The tropomyosin receptor kinase (TRK) family regulates key oncogenic signaling pathways, and genetic alterations in NTRK genes are implicated in a broad spectrum of malignancies. Although TRK inhibitors such as entrectinib effectively demonstrate robust clinical efficacy in NTRK fusion-positive tumors, their long-term therapeutic utility is frequently limited by the emergence of acquired resistance mutations, including the G595R substitution.

In this study, molecular dynamics simulations and MM-GBSA binding free energy calculations were employed to investigate the mechanistic impact of the G595R mutation on entrectinib binding. Our analyses reveal that substitution of glycine with the sterically bulky, positively charged arginine residue at position 595 induces severe steric clash within the ATP-binding pocket, disrupts conserved hydrophobic packing interactions, and displaces the N-methylpiperazinyl moiety of entrectinib. Moreover, the G595R mutant exhibits elevated root mean square deviation of the bound ligand and enhanced conformational flexibility in the glycine-rich loop (G-loop). Quantitative MM-GBSA decomposition identifies a substantial increase in binding free energy, attributable predominantly to attenuated van der Waals contributions and loss of key hydrogen bonds with Tyr591, Met592, His594, and Leu657. Domain cross-correlation analysis demonstrates weakened dynamic coupling between the G-loop and the hinge region, critical for allosteric control of kinase activity, thereby compromising the structural integrity required for high-affinity inhibitor binding. These findings provide a mechanistic explanation for entrectinib resistance at atomic resolution and illustrate how a single-point mutation can trigger long-range perturbations in protein dynamics and interdomain communication.

Splanchnic vein thrombosis (SVT) is an uncommon but clinically significant complication of myeloproliferative neoplasms (MPNs), contributing to morbidity and management complexity. Evidence regarding prognostic factors and optimal anticoagulation strategies remains limited. We aimed to evaluate the clinical characteristics, risk factors, treatment strategies, and survival outcomes in patients with SVT associated with MPNs. In this multicenter retrospective cohort study, 289 adult patients with SVT associated with MPNs were analyzed. The median age at SVT diagnosis was 49 years, with 74% of patients < 60 years, indicating a predominance in younger individuals. Portal vein thrombosis was the most common presentation (87.5%). Over a median follow-up of 82 months, survival was significantly better in patients < 60 years (p < 0.01). In multivariable analysis, age ≥ 60 years and myelofibrosis were independent predictors of inferior survival (both p < 0.01), whereas early recanalization was not associated with survival. Bleeding complications occurred in 27% of anticoagulated patients, with no fatal events. Direct oral anticoagulants and vitamin K antagonists showed comparable bleeding profiles, although major bleeding was more frequent with vitamin K antagonists. Despite early recanalization, most patients continued long-term anticoagulation. In conclusion, MPN-associated SVT predominantly affects younger patients, underscoring an age-independent prothrombotic risk. Survival is primarily driven by age and disease subtype rather than thrombotic characteristics. Given the persistent thrombotic risk despite bleeding complications, long-term anticoagulation remains central to management and requires individualized decision-making. Prospective studies are needed to optimize treatment strategies.

Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator implicated in tumor progression; however, its expression pattern and subcellular localization across different stages of endometrial carcinogenesis remain incompletely characterized. This study evaluated EZH2 expression in two biologically distinct endometrial carcinoma cell lines (Ishikawa and MFE-319) and in archived human endometrial tissues representing proliferative and secretory endometrium, hyperplasia, and Type I and Type II endometrial carcinomas. Histopathological evaluation was performed using hematoxylin and eosin staining. EZH2 expression was assessed by immunocytochemistry and Western blot analysis in the cell lines and by immunohistochemistry in tissue specimens, while apoptosis was evaluated by TUNEL assay in tissue samples. MFE-319 cells demonstrated significantly higher EZH2 expression than Ishikawa cells (H-score: 352.9 ± 78.9 vs. 137.6 ± 31.5, p < 0.0001), and Western blot analysis confirmed the same direction of change. Among tissue specimens, the highest EZH2 immunoreactivity was observed in Type II endometrial carcinoma (366.0 ± 63.7), with significantly higher expression than proliferative endometrium (231.5 ± 59.3), secretory endometrium (190.5 ± 52.4), and hyperplasia without atypia (261.0 ± 56.9), whereas no significant differences were detected among several intermediate histopathological groups. Nuclear localization of EZH2 became more prominent in atypical hyperplasia and carcinoma tissues. Apoptotic indices were significantly higher in both Type I and Type II carcinomas than in normal endometrium and hyperplasia groups, representing an association with increased EZH2 expression rather than evidence of a direct mechanistic relationship. These findings demonstrate that EZH2 expression differs across histopathological categories of endometrial lesions, with the highest expression observed in Type II endometrial carcinoma. The observed predominance of nuclear EZH2 in atypical hyperplasia and carcinoma further supports its association with aggressive tumor biology, although additional functional and clinicopathological studies are required to establish its clinical and biological significance.

