Search Results (740)

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

Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with low-grade serous and mucinous subtypes frequently driven by KRAS mutations. These mutations activate downstream MAPK and PI3K/AKT signaling pathways, contributing to tumor progression and resistance to therapy. Although the MEK inhibitor trametinib is used to target these pathways, its efficacy is limited in KRAS-mutant OCa due to compensatory activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor, in Ras/Raf-driven OCa models. EC359 significantly reduced cell viability, clonogenic survival, and induced cell death via ferroptosis in vitro. Mechanistic studies revealed that EC359 suppressed trametinib-induced activation of LIFR downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and MYC target genes while upregulating apoptosis-related genes. In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth in xenograft and PDX models without inducing toxicity. Our studies identify LIFR signaling as a critical vulnerability in Ras/Raf-mutant and low grade serous OCa. Further, it provides strong preclinical rationale for EC359 and trametinib combination therapy as a new therapeutic strategy for treating Ras/Raf-driven OCa and low-grade serous OCa. 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

Blocking the MAPK pathway is a strategy to stop cancer cells proliferation. Despite all the successes, the acquisition of drug resistance by cells, as well as the mutational status of the downstream protein KRAS, reduces the tumor response to therapy. Ribonuclease binase from Bacillus pumilus is among the agents that block this pathway through direct interaction with EGFR and RAS. The present study is aimed at the design, optimization, and characterization of a novel complex based on antitumor binase immobilized on microgranular clinoptilolite-containing rock to ensure its prolonged release in the gastrointestinal tract. A set of modern methods including transmission electron microscopy, scanning electron microscopy, and computed tomography was used to characterize the granularity, porosity and elemental composition of the carrier. The size of binase particles, measured by atomic force microscopy at 7 nm, allows enzyme penetration into meso- and macropores of the carrier. Calorimetric results confirm that binase is stable at high temperatures, even exceeding those in the body, and retains catalytic activity in the model fluids of the gastrointestinal tract. The parameters for processing a natural clinoptilolite-containing rock and the conditions for binase sorption were selected. The gradual release of the enzyme from the carrier lasts over 20 h, which provides cytotoxicity towards human adenocarcinoma cells during movement through the gastrointestinal tract. Thus, for the first time a promising long-acting complex with antitumor and detoxifying properties was successfully created. Full article

Low-grade-serous ovarian carcinomas (LGSOC) are rare tumors characterized by a high recurrence rate and limited treatment options. Most LGSOC are estrogen receptor (ER)-positive and demonstrate alterations in the RAS/MAPK pathway. Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors. Fulvestrant is an ER antagonist/degrader. We assessed the preclinical efficacy of fulvestrant, avutometinib + VS-4718 (FAKi), and the triple combination in a chemotherapy/aromatase inhibitor-resistant LGSOC patient-derived tumor xenograft (PDX) model. Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250). The animals were treated with either saline/control, fulvestrant, avutometinib/FAKi, or the triple combination of avutometinib/FAKi/fulvestrant. Avutometinib and FAKi were given five-days on and two-days off through oral gavage. Fulvestrant was administered subcutaneously weekly. Mechanistic studies were performed ex vivo using Western blot assays. Animals treated with the triple combination demonstrated stronger tumor growth inhibition compared to all the other experimental groups including control/saline (p < 0.001), single-agent fulvestrant (p = 0.04 from day eight and onwards), and avutometinib/FAKi (p = 0.02 from day 18). Median survival for mice treated with saline/control was 29 days while mice in all other experimental groups were alive at day 60 (p < 0.0001). Treatment was well tolerated across all experimental treatments. By Western blot, exposure of OVA(K)250 to the triple combination demonstrated a decrease in phosphorylated MEK (p-MEK) and p-ERK levels. The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC. Full article

