Somatic neoplasms arising in mature teratomas (SN-MT) are rare clinical entities that pose significant diagnostic and therapeutic challenges. This study aims to determine the frequency of SN-MT and evaluate the clinicopathological characteristics that distinguish these cases from uncomplicated mature teratomas (MT).

We retrospectively reviewed 500 cases of presumed ovarian mature teratomas evaluated at a single center between 2006 and 2021. After strict exclusion criteria, 385 patients were included. All histopathological slides underwent systematic pathological re-evaluation by expert pathologists. Clinical, radiological, and laboratory data were compared between the MT and SN-MT groups.

The overall incidence of somatic neoplasms (benign and malignant) was 3.1% (n = 12), with a malignant transformation rate of 2.07% (n = 8). The histological spectrum was highly heterogeneous and comprised both benign and malignant entities. Benign tumors identified in MTs included paraganglioma, choroid plexus papilloma, and adnexal tumor, whereas malignant tumors included squamous cell carcinoma (SCC), glioblastoma, anaplastic astrocytoma, adult-type granulosa cell tumor, and mixed carcinoma. The SN-MT group exhibited significantly larger mean tumor diameters compared to the MT group (9.45 ± 4.22 cm vs. 6.67 ± 3.32 cm, p < 0.05). On gross examination, mixed solid-cystic architecture was a powerful predictor of neoplasia (83.3% in SN-MT vs. 22.3% in MT, p < 0.0001). Preoperative serum tumor markers (CA 125, CA 19-9, and CEA) showed no significant discriminatory value. False-negative findings on intraoperative frozen section analysis may be attributable to the focal distribution of these lesions.

SN-MT is a rare but histologically diverse condition. Large tumor size and the presence of solid components on macroscopic examination should raise suspicion of somatic transformation. Given the limitations of frozen section analysis and serum markers, rigorous macroscopic sampling and expert pathological examination remain the gold standard for diagnosis. While early-stage disease carries a favorable prognosis, the heterogeneity of subtypes necessitates individualized management.

HER2-positive breast cancer accounts for 15-20% of all breast cancer cases. Although the development of monoclonal antibodies (e.g., trastuzumab, pertuzumab), tyrosine kinase inhibitors (e.g., lapatinib, pyrotinib), and antibody-drug conjugates (e.g., T-DM1, trastuzumab deruxtecan) has greatly improved patient prognosis, primary or acquired resistance to anti-HER2 therapy remains a major clinical challenge, leading to treatment failure and disease progression. Recent research has elucidated diverse resistance mechanisms, including HER2 signaling pathway aberrations (such as receptor mutations, alternative splicing, and bypass activation), tumor microenvironment remodeling (involving immunosuppressive cells, metabolic reprogramming, and immune checkpoint molecules), and ADC-specific resistance (impaired internalization, lysosomal dysfunction, payload efflux, and ferroptosis blockade). However, existing reviews primarily focus on trastuzumab and classical signaling pathways, with insufficient integration of ADC-specific mechanisms or microenvironmental immune evasion. Furthermore, the translation of mechanistic discoveries into clinical strategies remains weak, and a systematic summary of validated biomarkers (e.g., PIK3CA mutations, PTEN loss, p95HER2, ADAR1, HLA-G) and related clinical trials is lacking. The purpose of this review is threefold: (1) to systematically integrate recent advances in anti-HER2 resistance mechanisms from three perspectives-HER2 signaling abnormalities, tumor microenvironment remodeling, and ADC-specific barriers; (2) to provide an evidence-based framework for target prioritization by categorizing mechanisms according to their validation stage (clinically validated, substantial in vivo evidence, or in vitro studies only); and (3) to summarize current biomarker-driven clinical trials and emerging therapeutic strategies, including combination immunotherapy, CDK4/6 inhibitors, PI3K PROTACs, and cold atmospheric plasma. Ultimately, this review aims to bridge the gap between basic research and clinical practice, offering practical guidance for overcoming anti-HER2 resistance through precision combination strategies in HER2-positive breast cancer.

