BRAF V600E Mutation Research Articles

Cytokine release syndrome induced by dabrafenib and trametinib therapy in BRAF V600E-mutant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) with BRAF V600E mutations is responsive to targeted therapies, such as dabrafenib and trametinib. However, these treatments can lead to serious adverse events, including cytokine release syndrome (CRS). Herein, we report the case of a 75-year-old man with stage IVB NSCLC and a BRAF V600E mutation who developed severe CRS, manifesting hepatic and renal dysfunction, following treatment with dabrafenib and trametinib. Despite initial fever management, the patient's renal function deteriorated rapidly, necessitating hemodialysis. Elevated cytokine levels, including interleukin-6, interferon-γ, and tumor necrosis factor α, were detected. The patient was treated with steroid pulse therapy, which resulted in fever resolution, and his renal function gradually improved. Hemodialysis was discontinued as renal function recovered. This case underscores the importance for early recognition and management of CRS in patients receiving targeted therapies. Prompt intervention with steroids may prevent CRS progression and mitigate associated organ dysfunction. Further investigation is required to clarify the mechanisms of CRS in patients receiving targeted therapy, particularly in the absence of prior immune checkpoint inhibitor use.

Clinical features and prognostic factors of pediatric Langerhans cell histiocytosis: a single-center retrospective study

PurposeTo retrospectively evaluate the clinical features and prognostic factors of pediatric LCH patients treated in a single center of China.MethodsPediatric LCH cases were treated following the SD-LCH protocol at the Affiliated Provincial Hospital of Shandong First Medical University in Jinan, China. An analysis was conducted on 82 recently identified LCH cases to retrospectively evaluate the initial symptoms, therapeutic alternatives, and extended results. Follow-ups were conducted until July 31, 2023.ResultsThe median age at diagnosis was 2 (0.25–12) years. 42 (51.2%) were SS-LCH, and 40 (48.8%) were MS-LCH. The most common organ involved was bone (82.9%). Over the 16-year follow-up period, the 5-year EFS and OS rates were 75.2 ± 5% and 90.9 ± 3.3%, respectively. The cumulative reactivation rate was 23.2%. The 5-year EFS rate in SS-LCH and MS-LCH patients were 90.2 ± 4.6% and 58.8 ± 8.3%, and the 5-year OS rate in SS-LCH and MS-LCH patients were 90.2 ± 4.6% and 81.2 ± 6.5%, respectively. The 5-year OS and EFS rate in RO+ LCH and RO− LCH patients were 79.5 ± 7.5%, 53.8 ± 9.6% and 87.5 ± 11.7%, 76.2 ± 14.8%, insignificantly. Multivariate Cox regression showed that liver involvement predicted poor EFS and hematological system involvement was an independent prognostic factor for OS. Detection of the BRAFV600E mutation and targeted therapy significantly improved the prognosis post-2017.ConclusionLiver or hematological system involvement indicates a poor prognosis, and the SD-LCH protocol improves prognosis for pediatric LCH patients.

FDA Approval Summary: Tovorafenib for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma.

On April 23, 2024, FDA granted accelerated approval to tovorafenib, a type II RAF kinase inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (pLGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. Efficacy was evaluated in FIREFLY-1 (NCT04775485), a single-arm, open-label, multicenter trial that enrolled patients 6 months to 25 years of age with relapsed or refractory pLGG with an activating BRAF alteration who had received prior systemic therapy. The major efficacy outcome measure was radiologic overall response rate (ORR), defined as the proportion of patients with complete response, partial response, or minor response as determined by blinded independent central review using Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria. A key secondary endpoint was duration of response (DoR). In an efficacy population of 76 patients, the ORR was 51% (95% confidence interval (CI): 40, 63), and the median DoR was 13.8 months (95% CI: 11.3, not estimable). The required post-marketing clinical trial (FIREFLY-2) was well underway at the time of accelerated approval. This represents the first FDA approval of a systemic therapy for the treatment of patients with pLGG with BRAF fusions or rearrangements.