To describe cell-free DNA (cfDNA)-inferred putative clonal hematopoiesis (CH) candidates during first-line platinum-based chemotherapy followed by poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance in ovarian cancer.

In SCRUM-Japan MONSTAR-SCREEN-1, we analyzed clinically reported paired tumor tissue and plasma cfDNA profiling (324-gene assays). Baseline (B1) data were assessed in 35 treatment-naïve patients; longitudinal cfDNA was available at B1, after platinum without progression (B2), and during/after PARPi without progression (B3) in 8 patients. Putative CH candidates were defined as pathogenic variants (variant allele frequency <40%) in prespecified CH-related genes detected in plasma but not detected in matched tumor tissue at clinical reporting thresholds.

At B1, putative CH candidates were reported in 19/35 patients (54.3%), most commonly DNMT3A; positivity was associated with age ≥60 years. In the longitudinal cohort, tumor-derived TP53 variants were below the assay reporting threshold at B3 in all patients, whereas putative CH TP53 variants were reported in 0/8 patients at B1 and 6/8 patients at B3. DNA damage response gene candidates (TP53/ATM/CHEK2) more frequently became detectable above the reporting threshold during B2-B3 than during B1-B2, while epigenetic-gene candidates showed relatively stable detectability. No therapy-related myeloid neoplasm events were observed during follow-up.

This paired tissue-plasma longitudinal analysis highlights an interpretive challenge in cfDNA testing during first-line platinum-to-PARPi maintenance therapy: putative CH candidates may become detectable as tumor-derived cfDNA declines. Given cfDNA-only inference without matched WBC sequencing and the small serial cohort, these observations are supportive of prior reports of CH dynamics but require validation in larger WBC-integrated cohorts.

UMIN-CTR Clinical Trial Identifier: UMIN000036749.

Tentorial meningiomas account for 3-6% of all intracranial meningiomas. Complexity of topographic and anatomical location along with variability of surgical approaches underscores the importance of investigating these tumors. A systematic review was conducted in accordance with the PRISMA 2020 guidelines. We enrolled the studies devoted to outcomes after microsurgical treatment between 1984 and 2024. Demographic characteristics, neuroimaging data and postoperative outcomes were estimated. A total of 18 studies were selected. There were 668 patients, mean age was 52.6 years (478 females, 190 males). Mean tumor diameter was 33±5.4 mm. Preoperative hydrocephalus was detected in 17.1% of cases. The rate of gross total resection was 78%, complication rate - 34.3%, mortality rate - 3.3%. Microsurgical resection is the gold standard for meningiomas. The purpose of surgery is safe resection of tumor while preserving neurovascular structures. Adjuvant therapy may be considered for small tumors or subtotal resection.

Schwannomas are benign (WHO Grade I) tumors of peripheral nerves arising from Schwann cells. Discrepancies between biological behavior and histological characteristics of tumor may exist. We consider it appropriate to describe such a case and compare it with literature data.

A patient with subcutaneous schwannoma of the lower third of the right leg complicated by skin ulceration is presented. A review is devoted to data on atypical clinical course of schwannomas.

A 55-year-old man presented with tumor in the lower third of the right leg and skin ulceration 3.5×3 cm. The tumor appeared 10 months ago and significantly enlarged. Open biopsy revealed WHO Grade 1 schwannoma. Atypical course of disease required an extended resection of tumor and simultaneous skin defect closure with split-thickness thigh skin flap. Two months after surgery, the wound healed via primary intention. There were no signs of tumor recurrence, and Karnofsky score was 100.

Atypical course of cutaneous schwannoma with ulcers complicates accurate and timely diagnosis, as well as complicates patient management, selection of primary specialist and surgical approach. Benign tumor verified by biopsy and clinical manifestations typical for soft tissue cancer can require early surgical intervention based on oncological principles.