Objectives: Venetoclax (VEN) is approved for acute myeloid leukemia (AML) in association with azacitidine, in a 28-day schedule at a fixed dosage, which requires reduction if azoles are co-administered. The present study aims to evaluate VEN therapeutic drug monitoring (TDM) in a real-word setting, where the VEN schedule is frequently reduced, investigating: (i) the posaconazole impact, and (ii) whether VEN exposure correlates with safety and efficacy. Methods: We analyzed data from 43 AML patients treated with different VEN-containing regimens, for whom a near-trough VEN plasma concentration (Cmin) was determined at different timepoints (days 5-8-11-15-22-29) across different cycles (163 cycles, 290 determinations). The posaconazole impact was explored in the whole study population, while safety and efficacy were investigated only in patients treated with azacitidine-VEN, respectively in the safety (35 patients) and in the efficacy subset (29 patients at their first cycle). VEN exposure was expressed through multiple parameters, taking into account both VEN concentrations and the days of VEN administration. Results: Posaconazole was used in 40.5% of cycles and, despite dose adjustment, was associated with: (i) greater interpatient variability, (ii) higher VEN concentrations, (iii) delayed elimination, (iv) accumulation along the cycle, and (v) the need for VEN-dosage change. In the safety subset, VEN exposure correlated with neutropenia and its duration, Granulocyte Colony-Stimulating Factor requirement, platelet transfusions, cycle duration, and infections. Finally, no correlation was found between VEN exposure and response in the efficacy subset. Conclusion: VEN TDM appears valuable in clinical practice to reduce toxicity, especially in patients receiving posaconazole, where VEN exposure remains highly unpredictable.

Proliferating Cell Nuclear Antigen (PCNA) is a core protein in DNA replication and repair. Its functional dysregulation drives tumorigenesis and therapeutic resistance, making it a critical anticancer target. However, the fundamental conflict between PCNA's indispensable "guardian" function in normal cells and its hijacked "accomplice" role in cancer cells constitutes the central challenge for targeted intervention: how to eradicate tumors while avoiding severe toxicity to normal tissues. This review aims to systematically review the latest advances and translational dilemmas in the field of PCNA-targeted therapy. It outlines various intervention strategies, including small-molecule inhibitors, proteolysis-targeting chimeras, post-translational modification interference, and synthetic lethality approaches, analyzing their potential and limitations in preclinical research. The review focuses on dissecting key bottlenecks hindering clinical translation, such as the selectivity dilemma, delivery barriers, and resistance evolution. Concurrently, it critically examines how cross-disciplinary technologies-including artificial intelligence, spatiotemporal regulation, and synthetic biology-offer novel ideas to address these bottlenecks, while clarifying that most remain in early exploratory stages. By synthesizing progress, challenges, and future directions, this article provides a framework to inform the development of highly selective and translatable PCNA-based anticancer strategies.

Squamous cell carcinoma (SCC) of the bladder is an aggressive histologic subtype with distinct clinical behavior and limited treatment options after platinum-based chemotherapy. This study aimed to evaluate potential therapeutic targets in bladder SCC.

A retrospective cohort of 790 patients who underwent radical cystectomy for bladder cancer between 2011 and 2021 was screened to identify cases with histologically confirmed SCC. All SCC cases in the pathology department from 2003 to 2011 were also reviewed. Clinical and pathological data from 54 patients were analyzed. A tissue microarray (TMA) was constructed, and immunohistochemical (IHC) analyses were performed for programmed death-ligand 1 (PD-L1), nectin cell adhesion molecule 4 (NECTIN4), trophoblast cell-surface antigen 2 (TROP2), human epidermal growth factor receptor 2 (HER2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), and CD8⁺ T cells. Expression levels were assessed for prognostic relevance using the log-rank test and Kaplan-Meier survival analysis.