Deficient Mismatch Repair and BRAF Mutations in Metastatic Colorectal Cancer in the South Island of New Zealand.

Manatū Hauora, the Ministry of Health of New Zealand (NZ), published minimum standards for molecular testing of colorectal cancers (CRCs) in June 2018. These included mismatch repair (MMR) testing at diagnosis and BRAFV600E mutation analysis on newly diagnosed stage IV CRCs. This study aimed to determine the proportion of patients with CRC in the South Island of NZ with metastatic deficient mismatch repair (dMMR) CRC, the proportion of metastatic CRCs and dMMR CRCs that have a BRAFV600E mutation, and audit testing for BRAF mutations and appropriate referral to genetics services. People from the South Island with histologically diagnosed colorectal adenocarcinoma between July 1, 2018, and June 30, 2019, were identified by the National Cancer Registry. Data points extracted from the electronic medical record included staging, MMR status, BRAF mutation testing, and genetics referral. A total of 845 patients met the inclusion criteria; 166 of 845 (19.6%) had dMMR CRC, and of these 130 (78%) had BRAF mutation, 256 patients developed metastatic disease by data cut-off, 20 (7.8%) had dMMR, and 41 (22.2%) had BRAF mutation. When indicated, 275 of 330 (83.3%) were tested for BRAF mutation and 32 of 45 (71.1%) referred to genetics. Compared with other populations, South Island CRC patients had higher rates of dMMR and BRAF mutation. Less than 10% of patients (n = 20) had metastatic dMMR CRC. These patients could be considered candidates for immune checkpoint inhibitor therapy, a small number that would not significantly burden the NZ health system if funded. The vast majority of dMMR CRC was sporadic. Rates of testing could be improved.

Integrated intraoperative predictive model for malignancy risk assessment of thyroid nodules with atypia of undetermined significance cytology

Management of thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) cytology is challenging because of uncertain malignancy risk. Intraoperative frozen section pathology provides real-time diagnosis for AUS/FLUS nodules undergoing surgery, but its accuracy is limited. This study aimed to develop an integrated predictive model combining clinical, ultrasound and IOFS features to improve intraoperative malignancy risk assessment. A retrospective cohort study was conducted on patients with AUS/FLUS cytology and negative BRAFV600E mutation who underwent thyroid surgery. The cohort was randomly divided into training and validation sets. Clinical, ultrasound, and pathological features were extracted for analysis. Three models were developed: an IOFS model with IOFS results as sole predictor, a clinical model integrating clinical and ultrasound features, and an integrated model combining all features. Model performance was evaluated using comprehensive metrics in both sets. The superior model was visualized as a nomogram. Among 531 included patients, the integrated model demonstrated superior diagnostic ability, predictive performance, calibration, and clinical utility compared to other models. It exhibited AUC values of 0.92 in the training set and 0.95 in the validation set. The nomogram provides a practical tool for estimating malignancy probability intraoperatively. This study developed an innovative integrated predictive model for intraoperative malignancy risk assessment of AUS/FLUS nodules. By combining clinical, ultrasound, and IOFS features, the model enhances IOFS diagnostic sensitivity, providing a reliable decision-support tool for optimizing surgical strategies.

Influence of Body Mass Index on the Clinicopathological Features of Papillary Thyroid Carcinoma in a Chinese Population.