Magnetic resonance spectroscopy (MRS) is a complementary imaging technique enabling non-invasive metabolic characterization of tissues in clinical practice. Proton MRS is more common for analysis of metabolites such as lactate and choline. This is valuable for preoperative assessment of glioma grade. However, it does not directly reflect phosphate energy metabolism. Phosphorus MRS enables assessment of phosphorus-containing compounds involved in tumor energy metabolism and membrane turnover.

To assess the role of phosphorus MRS in metabolic characterization of low-grade and high-grade gliomas.

The study included 46 patients with gliomas: 31 patients with high-grade gliomas and 15 patients with low-grade gliomas. The control group comprised 15 healthy volunteers. All participants underwent phosphorus MRS with assessment of spectral parameters of phosphorus-containing metabolites, metabolic ratios and intracellular pH.

Phosphorus MRS revealed differences in metabolic profile of tumor tissue between high-grade and low-grade gliomas. High-grade gliomas were characterized by signs of impaired energy and membrane metabolism, including changes in phosphorus-containing metabolite ratios and shift in intracellular pH. Low-grade gliomas demonstrated less severe metabolic alterations.

Phosphorus MRS is a promising complementary imaging modality for non-invasive assessment of metabolic features of gliomas. This method may be used to refine their biological characteristics at the preoperative stage.

Ovarian cancer is the most lethal malignancy of the female reproductive system worldwide. Chemoresistance, particularly platinum resistance, is a major factor limiting improvement in prognosis, and its underlying mechanisms involve complex regulation of and escape from multiple programmed cell death pathways in cancer cells. Disulfidptosis is triggered by high expression of solute carrier family 7 member 11 (SLC7A11) under glucose starvation and shares upstream regulatory nodes with ferroptosis. Necrosis by sodium overload is driven by sodium ion overload mediated by transient receptor potential cation channel subfamily M member 4 (TRPM4), but its role remains to be further investigated. Other programmed cell death pathways are interwoven into a dynamic regulatory network through key regulatory molecules such as tumor protein p53, the caspase family, cysteine-aspartic proteases, and glutathione. Autophagy can inhibit pyroptosis; ferroptosis and pyroptosis can synergistically amplify cell-killing effects through the reactive oxygen species/NOD-like receptor thermal protein domain-associated protein 3 axis; ferroptosis and cuproptosis share the glutathione metabolic axis; and the interaction between ferroptosis and disulfidptosis can shift from antagonism to synergy under specific metabolic stress. Ferroptosis and necrosis by sodium overload mutually promote each other through cascades involving adenosine triphosphate depletion, reactive oxygen species accumulation, and mitochondrial damage. PANoptosis can overcome cancer-cell resistance to a single mode of cell death through the simultaneous activation of multiple cell death pathways. A comprehensive review of the roles and interactive networks of various programmed cell death modalities, including disulfidptosis, necrosis by sodium overload, apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, cuproptosis, and PANoptosis, in platinum resistance in ovarian cancer is expected to provide a solid theoretical basis and potential translational directions for reversing platinum resistance and optimizing clinical treatment strategies.

Osteosarcoma (OS) is a malignant bone tumor that predominantly affects adolescents. Due to its early metastatic tendency and chemoresistance, long-term survival rates in patients have not shown significant improvement over time, highlighting the urgent need for novel molecular targets and therapeutic strategies. Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, offers a promising avenue for overcoming drug-resistant tumors. ATP-binding cassette subfamily B member 6 (ABCB6) belongs to the ATP-binding cassette (ABC) transporter superfamily and is mainly localised to the outer mitochondrial membrane, where it participates in haem synthesis and intracellular iron transport. Recent studies have indicated that ABCB6 is aberrantly expressed in various malignancies and regulates tumor progression, yet its role and mechanism in OS remain unexplored. The present study aims to systematically characterise the expression pattern, clinical prognostic significance, and biological functions of ABCB6 in OS, and to dissect the molecular mechanism by which ABCB6 governs ferroptosis in OS cells, thereby providing a theoretical foundation for ABCB6-targeted therapy.

