Search Results (4,651)

Background: Renal cell carcinoma accounts for nearly 15,000 deaths annually in the US, and approximately 30–40% of patients present with metastatic disease (mRCC). The advent of immune checkpoint inhibitors (IO) and tyrosine kinase inhibitors (TKI) has revolutionized the treatment paradigm of patients with mRCC. However, the role of cytoreductive nephrectomy (CN) in the IO-TKI era, particularly for rare and understudied histologies such as non-clear-cell RCC, remains poorly understood. Methods: We conducted a retrospective cohort study of patients with metastatic non-clear-cell RCC. Patients were stratified by receipt of CN. Baseline demographic, clinical, histologic, and metastatic site variables were collected. Overall survival was analyzed using Kaplan–Meier methods and compared with the log-rank test. Cox proportional hazards regression was performed to identify independent predictors of survival, including CN, systemic therapy, year of diagnosis, histology, and metastatic sites. Results: Among 2753 patients with metastatic nccRCC, 1654 (60.1%) underwent CN and 1099 (39.9%) did not undergo CN. The 2-year and 5-year OS rates were 35.52% and 19.22% in the CN group versus 18.53% and 7.47% in the non-CN group (p < 0.001). In the doubly robust IPTW-weighted multivariable Cox regression analysis, CN was associated with improved overall survival, corresponding to a 40% lower risk of death compared with no CN (HR 0.60, 95% CI 0.54–0.66; p < 0.001). Additionally, more recent treatment eras were associated with progressively improved overall survival, with patients diagnosed between 2015 and 2017 and 2018 onward demonstrating significantly improved OS compared with those diagnosed between 2004 and 2014. Conclusions: Our study demonstrates that CN was associated with improved OS in patients with non-clear-cell mRCC by reducing the risk of death by 40% after adjusting for baseline characteristics. These findings emphasize the role of CN even in the IO-TKI era for the management of patients with non-clear-cell mRCC. However, these findings should be interpreted in the context of the retrospective study design, potential selection bias, and lack of granular systemic therapy data within the NCDB. Full article

Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease in which TP53 alterations represent major adverse prognostic factors; this study aims to describe the clinical implications of complex TP53 disruption in a rare case context. Molecular and cytogenetic profiling was performed using MLPA for copy number variations and targeted next-generation sequencing for mutation detection, following DNA extraction from peripheral blood and standardized bioinformatic analysis pipelines. The patient exhibited concomitant del(13q14) and del(17p13), alongside two pathogenic TP53 mutations, indicating functional inactivation of p53 and a high-risk genomic profile; despite this, treatment with a Bruton’s tyrosine kinase inhibitor resulted in significant hematological improvement within six months. These findings highlight that adverse TP53 alterations override favorable cytogenetic markers and emphasize the necessity of comprehensive genomic testing to guide prognosis and personalized therapy in CLL. Full article

(1) Background: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease associated with immune dysregulation. The TYRO3, AXL, and MER (TAM) signaling pathway, comprising AXL receptor tyrosine kinase (AXL), MER tyrosine kinase (MERTK), growth arrest-specific 6 (GAS6), and Protein S, is a key regulator of immune homeostasis. This study investigated these receptor–ligand components in patients with AS. (2) Methods: A total of 45 patients with AS and 44 healthy controls were enrolled. Serum GAS6 and Protein S levels were measured by ELISA, and AXL and MERTK expression levels were analyzed by RT-qPCR. Clinical and inflammatory parameters were also evaluated. (3) Results: ESR, CRP, and IL-6 levels were significantly higher, whereas Protein S levels were significantly lower in patients with AS than in controls. No significant differences were observed in GAS6, AXL, or MERTK expression levels, although lower expression trends were detected in patients. Logistic regression analysis identified CRP, IL-6, Protein S, and AXL expression as variables independently associated with AS. ROC analysis demonstrated significant discriminatory performance for AXL expression. (4) Conclusions: Alterations in the TAM signaling pathway, particularly reduced Protein S levels and altered AXL expression, may contribute to immune dysregulation and persistent inflammation in AS. Full article