Background: Previous studies suggested a relationship between obesity and a high risk of thyroid cancer. However, the association between high body mass index (BMI) and the aggressiveness of papillary thyroid carcinoma (PTC) is controversial. In this study, we aimed to investigate the impact of excess BMI on histopathologic aggressiveness of PTC in a Chinese population. Methods: Between January 2015 and September 2020, 4369 PTC patients who were tested for BRAF mutation at Jiangyuan Hospital were enrolled. Logistic regression analyses were used to evaluate the associations between BMI and clinicopathological features of PTC as well as tumor BRAF mutational status. Results: Of 4369 PTC patients, the mean BMI was 24.06 ± 3.49 kg/m2, and BRAFV600E mutations were detected in 3528 (80.8%) patients. BMI ≥24.0 at initial surgery was associated with tumor multifocality and bilaterality, but not with advanced tumor stage, extrathyroidal extension (ETE), ratio of positive lymph nodes >0.3, distant metastasis, or BRAFV600E mutation. Conclusion: Our present study suggested that compared to patients with a normal BMI, overweight and obese patients had a greater risk of multifocality and bilaterality of PTC. No significant associations were observed between higher BMI and the more advanced tumor-node-metastasis stage or BRAFV600E mutational status.

Long noncoding RNA FAM111A-DT promotes aggressiveness of papillary thyroid cancer via activating NF-κB signaling.

Long noncoding RNAs (lncRNAs) play crucial regulatory roles in the tumorigenesis and progression of various cancers. However, the functional roles of lncRNAs in papillary thyroid cancer (PTC) remain unclear. In this study, we investigated the functional role of the lncRNA FAM111A-DT in PTC progression and the underlying mechanisms. Different expression levels of lncRNAs in PTC were compared via analysis of the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatics analyses and qRT‒PCR were used to investigate the expression of FAM111A-DT in PTC. Cell proliferation was measured via CCK8, EdU, colony formation, and flow cytometry assays. Cell migration and invasion were examined by wound healing and Transwell assays. Apoptosis was detected via flow cytometry. RNA sequencing, qRT‒PCR, Western blot, immunofluorescence and dual-luciferase reporter assays were performed to assess the underlying mechanisms involved. FAM111A-DT was highly expressed in PTC and associated with poor prognosis, thyroid dedifferentiation, various clinical features and the BRAFV600E mutation in PTC patients. Overexpression of FAM111A-DT enhanced the proliferation, migration and invasion of PTC cells while reducing their degree of apoptosis. The NF-κB signaling pathway was activated in FAM111A-DT-overexpressing PTC cells. The NF-κB inhibitor PDTC attenuated the promotive effects of FAM111A-DT on aggressive phenotypes and NF-κB pathway activity in PTC cells. FAM111A-DT is upregulated in PTC, and its expression is associated with poor clinical outcomes. FAM111A-DT plays an oncogenic role by, at least partially, activating the NF-κB signaling pathway.

Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome.

Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up. Here we studied the TME in three clinical cohorts of metastatic CRC with diverse molecular subtype and treatment history. The MISSONI cohort included cases with microsatellite instability that received immunotherapy (n = 59, 24 months median follow-up). The BRAF cohort included BRAF V600E mutant microsatellite stable (MSS) cancers (n = 141, 24 months median follow-up). The VALENTINO cohort included RAS/RAF WT MSS cases who received chemotherapy and anti-EGFR therapy (n = 175, 32 months median follow-up). Using a Deep learning cell classifier, trained upon >38,000 pathologist annotations, to detect eight cell types within H&E-stained sections of CRC, we quantified the spatial tissue organisation and colocalisation of cell types across these cohorts. We found that the ratio of infiltrating endothelial cells to cancer cells, a possible marker of vascular invasion, was an independent predictor of progression-free survival (PFS) in the BRAF+MISSONI cohort (p = 0.033, HR = 1.44, CI = 1.029-2.01). In the VALENTINO cohort, this pattern was also an independent PFS predictor in TP53 mutant patients (p = 0.009, HR = 0.59, CI = 0.40-0.88). Tumour-infiltrating lymphocytes were an independent predictor of PFS in BRAF+MISSONI (p = 0.016, HR = 0.36, CI = 0.153-0.83). Elevated tumour-infiltrating macrophages were predictive of improved PFS in the MISSONI cohort (p = 0.031). We validated our cell classification using highly multiplexed immunofluorescence for 17 markers applied to the same sections that were analysed by the classifier (n = 26 cases). These findings uncovered important microenvironmental factors that underpin treatment response across and within CRC molecular subtypes, while providing an atlas of the distribution of 180 million cells in 375 clinically annotated CRC patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E Activity in Cancer.