Background/Objectives: Methotrexate (MTX) is currently the most widely used treatment for Rheumatoid Arthritis (RA) due to its demonstrated efficacy and well-known safety profile. However, the effectiveness and toxicity of MTX can vary among patients, partly due to genetic factors. Therefore, this study aimed to investigate the associations between the polymorphisms in the ABC subfamily G member 2 (ABCG2) gene and MTX effectiveness/toxicity in Saudi Arabia RA patients. Methods: The study is a retrospective, multicenter, case–control study that uses Sanger sequencing techniques for genotyping. Results: More than half of the patients (55.56%) were poor responders, with a slightly higher mean age. However, there was no significant difference between the two groups, not only in terms of age but also in other demographics and clinical factors. Regarding the rs2231137 polymorphism, the CC, CT, and TT genotype frequency were 91%, 7%, and 2%, respectively. The mutated variant (TT) was only observed in the positive rheumatoid factor group. Notably, none of these genotypes displayed any significant correlation with demographic characteristics, clinical features, or MTX efficacy/toxicity. Conclusions: This study is the first pharmacogenetic study of rs2231137 polymorphism in RA patients utilizing linear regression, revealing that rs2231137 polymorphism is not a predictor of either MTX efficacy or toxicity in RA patients. Therefore, more research is needed. Full article

Background: Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ~40% of cases. The efficacy of recently approved, mutant-specific KRAS inhibitors is limited by mutational status as well as intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as ADT-007, offer broader therapeutic potential by targeting multiple RAS isoforms. Here, we evaluate ADT-007 in 3D bioprinted ex vivo slice tissue (BEST) generated from KRAS-mutant and RAS wild-type (WT) CRC cell lines. Methods: Potency and selectivity of ADT-007 were benchmarked against bortezomib (proteasome inhibitor) and YM155 (survivin inhibitor) using high-content imaging and ATP-based luminescence assays. Apoptosis induction was assessed with Annexin V/propidium iodide and flow cytometry. Results: ADT-007 exhibited high potency and selectivity in KRAS-mutant BEST, reducing tumor burdens >30% at nanomolar concentrations, and demonstrated superior selectivity with minimal cytotoxicity in WT RAS BEST. Annexin V staining confirmed selective induction of apoptosis in KRAS-mutant cells. Conclusions: The selective potency and specificity of ADT-007 warrant further investigation of pan-RAS inhibitors for treating RAS-driven cancers. This study also underscores the translational utility of 3D BEST models for preclinical drug response assessment. Further validation in patient-derived BEST is necessary to evaluate the potential of ADT-007 in clinical settings. Full article

Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated genes in human cancer, including non-small cell lung carcinoma (NSCLC). Sustained expression of KRAS is required for survival in KRAS-dependent tumors. KRAS tumors can become independent upon bypassing this addiction. Tissue inhibitor of metalloproteinase-1 (TIMP-1) exhibits a range of novel functions in addition to its initially recognized activity as a physiological inhibitor of matrix metalloproteinases (MMPs). It has repeatedly been associated with cancer progression and poor prognosis in multiple cancers. This study investigates the relationship between TIMP-1 modulation and KRAS dependency in NSCLC. We found an inverse expression of KRAS and TIMP-1 in NSCLC lines. Modulating TIMP-1 levels altered KRAS expression and affected KRAS-dependency features. Overexpression of TIMP-1 decreases the KRAS levels in dependent cells and knocking-down TIMP-1 increases KRAS levels in independent cells with concomitant change in RAS-GTP levels. TIMP-1 modulation influenced apoptosis upon KRAS ablation, with TIMP-1 overexpression decreasing apoptosis in dependent cells and TIMP-1 knockdown increasing it in independent cells. Bioinformatic analysis depicted variant-specific perturbations between KRAS and TIMP-1 expression. Furthermore, EMT marker expression was altered upon TIMP-1 modulation, suggesting the role of TIMP-1 in EMT induction in KRAS-independent cells. These findings emphasize the intricate relationship between TIMP-1 and KRAS in NSCLC, shedding light on potential mechanisms underlying tumor behavior and response to therapy. Full article