Litchi chinensis seeds are rich in flavonoids and exhibit potent antioxidant activity. This study constructed a D-galactose-induced oxidative stress model in mice and applied ultra-high performance liquid chromatography–mass spectrometry (UHPLC-MS), network pharmacology, and molecular docking to clarify the antioxidant activity and material basis of ethanolic litchi seed extract. Litchi seed extract was orally given by gavage at 100 and 200 mg/kg in antioxidant tests, whereas a dosage of 500 mg/kg was adopted for the detection of absorbed constituents in plasma. The results showed that the total flavonoid content of litchi seed extract reached 68.37%. The extract could markedly reduce malondialdehyde (MDA) levels and elevate superoxide dismutase (SOD) activity in the serum, liver and kidney tissues of model mice, thereby mitigating oxidative damage. Thirteen prototype compounds absorbed into blood were characterized by UHPLC-MS. Most of these substances were flavonoids, with isorhamnetin, quercetin and naringenin as the major representatives. Core targets including IGF1R, PIK3R1, EGFR, PIK3CA, ERBB2 and proto-oncogene tyrosine-protein kinase Src (SRC) were screened using network pharmacology, among which SRC was identified as the pivotal hub target. Molecular docking results revealed that isorhamnetin, quercetin, naringenin, and diosmetin were able to bind stably to the SRC protein. The present study demonstrated that litchi seed extract exhibits remarkable antioxidant activity, with isorhamnetin, quercetin, naringenin, and diosmetin as the main bioactive antioxidant components. Full article

Background/Objectives: Advanced hormone receptor-positive (HR+), epidermal growth factor 2-negative (HER2−) breast carcinoma (BC) patients receive frontline therapy with cyclin-dependent tyrosine kinase 4/6 inhibitors + endocrine therapy (ET). At progression, the best management includes mutational analysis for ESR-1, allowing second-line therapy with elacestrant. The aim of this study was to evaluate the efficacy and safety of elacestrant in an Italian real-world setting. Methods: A multicenter, observational study with a mixed retrospective and prospective design was conducted in 13 medical oncology units across Italy. The study population included adult patients with HR+/HER2− locally advanced or metastatic breast cancer with an activating ESR1 mutation documented by liquid biopsy and progressing after at least one line of endocrine therapy containing a CDK4/6 inhibitor. Mutational analysis of plasma was performed using next-generation sequencing with a multigene panel that included ESR1, PIK3CA, AKT, and PTEN. The sample size was calculated according to the two-stage Simon design. Toxicity was classified according to CTCAE version 5.0 criteria. Survival analyses were conducted using the Kaplan–Meier method. Results: At the time of analysis, 39 evaluable patients were enrolled, all female and Caucasian, with a median age of 67 years (range 41–89). The efficacy analysis documented an overall ORR of 28% and a disease control rate of 56%. The median duration of response was 6+ months (95% CL: 3.5–10.6 m). Median overall survival was not reached with a median follow-up of 10 months. The toxicity profile was overall favorable: grade ≥2 asthenia was the most frequent adverse event (23%), followed by gastrointestinal toxicity, which was generally mild. No treatment-related toxicity was reported in 64% of patients. Dose reductions were necessary in 15% of cases, while permanent treatment discontinuation due to toxicity occurred in only 4%. Conclusions: The results of this Italian multicenter observational study confirm the efficacy and tolerability of elacestrant in HR+/HER2− metastatic breast cancer with ESR1 mutation, in a real-world context consistent with the data from the pivotal EMERALD study and with real-world data present in the literature. Full article

Congenital Myasthenic Syndrome represents a complex and heterogeneous group of inherited neuromuscular disorders, which result from variants in genes involved in different pathophysiological mechanisms related to the neuromuscular junction. LRP4 (Low-density lipoprotein receptor-related protein 4) represents one of the most important proteins involved in this complex signaling pathway, acting in a complex with agrin and Muscle Skeletal Receptor Tyrosine Kinase (MuSK) proteins. LRP4 became known to most neurologists due to the description of anti-LRP4 antibody-related Myasthenia Gravis. There are, however, different neurological and neuromuscular disorders that result from pathogenic variants in LRP4 gene, especially a rare and potentially treatable Congenital Myasthenic Syndrome. The authors performed a detailed narrative review, including descriptions of the main pathophysiological, clinical, and therapeutic aspects of LRP4-related Congenital Myasthenic Syndromes. Full article

