Search Results (486)

Melanoma is an aggressive form of skin cancer marked by unique genetic alterations that promote tumor growth and resistance to therapy. Advances in targeted therapy have markedly improved clinical outcomes by selectively inhibiting key oncogenic pathways. This review focuses on three clinically relevant agents—vemurafenib, trametinib, and imatinib—analyzing their mechanisms of action, clinical applications, efficacy, and limitations. Vemurafenib, a selective BRAFV600E inhibitor, significantly extends progression-free and overall survival in BRAF-mutant melanoma but is limited by acquired resistance and frequent cutaneous toxicities. Trametinib, a MEK1/2 inhibitor, acts downstream in the MAPK pathway and is typically combined with BRAF inhibitors to enhance efficacy and delay resistance. Imatinib, targeting c-KIT and PDGFR mutations, demonstrates therapeutic benefit primarily in acral and mucosal melanoma subtypes, though with lower response rates than BRAF-directed therapies. Adverse events associated with these drugs are generally manageable with appropriate monitoring. Despite substantial advances, secondary mutations and reactivation of oncogenic signaling remain major challenges. This narrative review integrates data from clinical, preclinical, and real-world studies to update the current understanding of targeted therapies in cutaneous melanoma and highlight ongoing research aimed at overcoming resistance and optimizing personalized treatment strategies. Full article

Objectives: The BRAF^V600E is the most common oncogene in thyroid cancer and is associated with the aggressiveness of papillary thyroid carcinoma (PTC). The aim of this study was to investigate the effectiveness of the arterial enhancement fraction (AEF) and dual-layer detector spectral computed tomography (DLCT) parameters for predicting the BRAF^V600E mutation in PTC. Methods: A total of 237 patients with PTC who underwent DLCT and BRAF^V600E mutation detection (mutant group: n = 187; wild group: n = 50) were retrospectively reviewed. The receiver operating characteristic curves evaluated the effectiveness of the prediction models based on the significantly different variables using logistic regression analysis. The nomogram of the prediction model with the highest AUC in the validation cohort was constructed. Results: The AUCs of the DLCT+ Hashimoto’s thyroiditis (HT) and AEF + DLCT + HT prediction models were 0.901 and 0.896, respectively, in the training cohort and 0.801 and 0.853 in the validation cohort. The calibration curve revealed the good agreement between the prediction results and the actual observations using the AEF + DLCT + HT model. The DCA demonstrated that the model can provide net benefit for all threshold probabilities. Conclusions: As an effective and visually noninvasive prediction tool, the AEF + DLCT + HT-based nomogram presented satisfactory effectiveness in preoperatively predicting the BRAF^V600E mutation in PTC. Full article

Background: BRAF mutations are found in 10% of colon cancers (CCs) and are associated with poor prognosis in metastatic disease. BRAF V600E predicts sensitivity to cetuximab + encorafenib in the metastatic setting. With new trials testing encorafenib-containing regimens for early-stage CC, we sought to characterize the clinical outcomes of early-stage BRAF V600E CC. Methods: We performed a systematic review and meta-analysis. Key inclusion criteria were a diagnosis of stage 2/3 BRAF V600E CC. Co-primary endpoints were overall survival (OS) and recurrence/disease-free survival (DFS). Meta-analysis was performed with a random-effects model incorporating sample size, hazard ratio (HR), and 95% confidence intervals (CIs). Results: A total of 206 studies underwent full-text review. Of these, six randomized controlled trials were included, comprising 6836 and 843 patients with wild-type (WT) and BRAF V600E, respectively. BRAF V600E was associated with inferior OS (HR 1.49, CI 1.21–1.75) and DFS (HR 1.17, CI 1.03–1.33). This finding remains in patients with microsatellite instability—low/stable or proficient mismatch repair (OS: HR 1.66, CI 1.36–2.02, DFS: HR 1.45, CI 1.22–1.72). Conclusions: BRAF V600E is associated with inferior prognoses compared to BRAF WT in early-stage CC. This finding will help optimize trial design for this population. Full article