Dysregulation of translation is a hallmark of cancer that enables rapid changes in cellular protein production to shape oncogenic phenotypes. Translation initiation is governed by the m7GpppX cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), the rate-limiting factor of cap-dependent translation initiation. eIF4E is overexpressed in many cancers and drives the production of oncoproteins that promote tumor growth and survival. Accordingly, eIF4E has been established as an attractive albeit challenging therapeutic target. Building upon our previous work of developing cell-permeable cap analogue prodrugs that inhibit eIF4E binding to the m7GpppX cap, herein we disclose the design of second-generation cap analogues with alternative N-9-substituted linkers which exhibit anticancer activity in BRAFV600E mutant melanoma cell lines.

Low-grade Nasopharyngeal Papillary Adenocarcinoma: A Clinicopathologic Series of 35 Cases.

Low-grade nasopharyngeal papillary adenocarcinoma (LGNPPA) is a rare neoplasm originating from the surface mucosal epithelium in the nasopharynx. To clarify its clinicopathologic, immunohistochemical, and molecular features, we retrospectively enrolled 35 patients diagnosed with LGNPPA between May 2016 and March 2024. Our cohort consisted of 14 male and 21 female patients aged 11 to 71 years (median: 37y). The most common symptoms were rhinorrhea and nasal obstruction. Most tumors originated from the roof of the nasopharynx and were clinically staged as T1N0M0. None of the patients had a history of thyroid tumors. Microscopically, most of the LGNPPA were composed of irregular papillary structures covered with single-layer columnar or cuboidal epithelium. Eighteen cases (18/35, 51.4%) showed squamous epithelium coverage, and 9 cases (9/35, 25.7%) showed the characteristic transformation of squamous epithelium into neoplasm. Squamous differentiation and a significant spindle cell component were noted in 9 cases (9/35, 25.7%) and 26 cases (26/35, 74.3%), respectively. All cases were positive for thyroid transcription factor-1 protein, CK7, EMA, and Galectin-3 but negative for thyroglobulin, PAX8, and Napsin A. Ki-67 labeling was low and ranged from 2% to 5%. The Epstein-Barr virus or human papilloma virus infection and BRAF V600E mutation were not detected in any of the cases. All patients underwent endoscopic surgical resection, and 4 patients received radiotherapy followed by endoscopic surgery. Complete follow-up data were available for 33 patients. All patients had no recurrent or metastatic disease in the last follow-up (3 to 88mo). A definitive diagnosis depends on histopathology and immunohistochemistry studies. The optimal treatment for patients with LGNPPA is total excision. Given the extremely indolent biological behavior of LGNPPA, it may be more appropriate to classify it as a primary papillary epithelial tumor rather than an adenocarcinoma of the nasopharynx.

Nuclear pseudoinclusion is associated with BRAFV600E mutation: Analysis of nuclear features in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most prevalent thyroid neoplasm, classified into BRAF-like and RAS-like subtypes. Nuclear alterations serve as a diagnostic criterion of PTC and are fully manifested in BRAF-like. This single-center retrospective study aimed to assess the different presentation of nuclear features in 40 samples of BRAFV600E- and 40 samples of RAS-mutated PTCs using both bivariate and multivariate analytic approaches. Nuclear features are evaluated histologically using the 3-point and 8-point scoring systems established by the World Health Organization and the Asian Thyroid Working Group, respectively. We found the presence of membrane irregularities, nuclear elongation, nuclear groove, sickle-shaped nuclei, nuclear pseudoinclusion, and higher nuclear scores are significantly associated with BRAFV600E. Multivariate analysis showed that nuclear pseudoinclusion is predictive for the presence of BRAFV600E mutation (OR=10.97, 95%CI=2.81-42.96, p=0.001) and has sensitivity of 55%, specificity of 92.5%, positive predictive value of 88%, negative predictive value of 67.3%, and accuracy of 73.8%. There are various pathways and protooncogenes associated with the development of thyroid neoplasm. This study found significant differences in nuclear features between BRAFV600E and RAS-mutated PTC. BRAFV600E tend to display florid nuclear features, whereas the RAS- mutation is associated with subtle nuclear features. These findings emphasize the distinct cytological profiles of BL and RL PTC, reinforcing the need for precise subtyping to guide tailored management.