Background: Outcomes in chronic myeloid leukemia (CML) remain heterogeneous despite effective BCR::ABL1 tyrosine kinase inhibitors (TKIs). Somatic mutations in epigenetic regulators, particularly additional sex combs-like 1 (ASXL1), have been implicated in adverse prognosis, but their clinical impact in CML has not been systematically defined. Methods: A systematic review was conducted using CINAHL, EMBASE, MEDLINE Ultimate, and PubMed from inception through August 2025. A total of 1339 records were identified; the eligible studies included adult and pediatric patients with chronic and advanced-phase (accelerated or blast) CML. After duplicate removal and screening, 11 studies met the inclusion criteria; these included adult patients only and were included in a qualitative synthesis and meta-analysis. ASXL1 mutation status was assessed using validated molecular methods. The outcomes included the molecular response, cytogenetic response, survival, and treatment resistance. Random-effects models were used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. Results: Across the included studies, ASXL1 mutations were detected in approximately 15% of patients. At 12 months, patients with ASXL1 mutations had significantly lower odds of achieving a major molecular response (MMR) compared with ASXL1-wildtype patients (OR 0.29; 95% CI 0.16–0.51; p < 0.0001; I² = 30%). No statistically significant difference was observed in the complete cytogenetic response (CCyR) (OR 0.30; 95% CI 0.02–5.31; p = 0.41; I² = 68%). Compared with patients harboring other non-ASXL1 somatic mutations, an ASXL1 mutation was not associated with a significant difference in MMR (OR 0.49; 95% CI 0.23–1.05; p = 0.067; I² = 0%). Conclusions: ASXL1 mutations may be associated with an inferior molecular response to TKI therapy in CML, supporting their role as an adverse prognostic biomarker. These findings highlight the potential value of incorporating myeloid mutation profiling into future CML risk-stratification strategies. Full article

Background: High-grade endometrial stromal sarcoma (HGESS) is a rare and aggressive uterine mesenchymal tumor with a significant potential for recurrence and metastasis. Advances in molecular pathology have identified recurrent gene fusions involving the neurotrophic tyrosine receptor kinase (NTRK) genes, which are crucial for tumorigenesis. The identification of NTRK fusions has significant therapeutic implications, as targeted therapies such as Larotrectinib, a selective tyrosine receptor kinase (TRK) inhibitor, have demonstrated remarkable efficacy in NTRK fusion-positive tumors across various tumor histologies. Case Presentation: This report depicts the case of a 42-year-old woman with HGESS harboring an NTRK fusion diagnosed by histopathology and immunohistochemistry after undergoing a vaginal myomectomy. She subsequently underwent a robotic total hysterectomy, bilateral salpingo-oophorectomy, and bilateral lymph node dissection. Following a four-year disease-free interval, HGESS relapsed. The patient received three cycles of gemcitabine plus docetaxel. Subsequent CT imaging indicated progression of the pelvic mass. Molecular testing identified an NTRK fusion. Accordingly, larotrectinib was initiated in the setting of progressive disease. After three months, imaging demonstrated a significant decrease in the pelvic mass and near-complete radiographic resolution of the pulmonary nodules. The patient remained on larotrectinib, with January 2024 imaging showing no evidence of recurrence. Conclusions: The case presented highlights a personalized approach based on molecular profiling, and the successful use of larotrectinib, a TRK inhibitor, after the identification of an NTRK fusion-positive HGESS, emphasizing the importance of molecular diagnostics and targeted therapy in managing this rare malignancy. Full article

