013) and less Hashimoto's thyroiditis (p=.006). There was no significant difference in clinicopathological factors such as sex, age, tumor size, capsular invasion, multifocality, hypothyroidism, recurrence, lymph node metastasis, and extrathyroidal extension. The BRAFV600E mutation is not uncommon in pediatric papillary thyroid carcinoma but is not significantly associated with aggressive biological behavior. It is not possible to determine whether to adopt more active diagnosis and treatment measures on the basis of the mutation of a single BRAFV600E gene.

The association of BRAF V600E gene mutation with proliferative activity and histopathological characteristics of congenital melanocytic nevi in children

BackgroundA lot of congenital melanocytic nevi (CMN) carry the somatic mutation in the oncogene BRAF V600E. But the detailed histopathologic characteristics and the proliferative activity of CMN with BRAF V600E gene mutation have not been systematically documented. ObjectiveTo identify the proliferative activity and histopathological features correlating them with BRAF V600E gene mutation status in CMN. MethodsCMN were retrospectively identified from the laboratory reporting system. Mutations were determined by Sanger sequencing. The CMN were divided into a mutant group and control group according to whether there was BRAF gene mutation and were strictly matched according to gender, age, nevus size, and location. Histopathological analysis, analysis of Ki67 expression by immunohistochemistry and laser confocal fluorescence microscopy were performed. ResultsThe differences in Ki67 index, the depth of nevus cell involvement and the number of nevus cell nests between the mutant group and the control group was statistically significant, with p-values of 0.041, 0.002 and 0.007, respectively. Compared with BRAF V600E negative nevi, BRAF V600E positive nevi often exhibited predominantly nested intraepidermal melanocytes, and larger junctional nests, but the difference in this data sets were not statistically significant. The number of nests (p = 0.001) was positively correlated with the proportion of Ki67 positive cells. Study limitationsA small sample of patients were included and there was no follow-up. ConclusionsBRAF V600E gene mutations were associated with high proliferative activity and distinct histopathological features in congenital melanocytic nevi.

Clinical and molecular characteristics and prognosis of classical hairy cell leukemia and hairy cell leukemia variant

Objective: To evaluate the clinical characteristics, treatment response, and outcomes in patients with classical hairy cell leukemia (cHCL) and HCL variant (HCL-V). Methods: This is a retrospective case series study. Between January 2011 and December 2021, clinical data of 30 patients newly with diagnosed HCL at Peking Union Medical College Hospital were analyzed. The main outcome measures include clinical characteristics, treatment efficacy and survival. The Kaplan-Meier method was used for survival analysis. Results: Twenty-one cases of cHCL and 9 cases of HCL-v were included. The median age at diagnosis was 55.5 (range, 30-86) years, with the ratio of male to female 2.75∶1. The main clinical manifestations included fatigue in 11 cases (36.7%), abdominal distension in 7 cases (23.3%), and infection in 4 cases, while 8 cases were asymptomatic. Splenomegaly was reported in 24 cases (80.0%), including 7 (23.3%) with megalosplenia. The white blood cell count, lymphocyte count, and the proportion of peripheral hairy cells in HCL-v group were significantly higher than those in cHCL group, whereas the development of anemia, thrombocytopenia, and monocytopenia in cHCL group was more remarkable than that in HCL-v group (all P<0.05). The BRAF-V600E gene mutation was detected only in cHCL patients (11/14 vs. 0/9, P<0.001). In terms of immunophenotype, the expression of CD25, CD103, CD123 and CD200 in cHCL group (20/20, 20/20, 4/7, 7/17) were all stronger than those in HCL-v group (3/9, 7/9, 0/4, 2/8). Twenty-two patients were treated, of which 13 cases (12 cases of cHCL and 1 case of HCL-v) with cladribine, and 9 cases (4 cHCL and 5 HCL-v) with interferon. Complete remission rate and overall response rate were comparable between cladribine and interferon treatment groups (both P<0.05). The median follow-up time was 31 (range, 1-125) months, and the median overall survival (OS) of the entire group was 125 months. The 5-year OS rate in HCL-v patients represented a trend of inferior (50.0% vs. 95.0%, P=0.207). Conclusions: The clinical features of HCL are unspecific, which includes fatigue, splenomegaly and recurrent infection. The clinical features, immunophenotype, treatment response and prognosis of HCL-v are different from those of cHCL. BRAF-V600E gene mutation is suggested as a key marker for differential diagnosis. Cladribine is recommended as front-line regimen of cHCL patients with satisfactory efficacy and prognosis. Conversely, response and clinical outcome in HCL-v patients still need to be improved.