Alternating Oxaliplatin and Irinotecan Chemotherapy Combined With Capecitabine and Bevacizumab for Microsatellite-stable Stage IV Metastatic Colon Cancer With a BRAF V600E Mutation: Two Case Reports Indicating Survival Improvement over Standard Therapy.

Colorectal cancer (CRC) has the third-highest incidence among human cancers. Advancements in chemotherapy and targeted therapy have improved the treatment outcomes for patients with CRC. However, the management of patients with unresectable metastatic CRC (mCRC) continues to be a significant challenge for clinicians worldwide, particularly for those with microsatellite stability (MSS) and the BRAF V600E mutation, as they are associated with the poorest prognosis. The present study describes two patients with unresectable MSS, BRAF V600E-mutated stage IV metastatic CRC using a biweekly alternating regimen of irinotecan and oxaliplatin combined with capecitabine and bevacizumab. Case 1 stabilized after alternating treatment, whereas Case 2 progressed after alternating treatment, with progression-free survival (PFS) of 20+ and 24.5 months, respectively. Circulating levels of carcinoemryonic antigen (CEA) dropped to near normal in both cases. A partial response (PR) was determined for both cases. The two cases suggest that an alternating chemotherapy regimen of oxaliplatin and irinotecan, combined with capecitabine and bevacizumab is effective in the treatment of MSS, BRAF V600E-mutated stage IV metastatic CRC. The progression-free survival was significantly prolonged (both exceeding 20 months) compared to the first-line standard chemotherapy regimen for this disease. With a good balance between toxicity and efficacy, this alternating chemotherapy regimen can be considered as a potential first-line option for microsatellite-stable metastatic colon cancer.

Development and validation of a radiomics nomogram for preoperative prediction of BRAFV600E mutation status in adult patients with craniopharyngioma.

Although craniopharyngiomas are rare benign brain tumors primarily managed by surgery, they are often burdened by a poor prognosis due to tumor recurrence and long-term morbidity. In recent years, BRAFV600E-targeted therapy has been promising, showing potential as an adjuvant or neoadjuvant approach. Therefore, we aim to develop and validate a radiomics nomogram for preoperative prediction of BRAFV600E mutation in craniopharyngiomas. A total of 398 patients with craniopharyngioma (training cohort: n = 278; validation cohort: n = 120) were retrospectively reviewed. We extracted 851 radiomic features from MRI images and adopted a support vector machine (SVM) classifier to develop a radiomic model. Also, a clinical-radiomics nomogram was constructed based on a multivariable logistic regression analysis. The performance of the nomogram was evaluated by its discrimination, calibration, and clinical utility. The radiomic model using the SVM based on three selected features showed good discrimination in the training and validation cohorts (area under the curve [AUC], 0.941 and 0.945, respectively). A higher Rad-score, smaller tumor volume, and homogenous enhancement were demonstrated as independent predictors of BRAFV600E mutation in craniopharyngioma. The nomogram incorporating the Rad-score and clinical-radiological factors exhibited AUCs of 0.958 (95% CI, 0.936-0.980) and 0.956 (95% CI, 0.921-0.991) in the training and validation cohorts, respectively, showing good clinical benefit and calibration. The radiomics nomogram could provide an accurate, non-invasive preoperative prediction of BRAFV600E mutation in craniopharyngioma and may provide potential guidance for the preoperative administration of BRAF V600E mutation inhibitors and promote personalized treatment. Further prospective validation is still needed.