Objectives: Papillary thyroid carcinoma (PTC) frequently presents with cervical lymph node metastasis (CLNM), yet preoperative tools often encode BRAF V600E as a binary variable, potentially overlooking information contained in mutation abundance. We sought to quantify the dose–response relationship between BRAF V600E abundance and CLNM and to develop an interpretable model for preoperative risk stratification. Methods: We performed a single-center retrospective study of consecutive PTC patients who underwent preoperative BRAF V600E testing and surgery from 2019 to 2023. Patients were randomly split 70/30 into training and test sets. Candidate predictors included clinical and ultrasound features and BRAF V600E abundance. We used multivariable logistic regression and restricted cubic splines (RCS) to assess nonlinearity and compared six machine-learning algorithms (LR, KNN, SVM, XGB, LightGBM, and NN). Model performance was evaluated by F1, AUC, calibration, and decision-curve analyses; SHAP aided interpretation. Ethics approval: SYSKY-2024-169-01. Results: The cohort included 667 patients; CLNM occurred in 391 (58.6%). CLNM cases had higher BRAF abundance (median 23% vs. 17%) and characteristic clinical/sonographic differences. RCS revealed a nonlinear association between abundance and CLNM, with a steep risk rise of up to ~20.7% followed by a plateau. Among six algorithms, XGBoost showed the best validation performance (AUC 0.752; F1 0.73). SHAP indicated that maximum tumor diameter, BRAF abundance, age, and microcalcifications contributed most to predictions. Conclusions: Modeling BRAF V600E as a quantitative abundance—rather than a binary status—improves preoperative CLNM risk assessment in PTC. An interpretable XGBoost model integrating abundance with routine features demonstrates acceptable discrimination and potential clinical utility for individualized surgical planning and counseling. Full article

Only about 5% of colorectal cancers are hereditary, which is due to the low carrier rate of pathogenic gene mutations. The typical pattern of these cases is intergenerational aggregation within families and early onset. But public awareness of early diagnosis and intervention of HCRC is insufficient, resulting in most patients being diagnosed only after developing cancer, thereby missing the optimal window for treatment. This article reviews the latest developments in precision screening, treatment, evaluation and prevention strategies for HCRC, including innovative uses of artificial intelligence (AI) in molecular diagnostics, imaging technology advances, and potential application prospects. Regarding precision screening, tests of genomics, transcriptomics, microbiome, etc., combined with personalised risk stratification, can, respectively, effectively detect pathogenic mutations and “cancer-promoting” intestinal environments in the preclinical stage. AI combined with endoscopic and imaging tools has improved the accuracy of polyp detection and tumor profiling. Liquid biopsy and molecular marker detection provide new non-invasive monitoring solutions. In precision treatment, beyond traditional approaches like surgery and chemotherapy, immunotherapy with checkpoint inhibitors may be considered for HCRC patients with mismatch repair deficiency (dMMR). For patients harboring somatic mutations such as KRAS or BRAF V600E, targeted therapy can be guided by these specific mutations. Regarding precision assessment, AI incorporates microsatellite instability (MSI) detection and imaging diagnostic techniques, crucial for integrating genetic, environmental, and lifestyle data in follow-up. This helps assess the risk of recurrence and adjust the long-term medication regimens, as well as provide effective nutritional support and psychological counselling. In summary, the rapid development of precision medicine is driving the clinical management of HCRC into the era of tailored care, aiming to optimise patient outcomes. Full article

Despite technological progress, glioblastoma (GBM) continues to confer dismal prognoses. Modern neuroimaging methods are assuming an ever greater role in diagnosing and monitoring brain tumors. This review shows current neuroimaging approaches and systemic therapeutic strategies for glioblastoma, with a focus on emerging and innovative treatments. Advances in multiparametric magnetic resonance imaging—MRI (diffusion, perfusion, and spectroscopy) and novel positron emission tomography (PET) tracers, complemented by radiomics and artificial intelligence (AI), now refine tumor delineation, differentiate progression from treatment effects, and may help predict treatment responses. Maximal safe resection followed by chemoradiotherapy with temozolomide remains the standard, with the greatest benefit seen in O⁶-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Bevacizumab and other targeted modalities offer mainly progression-free, not overall survival, gains. Immune checkpoint inhibitors (e.g., nivolumab) have not improved survival in unselected GBM, while early multi-antigen CAR-T (chimeric antigen receptor T-cell) strategies show preliminary bioactivity without established durability. While actionable alterations (NTRK fusions and BRAF V600E) justify selective targeted therapy trials, their definitive benefit in classical GBM is unproven. Future priorities include harmonized imaging molecular integration, AI-driven prognostic modeling, novel PET tracers, and strategies to breach or transiently open the blood–brain barrier to enhance drug delivery. Convergence of these domains may convert diagnostic precision into improved patient outcomes. Full article