Acute myeloid leukemia (AML) is a biologically heterogeneous malignancy in which therapeutic decision-making is increasingly guided by molecular and immunophenotypic diagnostics. Advances in genomic profiling and risk stratification have enabled the integration of targeted agents into frontline and relapsed/refractory treatment strategies. Among these, midostaurin, venetoclax, and gemtuzumab ozogamicin represent paradigm-shifting therapies whose clinical benefit depends on accurate and timely diagnosis. This review examines the diagnostic frameworks that inform the use of these agents and discusses their incorporation into contemporary AML management. Midostaurin has demonstrated improved outcomes in patients with FLT3-mutated AML when combined with intensive chemotherapy, underscoring the importance of early molecular testing. Venetoclax, a BCL-2 inhibitor, has expanded therapeutic options for older or unfit patients when used with hypomethylating agents or low-dose cytarabine, with emerging evidence linking response to cytogenetic and molecular features. Gemtuzumab ozogamicin, an anti-CD33 antibody–drug conjugate, illustrates the clinical relevance of immunophenotypic assessment and risk-adapted dosing strategies. We highlight current evidence supporting diagnosis-driven therapy selection, practical considerations for clinical implementation, and ongoing challenges, including resistance mechanisms and optimal sequencing. Integrating precise diagnostic tools with targeted therapies represents a critical step toward personalized AML care and improved patient outcomes. Full article

Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms, accounting for approximately 1–3% of all gastrointestinal tumors, with an annual incidence of 1–2 cases per 100,000 population worldwide. They arise from the interstitial cells of Cajal and are most commonly located in the stomach and small intestine. Methods: We report a case of a 39-year-old man admitted with a preliminary diagnosis of an appendiceal inflammatory mass with suspected abscess formation. Results: The patient presented with right iliac fossa pain, fever, signs of pronounced systemic intoxication and laboratory findings consistent with inflammatory syndrome. Abdominal computed tomography revealed a mass in the right iliac region with infiltration of the surrounding adipose tissue, suggestive of an appendiceal infiltrate. Emergency surgical exploration identified a tumor originating from the cecum. Radical resection of the ileocecal region with side-to-side ileo-ascending anastomosis was performed. Histopathological examination confirmed a spindle-cell variant of GIST. The postoperative course was uneventful. Conclusions: This case highlights the diagnostic challenges of atypically localized GISTs, which may clinically and radiologically mimic inflammatory conditions such as appendiceal infiltrate. Conventional imaging modalities may be insufficient for definitive differential diagnosis. Surgical resection remains the cornerstone of treatment, with histopathological and immunohistochemical evaluation establishing the final diagnosis. Early identification and complete tumor excision are essential for optimizing clinical outcomes and long-term prognosis. Adjuvant therapy with tyrosine kinase inhibitors should be considered based on individual recurrence risk. Full article

Retroviruses, after their genomes are integrated into the host genome, replicate through host cell replication. In this hitchhiking phase, their only way of increasing their fitness is to encourage the host cell to have unregulated, rapid cell replication. The v-Src gene in avian sarcoma virus and the v-sis gene in the simian sarcoma virus were originally mined from the host genome by the virus to increase host cell replication rate, with the corresponding host cellular counterparts c-Src (non-receptor tyrosine kinase) and c-sis (platelet-derived growth factor). The resulting out-of-control replication ultimately would lead to cancer. The battle between the host and the retroviruses left many retroviral corpses known as endogenous retroviruses, and the host occasionally domesticates retroviral genes. The syncytins (whose fusogenic function is crucial for the trophoblast fusion and the formation of a syncytium during placenta morphogenesis) and suppressyn (which serves the dual function of regulating syncytialization and host resistance against retroviruses) are examples of successful domestication. Syncytin-1 and suppressyn have each been “domesticated” independently multiple times by different mammalian lineages. Molecular phylogenetics is an essential tool for tracing the evolutionary trajectories of such genetic exchanges between retroviruses and their hosts and for determining the direction of the genetic exchange. Full article