Predictive role of [18F]FDG PET-CT radiomic parameters for KRAS/BRAF/EGFR mutations in metastatic colorectal cancer patients.

The objective of this study was to evaluate the predictive value of 18F-fluorodeoxyglucose [18F]FDG positron emission tomography (PET-CT) radiomic parameters in relation to KRAS/BRAF/EGFR mutations in patients with metastatic colorectal cancer (mCRC). Blood samples were collected from 90 mCRC patients to assess KRAS G13V, BRAF V600E, and EGFR exon 20 mutations. [18F]FDG PET-CT scans were performed, and radiomic parameters, including the SUV max, max TBR, total MTV, and total TLG, were calculated and correlated with different genotypes and haplotypes of the aforementioned mutations. The SUV max, TLG, and TBR were significantly greater in patients with the KRAS G13V and BRAF V600E mutations than in patients with the wild-type genotype. The SUVmax was also significantly greater in patients with EGFR exon 20 mutations. Haplotype analysis revealed that the SUVmax was significantly greater in patients with KRAS/BRAF/EGFR mutations than in other patients, with a specificity of 68.18% and sensitivity of 65.28%. The results suggest that [18F] FDG PET-CT radiomic parameters, particularly the SUV max, have the potential to serve as noninvasive tools for predicting the KRAS/BRAF/EGFR mutation status in mCRC patients.

Impact of BRAF and MEK Inhibitors on Gingival Hyperplasia in Melanoma Patients—A Case Report

Background: Although BRAF inhibitors, such as vemurafenib, produce a marked response in patients with advanced melanoma with a BRAF V600 mutation, they eventually develop resistance to this treatment. To address this issue, vemurafenib is increasingly combined with the MEK inhibitor cobimetinib, leading to improved response rates and enhanced survival. However, this treatment modality is associated with numerous side effects. We present a case of gingival hyperplasia in a patient treated with vemurafenib, along with the strategy adopted for the management of this condition, and the impact of subsequent cobimetinib administration on its severity. Methods: The 59-year-old male patient in the focus of this report presented at the Department of Periodontology at the Medical Faculty, University of Novi Sad, in 2019, complaining of gingival overgrowth and bleeding. The patient reported persistent gum swelling during the preceding six months, which he ascribed to the use of vemurafenib, 960 mg twice daily, since 2018, when this medication was prescribed as a part of malignant melanoma treatment. Detailed clinical examination revealed significant gingival overgrowth around all present teeth, affecting the vestibular as well as the oral sides. The patient underwent thorough scaling and root planing, followed by the surgical removal of hyperplastic gingiva. After gingivectomy, the patient was scheduled for follow-up visits at one-month intervals. Six months after gingivectomy, vemurafenib dose was reduced to 720 mg twice daily, and cobimetinib was introduced at 60 mg per day. Results: The treatment protocol adopted in this study, combined with cobimetinib administration, stabilized the gingiva condition in this patient. However, due to his overall poor oral hygiene, gingiva remained inflamed and edematous, but was no longer hyperplastic and hyperkeratotic in appearance. Conclusions: This case underscores the importance of recognizing and adequately addressing this complication, as its adverse effect on a patient’s quality of life can potentially compromise treatment protocol adherence.

Unraveling the Genetic Landscape of Langerhans Cell Histiocytosis in Korean Patients: Comprehensive Insights from Mutational Profiles and Clinical Correlations.