Human OS cell lines (HOS and 143B) and human bone marrow mesenchymal stem cells (BMSCs) were used as research subjects. Stable ABCB6-knockdown OS cell lines were established via lentivirus-mediated RNA interference, and rescue experiments were performed using lentiviral overexpression of hypoxia-inducible factor 1-alpha (HIF1A). Cell proliferation was assessed by cell counting kit-8 (CCK-8) and colony formation assays; migration was evaluated by Transwell and scratch wound-healing assays; apoptosis was detected by flow cytometry. Ferroptosis-related phenotypic assays were employed to determine the impact of ABCB6 expression on ferroptosis. Transcriptome sequencing was conducted to analyse differentially expressed genes and enriched pathways; chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were applied to verify the direct binding of HIF1A to the promoter of glutathione peroxidase 4 (GPX4) and its transcriptional regulation. Iron chelator and proteasome inhibitor interventions were used to validate the regulation of HIF1A protein stability by Fe²⁺. In vivo, ABCB6-knockdown and control 143B cells were injected subcutaneously into nude mice to establish a xenograft tumor model, and tumor growth was monitored.

Both messenger RNA (mRNA) and protein levels of ABCB6 were significantly higher in OS cell lines than in BMSCs (both P<0.05), and analysis of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-OS cohort revealed that patients with high ABCB6 expression had markedly worse overall survival than those with low expression [hazard ratio (HR)=2.94, 95% confidence interval (CI) 1.36 to 6.36, P<0.05]. ABCB6 knockdown significantly suppressed OS cell proliferation and colony formation, reduced migratory capacity, and increased the apoptosis rate, accompanied by downregulation of N-cadherin and upregulation of E-cadherin and cleaved caspase-3 (all P<0.05). ABCB6 silencing markedly elevated the proportion of Liperfluo-positive cells and dihydroethidium (DHE) oxidation levels, increased intracellular Fe²⁺ concentration, decreased the glutathione (GSH)/oxidized glutathione (GSSG) ratio, reduced mitochondrial membrane potential, and induced typical ferroptotic mitochondrial morphological changes (shrinkage and cristae reduction) as observed by transmission electron microscope (all P<0.05); these oxidative alterations were reversed by the ferroptosis inhibitors. ABCB6 knockdown downregulated GPX4 at both protein and mRNA levels, whereas solute carrier family 7 member 11 (SLC7A11) expression remained unchanged (P>0.05). Transcriptome sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed significant enrichment of the HIF-1 signalling pathway in the control group (P<0.001); ABCB6 knockdown decreased HIF1A protein expression, and treatment with an iron chelator or a proteasome inhibitor reversed this degradation through Fe²⁺ chelation or inhibition of the ubiquitin-proteasome pathway, respectively (all P<0.05). Chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and dual-luciferase reporter assays confirmed that HIF1A directly binds to the GPX4 promoter and activates its transcription. Overexpression of HIF1A in ABCB6-knockdown cells restored GPX4 expression and significantly rescued the proliferation inhibition, migration impairment, and apoptosis increase caused by ABCB6 silencing, while also restoring mitochondrial membrane potential (all P<0.05). In the xenograft model, tumors from the ABCB6-knockdown group exhibited significantly reduced volume and weight compared with the control group (all P<0.05); immunohistochemistry confirmed downregulation of HIF1A and GPX4, reduced Ki-67 and N-cadherin positivity, and increased cleaved caspase-3 and E-cadherin positivity in the knockdown group (all P<0.05).

This study systematically uncovers, for the first time, the oncogenic role and prognostic value of ABCB6 in OS, and delineates the complete "ABCB6/Fe²⁺/HIF1A/GPX4" axis that governs ferroptosis in OS cells. These findings not only provide a novel biomarker for molecular subtyping and prognostic evaluation of OS, but also establish a theoretical basis for therapeutic strategies that target the ABCB6/HIF1A/GPX4 axis to induce ferroptosis. Future investigations may explore the upstream regulators of ABCB6 and its potential utility in reversing chemoresistance in OS.

Hepatitis B virus (HBV) infection remains a leading global cause of advanced liver disease and imposes a substantial economic burden. Early prevention is critical, as perinatally acquired HBV carries a high risk of progression to cirrhosis or hepatocellular carcinoma (HCC). Hepatitis B vaccination has been proven effective in preventing cancer, yet coverage of the complete vaccine series remains suboptimal. This implementation gap perpetuates the clinical burden, manifesting decades later as hepatic decompensation and liver cancer. This narrative review synthesizes the current HBV landscape, highlighting how gaps in vaccination policy and delivery contribute to real-world gastrointestinal outcomes. By reframing HBV vaccination as a core component of gastrointestinal and hepatology practice, clinicians can play a pivotal role in preventing cirrhosis and HCC while improving population health.