Mitochondria play a central role in energy metabolism, redox homeostasis, and signal transduction in the thyroid cells. Increasing evidence indicates that mitochondrial DNA (mtDNA) mutations, copy number variations, and haplogroup-specific polymorphisms are closely associated with metabolic reprogramming and malignant progression of thyroid cancer. This review summarizes recent advances in the understanding of the impact of mitochondrial genome instability and metabolic plasticity on thyroid tumorigenesis. We discuss how mtDNA alterations disrupt oxidative phosphorylation (OXPHOS), trigger adaptive metabolic rewiring, and interact with key oncogenic pathways, such as HIF-1α, BRAFV600E mutations, and TSHR signaling in thyroid cancer. We also highlight the emerging diagnostic and therapeutic potential of mtDNA in thyroid cancer and outline current challenges and future research directions. Gaining deeper insights into the mitochondria–metabolism axis may provide novel biomarkers and metabolic intervention strategies for precision medicine in thyroid oncology. Full article

Background: Bethesda III and IV thyroid nodules, which fall under the category of indeterminate cytology, pose challenges in clinical decision-making due to their ambiguous risk of malignancy. Molecular testing has been increasingly employed to aid risk stratification and optimize the extent of surgical intervention. Methods: A retrospective review of 410 patients with Bethesda III and IV thyroid nodules who underwent thyroid surgery at McGill University teaching hospitals between January 2016 and April 2022. Patients were grouped based on whether or not they underwent preoperative molecular testing. Data were collected on demographic variables, histopathologic diagnosis, mutation profiles, and surgical outcomes. The primary outcome was to assess for concordance between surgical intervention and final pathology in both groups, with a focus on identifying optimal versus suboptimal management. Optimal management is defined as surgery appropriate to the aggressiveness of disease, meaning a hemi-thyroidectomy for a non-aggressive malignancy, total thyroidectomy for an aggressive malignancy, and no surgery for a benign nodule. Furthermore, suboptimal management includes unnecessary surgery or incorrect surgery for the level of aggressivity of the nodule. Results: Among the 410 patients, 203 underwent molecular testing, while 207 did not. Of those who underwent molecular testing, 117 had Bethesda III nodules and 86 had Bethesda IV nodules. In the non-tested group, 129 and 78 patients had Bethesda III and IV nodules, respectively. Optimal surgical intervention was achieved in 67.5% of patients who underwent molecular testing, compared with 25.1% in those who did not (p < 0.001). Subgroup analysis revealed that 61.5% of Bethesda III nodules with molecular testing received optimal care versus 21.0% of those without testing. In the Bethesda IV cohort, optimal surgery was achieved in 75.6% with testing versus 32.1% without. Among the suboptimally managed patients, 70.1% (155/221) were from the group that did not undergo molecular testing. In addition, molecular testing identified aggressive mutations such as BRAF V600E and TERT promoter mutations more frequently in Bethesda III nodules, while RAS-like mutations, associated with indolent behavior, predominated in Bethesda IV nodules. Conclusions: In this study, molecular testing significantly improved risk stratification and the likelihood of optimal surgical management in patients with Bethesda III and IV thyroid nodules. Incorporating molecular diagnostics into the standard preoperative workflow may enhance patient care, reduce unnecessary surgeries, and optimize the extent of surgery. Future studies should evaluate the cost-effectiveness and broader implementation of molecular testing in diverse healthcare settings. Full article

Immunotherapy and RAF-targeted therapy have become standard treatments for melanoma, significantly improving outcomes compared to earlier therapies. When resistance to initial treatment develops, the older chemotherapy drug Dacarbazine is used. However, resistance to both therapies has emerged, promoting ongoing research to further enhance survival rates. Among various theories, autophagy is believed to play a critical role in acquired drug resistance, as increased autophagy has been observed in resistance to multiple anticancer agents. In this study, Dabrafenib was administered to melanoma cells with an RAF mutation, while Dacarbazine was given to cells with an Raf wild type. Both cell lines showed increased autophagy and FAO following treatment with the anticancer drugs. When FAO was blocked during drug treatment, melanoma cells became more susceptible to cell death. In xenograft models, B16F10 melanoma (Raf wild type) demonstrated regrowth due to acquired resistance after two weeks of Dacarbazine treatment. Conversely, a combination of Dacarbazine and the FAO inhibitors KN510 and KN713 (a combination of KN510 and KN713:KN510713) caused near-complete remission without regrowth. A375 melanoma (BRAF^V600E) developed resistance after four weeks of Dabrafenib treatment, yet the combination of Dabrafenib and KN510713 resulted in near-complete remission with no signs of regrowth. Based on these findings, combining FAO inhibitors with first-line therapies may be a promising approach for managing melanoma, regardless of RAF mutation status. Full article