This study aimed to conduct a comprehensive genetic analysis of patients with Langerhans cell histiocytosis (LCH), focusing on the frequency of MAPK pathway mutations, detailed mutation profiles of MAPK pathway genes, and their correlation with clinical features and prognosis in Korean LCH patients. We performed targeted next-generation sequencing, capable of capturing exons from 382 cancer-related genes, on genomic DNA extracted from formaldehyde-fixed and paraffin-embedded samples of 45 pathologically confirmed LCH patients. The majority of patients (91.1%) exhibited single-system disease, with bone being the most common location (84.4%). Initial treatments varied, and no patients died during a median follow-up of 6.8 years. Our genetic assays revealed that all patients had MAPK pathway alterations, including BRAF mutations in 51.2%, MAP2K1 mutations in 42.2%, RAF1 mutations in 4.4%, and a KRAS mutation in 2.2%. These mutations were mutually exclusive. Detailed mutation profiles indicated that among the BRAF mutations, there were 18 point mutations and 5 in-frame deletions, while most MAP2K1 mutations were in-frame deletions, with only one missense mutation. We detected previously unreported variations of point mutations in BRAF, MAP2K1, KRAS, and the first instance of a RAF1-KLC1 fusion in LCH. MAP2K1 mutations occurred more frequently in older patients, whereas BRAF V600 mutations were commonly associated with unifocal bone disease. Genetic mutations did not correlate with high-risk features or event-free survival. This study identified mutually exclusive MAPK pathway mutations in every LCH patient through comprehensive genetic analysis, highlighting the importance of inclusive testing in understanding the disease's genetics.

NTRK translocation: from general to specific

The molecular-genetic profile of lung cancer is highly diverse, complicating the formation of a unified patient portrait and necessitating the incorporation of specific genetic testing into diagnosis. There are key mechanisms for the activation of oncogenes, including point mutations, copy number changes (amplifications), and fusions, which are observed in non-small cell lung cancer (NSCLC). Modern molecular-targeted therapy for patients with NSCLC increases the duration of disease control and, in some cases, can transform a once-fatal disease into a chronic condition. Currently, the standard testing panel includes the identification of mutations in the EGFR gene (exons 18–21), ALK translocations, ROS1 translocations, and BRAF V600E mutations. However, less common alterations such as RET and NTRK translocations also occur. The use of next-generation sequencing (NGS) allows for the identification of rarer genetic alterations. NTRK gene fusions are considered oncogenic factors for various solid tumors in both adults and children. The prevalence of NTRK gene alterations varies by tumor type. However, in lung cancer, this type of genetic alteration is rare, with an overall prevalence of less than 3%, and typically the occurrence rate is less than 1%. Currently, three drugs have been included in international clinical guidelines as potential treatment options for NTRK translocations, demonstrating their effectiveness. Several other drugs are at various stages of clinical trials. In this review, we will highlight the existing data for a better understanding of the patient profile with NTRK and present a clinical case.

Updates on hairy cell leukemia (HCL) and HCL-like disorders

Hairy cell proliferations represent very different entities. They include hairy cell leukemia in its classic form (HCL), a well-defined entity, but also the variant form of HCL (LT-V ou HCL-V), whose presentation is far from HCL and whose prognosis is poorer. Other hairy cell proliferations include splenic red pulp lymphoma (SDRPL) and splenic marginal zone lymphomas (SMZL) with circulating villous cells. In this article, we emphasize the novelties concerning the different recent biological aspects of HCL, including the unusual clinical presentations but also the importance for the diagnosis of the detection of the BRAFV600E mutation, a molecular marker of the disease, and the presence of other non-canonical mutations that should be identified because of the contraindication to the use of BRAF inhibitors. Finally, the presence of a non-mutated profile of immunoglobulin heavy chains (IGHV), observed in 20% of cases, is associated with a poor prognosis. We also provide guidance in characterizing other hairy cell proliferations when examining the blood smear. The first-line treatment of HCL has recently changed and immunochemotherapy combining cladribine plus rituximab has become the gold standard. In relapsed or refractory forms, other treatments should be discussed in a multidisciplinary consultation meeting and combine BRAF inhibitors with anti-CD20 antibodies, BTK inhibitors or Bcl-2 inhibitors. The choices should be discussed according to the patient's profile but also their biological profile.