Background/Objectives: The orphan nuclear receptors 4A1 (NR4A1) and NR4A2 are overexpressed in multiple solid tumors, and both receptors exhibit tumor promoter-like activities. A recent study reported that luteolin, a flavonoid that binds NR4A1, decreased the expression of the pro-oncogenic receptor tyrosine kinase MerTK in colon cancer cells. Methods/Results: In this study, we observed that MerTK protein was expressed in human SW480 and HCT116 and mouse CT26 colon cancer cell lines, and was significantly downregulated after treatment with 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) compounds, which are dual NR4A1/NR4A2 ligands. Moreover, knockdown of NR4A1 and NR4A2 also decreased MerTK protein expression and DIM-3,5 ligands, and receptor knockdown also decreased MerTK RNA levels expression. MerTK expression was also downregulated by knockdown of Sp1, Sp3, or Sp4 and by treatment with mithramycin. Subsequent studies using chromatin immunoprecipitation and transfection of a MERTK (promoter)–luciferase construct containing transcriptionally active GC-rich promoter elements indicated that MerTK expression in colon cancer cells was regulated by NR4A/Sp complexes, including NR4A1, NR4A2, Sp1, Sp3, and Sp4 transcription factors. Conclusions: The participation of NR4A1 and NR4A2 in the regulation of MerTK indicates that DIM-3,5 ligands represent a novel class of agents that can be used to inhibit MerTK expression in cancer cells by acting as dual NR4A1 and NR4A2 inverse agonists. Full article

Background: Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity. Methods: Ligand geometries were optimized at the B3LYP/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area. Results: Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation–π contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues. Conclusions: Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors. Full article

Background/Objectives: The prognosis of patients with Philadelphia chromosome-positive (Ph⁺) acute lymphoblastic leukemia (ALL) has improved with the addition of tyrosine kinase inhibitors (TKIs) to conventional chemotherapy. However, there are limited therapeutic options for patients resistant or intolerant to current TKIs. Methods: A comprehensive search was made on PubMed.ncbi.nlm.nih.gov for published studies and ClinicalTrials.gov for registered trials, regarding the first results of and promising strategies with olverembatinib, a novel third-generation TKI, for the treatment of Ph⁺ ALL. Results: First trials involving olverembatinib showed significant anti-leukemic clinical activity both in newly diagnosed and relapsed/refractory patients with Ph⁺ ALL, especially those harboring the T315I mutation. Furthermore, olverembatinib demonstrated a favorable tolerability compared with the other TKIs. Conclusions: This augurs a new era in the standard of care for many patients with unmet clinical needs. However, further studies are warranted to assess olverembatinib’s real value and its cost-effectiveness. Full article

Head and neck squamous cell carcinoma (HNSCC) remains one of the most aggressive and heterogeneous malignancies worldwide, characterized by high rates of locoregional recurrence, metastatic dissemination, and therapeutic resistance. Angiogenesis plays a central role in tumor progression by supporting vascular remodeling, hypoxia adaptation, invasion, immune evasion, and metastatic spread. In HNSCC, angiogenic activation is regulated through complex interactions involving hypoxia-inducible factors, vascular endothelial growth factor (VEGF) signaling, stromal remodeling, inflammatory pathways, and epigenetic mechanisms within the tumor microenvironment. Recent evidence has also highlighted the role of non-coding RNAs, particularly microRNAs, and exosome-mediated communication in modulating angiogenic and immune-related signaling pathways. Although antiangiogenic therapies, including monoclonal antibodies and tyrosine kinase inhibitors, have demonstrated biological activity in HNSCC, their clinical efficacy remains limited by tumor heterogeneity, adaptive resistance mechanisms, toxicity, and the lack of validated predictive biomarkers. Several emerging therapeutic strategies are under preclinical or early clinical investigation in HNSCC, including miRNA-based approaches, nanoparticle-assisted delivery systems, vascular normalization concepts, and combinations with immune checkpoint inhibitors; however, robust clinical evidence for most of these strategies remains limited, and their translation to routine practice requires further validation. This review provides a comprehensive overview of the molecular mechanisms regulating angiogenesis in HNSCC and critically discusses current and emerging pharmacological strategies targeting these pathways. Particular emphasis is placed on VEGF/VEGFR signaling, the integration of miRNA and exosome biology, resistance mechanisms, and translational perspectives for biomarker-guided personalized therapy. The novelty of this review lies in the systematic integration of miRNA- and exosome-mediated angiogenic regulation, therapeutic resistance pathways, and precision medicine strategies into a unified pharmacological framework, addressing gaps not fully covered by prior reviews focused primarily on VEGF-targeted agents. Full article