Aggressive thyroid carcinomas—anaplastic (ATC) and poorly differentiated (PDTC)—are rare but highly lethal malignant entities. Their immunophenotypical characterization is still incomplete, and no standardized diagnostic algorithms have been used. Our study retrospectively analyzes 40 thyroidectomy cases as follows: 12 ATC and 28 PDTC from 2014 to 2024 by evaluating clinical data, histopathological aspects, molecular analysis for presence of BRAFV600E and TERTC228/250T mutations, as well as immunohistochemical expression of BRAF_V600E, total BRAF, K-RAS, TERT, PAX-8, TTF-1, P53, and Ki-67. BRAF_V600E was present in 70% of cases, with higher prevalence in ATC. Total BRAF correlated positively with K-RAS and TERT and negatively with BRAF_V600E. TERT abnormal expression was highly prevalent in over 90% of cases, while loss of TTF-1 and PAX-8 is associated with anaplastic transformation. Ki-67 proliferative index had significantly higher values in ATC, thus supporting its role as a marker for aggressiveness. On univariate analysis, higher Ki-67 indices and lymph node invasion are independent predictor factors for the presence of metastases. However, on multivariate analysis, they both lose significance. Upon multivariate analysis, loss of TTF-1 and tumor necrosis were significant predictors for anaplastic histotype. Specific BRAF_V600E immunohistochemistry may be a good screening tool for the BRAF_V600E mutation. Molecularly, there is a relatively frequent association of the BRAFV600E mutation and TERTC228, mainly in the PDTC subgroup. Patterns of marker expression suggest that BRAF or RAF activation with subsequent loss of TTF-1 or PAX-8, TERT upregulation, and TP53 alteration are frequent occurrences in aggressive thyroid carcinomas. The association between TTF-1 loss and anaplastic transformation, presence of necrosis alongside BRAF_V600E, underlines their diagnostic potential in subclassifying aggressive thyroid carcinomas. Full article

Background: Differentiated thyroid cancer (DTC) is commonly treated with radioactive iodine (RAI), but resistance to RAI remains a significant clinical challenge. The molecular mechanisms driving dedifferentiation and RAI refractoriness, particularly in BRAF^V600E-mutated tumors, are not fully understood. Methods: RNA sequencing was conducted on BRAF^V600E-mutated DTC and RAIR-DTC tissue samples to identify differentially expressed genes. Gadd45B was identified as significantly downregulated in RAIR-DTC. Functional studies including overexpression and knockdown experiments were performed in thyroid cancer cell lines and xenograft models. Downstream targets, including MAP3K4 and MYCBP, were evaluated through co-immunoprecipitation, luciferase assays, and Western blot. The therapeutic efficacy of recombinant Gadd45B protein in combination with BRAF^V600E and TERT inhibitors was assessed in patient-derived xenograft (PDX) models. Results: Gadd45B overexpression suppressed MAPK pathway activity by interacting with MAP3K4 and downregulated c-MYC stability through competition with MYCBP. These interactions enhanced the expression of iodine-metabolism genes (NIS, TPO, Tg), increased RAI uptake, and reversed tumor dedifferentiation. In vivo, Gadd45B restoration reduced tumor burden and improved RAI uptake. Combined treatment with Gadd45B protein, PLX4720, and BIBR1532 produced synergistic therapeutic effects in PDX models. Conclusions: Gadd45B plays a pivotal role in regulating the differentiation status and RAI sensitivity of BRAF^V600E-mutated thyroid cancer. These findings identify Gadd45B as a promising therapeutic target for restoring RAI responsiveness in RAIR-DTC patients. Full article