Rheumatoid arthritis (RA) and osteoarthritis (OA) are frequently occurring multifactorial diseases affecting joints. OA and RA may share not only tissue locations but also some molecular mechanisms. We compared different pathologies: anti-cyclic citrullinated peptide antibody (ACCP)-positive RA—the classical ‘antigen-driven’ pathology, starting in synovia with no signs of inflammatory process; ACCP-negative RA, starting with synovial inflammation triggered by nonspecific factors, which becomes a chronic process due to inherited innate immune peculiarities; and OA, starting with inadequate chondrocyte functioning and cartilage degradation with inflammation as a driving force. Notable coincidences in RA and OA development were revealed: shared mutations of 29 genes encoding molecules involved in immune-inflammatory processes and in ECM production; unidirectional association of OA and ACCP-negative RA with non-genetic triggers; and overactivation of signaling pathways with the same consequences for RA and OA. Innate and adaptive immune responses were involved in OA development. Similar to that observed in RA, lymphoid nodular aggregates were revealed in 30% of OA synovia. Myeloid, and especially pauci-immune and fibroid synovial pathotypes, are possible in OA. Indistinguishable from that in RA, pannuses were found in OA articular tissues. Thus, these coincidences may be evidence of evolution of some OA variants in RA. Full article

Histiocytic sarcoma (HS) is an ultra-rare hematopoietic neoplasm that frequently occurs in extranodal sites of adults. Clinically, HS demonstrates aggressive behavior and can arise de novo or in association with other hematological neoplasms. The median overall survival from the time of diagnosis is approximately six months. Histologically, HS is composed of sheets of large, round to oval cells with abundant eosinophilic cytoplasm and can be confused with a variety of benign and malignant conditions. Immunohistochemistry plays a crucial role in the diagnosis of HS, showing expression of CD163, CD68, lysozyme, and PU.1 and negative staining with follicular dendritic cell markers and myeloid cell markers. Recent studies have demonstrated a high rate of PD-L1 expression, suggesting a potential therapeutic target. Several genomic alterations have been identified in HS, including mutations involving the RAS/MAPK and PI3K/AKT/mTOR signaling pathways, CDKN2A mutations/deletions, and TP53 mutations. There is no standard protocol for the management of HS. Surgical resection with or without radiotherapy is the most common first-line treatment for unifocal/localized disease. The systemic treatment options for multifocal/disseminated disease are very limited. This review provides an overview of the current knowledge on the clinicoradiological features, histopathology, pathogenesis, and management of HS. Full article

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with cure rates exceeding 80% due to advancements in treatment protocols and supportive care. However, in children with Down syndrome (DS), ALL (DS-ALL) presents distinct genomic and clinical challenges. These include mutations in Janus kinase 2 (JAK2), neuroblastoma RAS viral oncogene homolog (NRAS), and E1A-binding protein p300 (EP300), as well as cytokine receptor-like factor 2 (CRLF2) rearrangements—such as P2RY8-CRLF2 fusion—and intrachromosomal amplification of chromosome 21 (iAMP21). These aberrations are associated with poor prognosis and increased risk of relapse. The objective of this study was to present a unique DS-ALL case with five concurrent high-risk genomic lesions and to contextualize its management in light of existing literature, emphasizing minimal residual disease (MRD)-guided therapy and supportive care. Case Report and Results: We present the case of a three-year-old boy with DS and B-cell ALL (B-ALL), in whom multiple high-risk genomic features co-occurred. Despite these adverse prognostic markers, the patient achieved complete remission following an intensive high-dose induction protocol. We also discuss therapeutic strategies that aim at balancing individualized treatment approaches with optimized supportive care to reduce toxicity and minimize relapse risk. Conclusions: This case underlines the importance of comprehensive molecular diagnostics, serial MRD monitoring, and personalized multidisciplinary care in DS-ALL. 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