Deep learning-based multifeature integration robustly predicts central lymph node metastasis in papillary thyroid cancer

BackgroundFew highly accurate tests can diagnose central lymph node metastasis (CLNM) of papillary thyroid cancer (PTC). Genetic sequencing of tumor tissue has allowed the targeting of certain genetic variants for personalized cancer therapy development.MethodsThis study included 488 patients diagnosed with PTC by ultrasound-guided fine-needle aspiration biopsy, collected clinicopathological data, analyzed the correlation between CLNM and clinicopathological features using univariate analysis and binary logistic regression, and constructed prediction models.ResultsBinary logistic regression analysis showed that age, maximum diameter of thyroid nodules, capsular invasion, and BRAF V600E gene mutation were independent risk factors for CLNM, and statistically significant indicators were included to construct a nomogram prediction model, which had an area under the curve (AUC) of 0.778. A convolutional neural network (CNN) prediction model built with an artificial intelligence (AI) deep learning algorithm achieved AUCs of 0.89 in the training set and 0.78 in the test set, which indicated a high prediction efficacy for CLNM. In addition, the prediction models were validated in the subclinical metastasis and clinical metastasis groups with high sensitivity and specificity, suggesting the broad applicability of the models. Furthermore, CNN prediction models were constructed for patients with nodule diameters less than 1 cm. The AUCs in the training set and test set were 0.87 and 0.76, respectively, indicating high prediction efficacy.ConclusionsThe deep learning-based multifeature integration prediction model provides a reference for the clinical diagnosis and treatment of PTC.

THE ASSOCIATION BETWEEN B-RAF V600E GENE MUTATION WITH AGE, GRADING, AND CLINICAL RESPONSE IN COLORECTAL CANCER AT THE CENTER GENERAL HOSPITAL (RSUP) PROF. Dr. I GOESTI NGOERAH GDE NGOERAH IN BALI

Background: Colorectal cancer (CRC) is the most common type of cancer found in people over 50 years of age and is a disease associated with aging. CRC is the most preventable and curable cancer due to the pre-clinical phase until it becomes cancer between 10 - 20 years. The B-RAF mutation plays an important role in the prognosis and treatment of CRC patients. The B-RAF V600E mutation is the most common B-RAF mutation. This study aims to analyze the relationship between mutations in the B-RAF V600E gene with age, grading, and clinical response in CRC patients in Bali. Method: We used FFPE samples that were confirmed as CRC tissues by the pathologist. Identification of BRAF V600E mutation was identified using polymerase chain reaction (PCR) and direct sequencing. Data on age, grade, and clinical response were recorded from the patients medical record. Data was analized using Fisher-exact test. Results: The B-RAF V600E mutation samples were identified in 3 out of 74 samples (4.1%). The B-RAF V600E mutation was found in 3/3 of the samples (100%), which aged over 50 years old. All those mutated cases (100%) were low grade. Positive vs. negative clinical response was shown at 2/3 (66.7%) samples vs. 1/3 (33.3%) sample. No significant correlation was found between B-RAF V600E gene mutation and age (p=0.643), grading (p=0.808), and clinical response (p=0.358). Conclusion: We have identified the prevalence and type of BRAF mutation in our cases, however, there is no significant correlation between mutation B-RAF V600E gene and age, grade and clinical response of CRC patients at the center general hospital (RSUP) Prof. Dr. IGNG Ngoerah, Bali.

Advantages and clinical significance of enhanced CT combined with BRAF V600E gene detection in the diagnosis of papillary thyroid carcinoma

The diagnosis of papillary thyroid carcinoma (PTC) remains the focus of clinical research. Studies have shown that the BRAFV600E gene mutation is closely related to the development of PTC. In this study, we used the advantages and clinical significance of enhanced CT combined with BRAFV600E gene testing in the diagnosis of PTC. A total of 170 PTC patients who received treatment in our hospital between January 2020 and December 2020 were collected and divided into group A (enhanced CT combined with BRAFV600E gene detection) and group B (fine needle aspiration cytology, FNAC) according to different diagnostic methods. We recorded the general information of the patients and measured the levels of serum tumor markers including carcinoembryonic antigen (CEA), cytokeratin fragment 19 (CYFRA21-1), neuron-specific enolase (NSE) and carbohydrate antigen 125 (CA125). After pathological diagnosis, the specificity, sensitivity, accuracy, positive predictive value, and negative predictive value of the two diagnostic methods were contrasted. The accuracy of the two methods and the pathological test in identifying benign lesions, malignant tumors, was also compared. All patients' serum tumor markers CEA, CYFRA21-1, NSE and CA125 levels were above normal. The detection rate of specificity, sensitivity, accuracy, positive predictive value and negative predictive value of enhanced CT combined with BRAF V600E gene detection were superior to those of FNAC. And the accuracy of enhanced CT combined with BRAF V600E gene detection, which was confirmed by corresponding pathological detection results, was significantly increased (P<0.05). Enhanced CT combined with BRAF V600E gene detection can improve the diagnostic accuracy of PTC, and its clinical indicators and safety are superior to FNAC.