Precision oncology is witnessing an increasing number of molecular targets fueled by the continuous improvement of cancer genomics and drug development. Tumor genomic profiling is nowadays (August 2025) part of routine cancer patient care, guiding therapeutic decisions day by day. Nevertheless, implementing and distilling the increasing number of potential gene targets and possible precision drugs into therapeutically relevant actions is a challenge. The availability of prescreening programs for clinical trials has expanded the description of the genomic landscape of gastrointestinal tumors. The selection of the genomic test to use in each clinical situation, the correct interpretation of the results, and ensuring clinically meaningful implications in the context of diverse geographical drug accessibility, economic cost, and access to clinical trials are daily challenges of personalized medicine. In this context, well-established negative predictive biomarkers, such as extended RAS extended mutations for anti-EGFR therapy in colorectal cancer, and positive predictive biomarkers, such as MSI status, BRAF p.V600E hotspot mutation, ERBB2 amplification, or even NTRK1, NTRK2, NTRK3, RET, and NRG1 fusions across gastrointestinal cancers, are mandatory to provide tailored clinical care, improve patient selection for treatment and clinical trials, maximize therapeutic benefit, and minimize unnecessary toxicity. In this review, we provide an updated overview of actionable genomic alterations in GI cancers and discuss their implications for clinical decision making. Full article

Background: Blood-based comprehensive genomic profiling (CGP), a form of liquid biopsy, is often used for biliary tract cancer (BTC) when tissue-based CGP (tissue CGP) is unavailable, despite lower detection rates. This study explored factors linked to detecting actionable genomic alterations to optimize its use. Methods: We retrospectively analyzed BTC cases in Japan’s C-CAT (June 2019–January 2025), restricting panel comparisons to FoundationOne^® CDx (F1; n = 5019) and FoundationOne^® Liquid CDx (F1L; n = 1550). Missing covariates were handled by multiple imputations (m = 20). Between-panel balance used 1:1 propensity-score matching (caliper 0.2). Outcomes were modeled with logistic regression. Targets included MSI-H, TMB-H, FGFR2/RET/NTRK fusions, BRAF V600E, KRAS G12C, IDH1 mutations, and ERBB2 amplification. An exploratory analysis stratified results by the number of prespecified enrichment factors (0–4). Liquid biopsy was performed using plasma-based comprehensive genomic profiling assays (FoundationOne^® Liquid). Results: Missingness was low; after matching (n = 1549 per group) covariates were well balanced (all|SMD|≤0.05). Detection of any actionable alteration was lower with F1L than F1 (16.8% vs. 24.8%; OR 0.61, 95% CI 0.49–0.75; p < 0.001). F1L also had lower TMB-H (OR 0.62, 0.43–0.90; p = 0.01) and ERBB2 amplification (OR 0.42, 0.31–0.57; p < 0.001), with no significant differences for MSI-H, IDH1, KRAS G12C, or BRAF V600E. Within F1L, non-perihilar location (OR 2.05), liver (1.90), lymph-node (1.41), and lung metastases (1.52) predicted detection of actionable genomic alterations. F1L detection increased from 5.8% (zero factors) to 32.8% (four factors), approximating tissue at three factors. Conclusions: The utility of liquid biopsy can be maximized by carefully selecting samples on the basis of conditions that increase the detection rate. Full article

We hereby present a case of a 51-year-old woman with a pigmented nodule in the right axillary region. Histopathological examination revealed features consistent with an intradermal nevus. Notably, adjacent to the nevus, intralymphatic protrusion and lymphatic invasion were observed, comprising cells with morphological and immunohistochemical characteristics consistent with nevus cells. Next-generation sequencing revealed the BRAF V600E mutation. To date, 26 similar cases involving intralymphatic nevus cell protrusion and lymphatic invasion have been reported in the literature. Although this finding is rare and may pose a diagnostic challenge for pathologists, it should not be interpreted as indicative of malignancy. Rather, it must be assessed in the context of the lesion’s overall histological architecture. Full article

Differentiated thyroid cancer (DTC) is the most prevalent endocrine malignancy in the world. Accurate diagnosis and prognostication are essential for optimizing its treatment and improving patient outcomes. This narrative review explores the diagnostic and prognostic histopathological, immunohistochemical, molecular, and genetic biomarkers in DTC, emphasizing their role in risk stratification and personalized management. Histopathological biomarkers, including tumor size, extrathyroidal extension, lymphovascular invasion, and aggressive subtypes (e.g., tall cell, hobnail, and insular variants), correlate with poor prognosis. Additionally, genetic alterations such as BRAF:p.V600E, RAS mutations, TERT promoter mutations, and RET/PTC rearrangements provide molecular insights into tumor progression and therapeutic response. Some of these molecular/genetic mutations have surrogate proteins that are feasible for immunohistochemical analysis, providing faster and cost-effective alternatives. Advances in next-generation sequencing have further refined risk stratification, facilitating precision medicine approaches. Future research should focus on validating novel biomarkers and developing targeted therapies to improve patient outcomes. Full article