Thyroid cancer (TC), the most prevalent endocrine neoplasia, has shown a progressive incidence, highlighting the need for new therapeutic approaches—especially for radioiodine-refractory cases, often associated with mutations in genes such as BRAF, RAS, and TP53. This review proposes a mechanistic model that highlights two interrelated characteristics of the tumor microenvironment (TME): redox imbalance and chronic inflammation, key elements in tumor progression and treatment resistance. Thus, natural phenolic compounds, such as curcumin, quercetin, resveratrol, and epigallocatechin gallate (EGCG), function not as simple antioxidants but as pleiotropic agents that reprogram the TME. A central mechanism of action for these compounds is the modulation of the purinergic axis (CD39/CD73/adenosine), a critical immune-metabolic checkpoint. By selectively inducing lethal oxidative stress in tumor cells, suppressing pro-survival inflammatory pathways—such as that mediated by nuclear factor kappa B (NF-κB)—and destabilizing the immunosuppressive shield conferred by adenosine, certain phytochemicals demonstrate the potential to restore immune surveillance and promote tumor apoptosis. In this context, a critical analysis of the evidence related to targeting purinergic signals becomes essential, since pharmacological reinforcement of this pathway, especially when combined with immunotherapies based on immune checkpoint blockade, emerges as a promising strategy for overcoming therapeutic resistance. Full article

Background/Objectives: RAS mutations are among the most common genetic alterations in thyroid cancer and are generally associated with less aggressive behavior. However, when co-occurring with TERT (telomerase reverse transcriptase) promoter mutations, known markers of poor prognosis, tumors exhibit markedly more aggressive features. The allele frequency (AF) of RAS may serve as a potential indicator of clonal dominance and the likelihood of additional high-risk mutations, such as TERT mutation. This study aims to assess whether a high RAS AF correlates with the presence of coexisting TERT promoter mutations and other molecular alterations. Methods: A retrospective chart review was performed on 111 patients with thyroid nodules harboring RAS mutations, either alone or in combination with TERT promoter mutations. All patients underwent molecular testing with ThyroSeq v3 and subsequent thyroidectomy at McGill University teaching hospitals. RAS AF was analyzed in relation to TERT mutation status, nodule size, and other molecular alterations including copy number alterations (CNA) and gene expression profiles (GEP). Results: The mean RAS AF was significantly higher in nodules with both RAS and TERT mutations (38.1%) compared to those with RAS mutations alone (22.1%) (p = 0.002). Nodules with coexisting TERT mutations were also significantly larger (mean size: 3.7 cm vs. 2.4 cm; p = 0.005). Malignant nodules, regardless of TERT status, showed a trend toward higher RAS AF than benign nodules (23.0% vs. 16.3%; p = 0.052). Higher RAS AF was also associated with the presence of CNA and/or GEP positivity. Notably, GEP was positive in 100% of nodules with both RAS and TERT mutations, compared to 37.5% in RAS-only nodules (p = 0.002). Conclusions: A high RAS AF increases the likelihood of a TERT promoter mutation and other genetic alterations, highlighting the importance of RAS AF in optimizing patient care and management. Full article

Background: Liver resection remains the gold standard treatment for colorectal cancer (CRC) liver metastases, while stereotactic body radiotherapy (SBRT) offers an alternative for patients with unresectable metastases. However, the precise indications for SBRT, optimal radiation doses, and treatment regimens have yet to be definitively established. Methods: A total of 91 patients with 152 lesions underwent SBRT, receiving a total dose ranging from 40 to 60 Gy delivered in 4–5 fractions per lesion, with a median dose of 50 Gy. Results: The three-year local control (LC) and overall survival (OS) rates were 62.6% and 45.1%, respectively. No cases of Grade ≥ 3 toxicity were observed. Factors negatively affecting LC included metastasis diameter ≥ 2.7 cm and number of metastases ≥ 3, with hazard ratios (HR) of 2.73 and 2.24, respectively. A biologically effective dose (BED) of ≥137.7 Gy was associated with a significant improvement in local control (LC) (HR 0.25), a finding that was also confirmed by the inverse probability of treatment weighting (IPTW) analysis. Significant predictors for poorer OS included RAS gene mutations, metastasis diameter ≥ 2.6 cm, and synchronous metastases, with HRs of 2.27, 2.03, and 2.11, respectively. Landmark analysis demonstrated that local recurrence within 12 months after SBRT significantly reduced OS (HR 2.68). Conclusions: SBRT is a safe and effective method for achieving local control of CRC liver oligometastases. Further research is warranted to optimize treatment protocols and refine patient selection criteria. Full article