Molecular Mutations and Clinical Behavior in Bethesda III and IV Thyroid Nodules: A Comparative Study.

Background: Thyroid cancer is the most common endocrine malignancy, and accurate diagnosis is crucial for effective management. Fine needle aspiration cytology, guided by the Bethesda System for Reporting Thyroid Cytopathology, categorizes thyroid nodules into six categories, with Bethesda III and IV representing indeterminate diagnoses that pose significant challenges for clinical decision-making. Understanding the molecular profiles of these categories may enhance diagnostic accuracy and guide treatment strategies. Methods: This study retrospectively analyzed data from 217 patients with Bethesda III and IV thyroid nodules who underwent ThyroSeq v3 molecular testing followed by thyroid surgery at McGill University teaching hospitals. The analysis focused on the presence of specific molecular mutations, copy number alterations (CNAs), and gene expression profiles (GEPs) within these nodules. The relationship between these molecular findings and the clinico-pathological features of the patients was also examined. Results: This study identified notable differences in the molecular landscape of Bethesda III and IV thyroid nodules. Bethesda IV nodules exhibited a higher prevalence of CNAs and distinct GEPs compared to Bethesda III nodules. Interestingly, the BRAFV600E mutation was found exclusively in Bethesda III nodules, which correlated with more aggressive malignant behavior. These findings underscore the potential of molecular profiling to differentiate between the clinical behaviors of these indeterminate nodule categories. Conclusions: Molecular profiling, including the assessment of CNAs, GEPs, and specific mutations like BRAFV600E, provides valuable insights into the nature of Bethesda III and IV thyroid nodules. The distinct molecular characteristics observed between these categories suggest that such profiling could be instrumental in improving diagnostic accuracy and tailoring treatment approaches, ultimately enhancing patient outcomes in thyroid cancer management.

High Prevalence of TBC1D12 5'UTR Mutations in Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is a rare but one of the most lethal types of human cancer. Although increasing evidence demonstrated that ATC tumors had a high mutation burden, little is known about the aberrancy of the noncoding genome of ATC except the well-investigated telomerase reverse transcriptase (TERT) promoter mutations. Methods: The mutational statuses of TBC1D12 5' untranslated region (5'UTR), GPR126 intron 6, SDHD and PLEKHS1 promoters, as well as the TERT promoter and BRAFV600E mutations were determined using Sanger sequencing in 28 patients with ATC (19 women and 9 men) with a median (interquartile range) age of 64 (55-71) years, 14 thyroid cancer cell lines and a normal thyroid cell line. The prevalence of TBC1D12 5'UTR mutations in papillary thyroid cancer (PTC) and their association with clinicopathologic characteristics were explored by analyzing The Cancer Genome Atlas thyroid cancer dataset. Results: The noncoding mutations in TERT, SDHD and PLEKHS1 promoters, TBC1D12 5'UTR, and GPR126 intron 6 were collectively found in 82.1% (23/28) of ATC samples. Specifically, TERT promoter mutations were detected in 22 (78.6%) samples; GPR126 intron mutations were detected in 2 (7.1%) samples; and both SDHD and PLEKHS1 promoter mutations were detected in 1 (3.6%) ATC sample. Two hotspot mutations in TBC1D12 5'UTR were observed in 14 of 28 (50%) ATCs, 7 of 492 (1.4%) PTCs, and 1 cell line derived from ATC. TBC1D12 5'UTR mutations were significantly associated with older age at diagnosis (60 vs. 46 for wild type, p = 0.003), pathological T3/T4 stage (85.7% vs. 37.7%, p = 0.010), and advanced tumor stages (85.7% vs. 32.5%, p = 0.006) in PTC. Conclusions: This preliminary study for the first time showed a high prevalence of TBC1D12 5'UTR mutations in ATC and indicated an association between TBC1D12 mutation and aggressive characteristics of PTC, which needs to be confirmed in large cohort studies.