A TMA comprising samples from 42 of 54 patients (22 pure SCC, 20 partial SCC) was successfully constructed. NECTIN4 (positive vs. negative) expression, PD-L1 (combined positive score ≥ 10 vs. <10) expression, and CD8⁺ density (high vs. low) showed a nearly equal distribution across the cohort. HER2 expression was detected in 14.3% of cases, CEACAM5 in 21.4%, and TROP2 in 83.3% of tumors. High NECTIN4 expression, increased CD8⁺ density, and administration of adjuvant chemotherapy were associated with improved overall survival.

Several actionable targets were identified in bladder SCC, supporting further exploration of targeted therapies.

Extracellular vesicles (EVs) are actively secreted, membrane-enclosed nanoparticles that serve as pivotal mediators of intercellular communication. They function as key mediators of intercellular communication by transporting diverse biomolecules, including proteins, nucleic acids, and metabolites. Within the tumor microenvironment, EVs drive complex cellular crosstalk and critically regulate tumor progression by remodeling the extracellular matrix, conferring drug resistance, and reprogramming immune responses. Given their natural biocompatibility, tissue tropism, and ability to cross biological barriers, EVs have emerged as promising platforms for immunotherapy, tumor vaccines and targeted drug delivery system. Moreover, the rapid expansion of EV-based clinical trials highlights their promise in precision medicine. Concurrently, the limitations associated with EV-based therapeutic strategies are critically evaluated to inform future development. This review has also detailed the importance of single-vesicle analysis, which represents a rapidly evolving frontier in EV science. Aiming to bridge the gap between mechanistic understanding and clinical practice, this review delineates the pivotal roles of EV-mediated communication in reshaping the dynamic homeostasis of the tumor microenvironment. Moreover, we provide a critical analysis of current EV-based therapeutic pipelines and their translational challenges, offering key perspectives and theoretical support for the future of precision medicine.

Objectives: Ferroptosis resistance may contribute to tumor progression and immune escape. This study evaluated the prognostic and immunological significance of glutathione peroxidase 4 (GPX4), a core ferroptosis-suppressive enzyme, in surgically resected lung adenocarcinoma. Methods: We retrospectively analyzed 104 patients with primary lung adenocarcinoma who underwent curative resection. GPX4 protein expression was assessed by immunohistochemistry (IHC) using the histological score (H-score), and patients were classified as GPX4-low (n = 54) or GPX4-high (n = 50). Intratumoral immune contexture was quantified using CD3, CD4, CD8, CD68, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) staining. Disease-free survival (DFS) and overall survival (OS) were analyzed using Cox regression. Cutoff sensitivity analyses, category consolidation, ridge-penalized Cox regression, events-per-variable assessment, bootstrap internal validation, and interobserver reproducibility testing were performed to strengthen statistical robustness. Results: GPX4-high tumors were associated with systemic inflammatory and immune-related features, including elevated fibrinogen (p = 0.015), lower lymphocyte-to-monocyte ratio (p = 0.003), and altered aspartate aminotransferase-to-alanine aminotransferase ratio (p = 0.028). GPX4-high tumors showed reduced intratumoral CD3⁺, CD4⁺, CD8⁺, and CD68⁺ immune-cell infiltration, together with increased PD-1 and PD-L1 expression, indicating an immune-cold yet checkpoint-enriched phenotype. After category consolidation and ridge-penalized multivariable adjustment, high GPX4 expression remained independently associated with worse DFS (HR, 8.63; 95% CI, 2.99-24.91; p < 0.001) and OS (HR, 6.94; 95% CI, 2.44-19.74; p < 0.001). GPX4-based prognostic models showed bias-corrected C-index values of 0.782 for DFS and 0.826 for OS, with calibration slopes of 0.964 and 0.937, respectively. Conclusions: High GPX4 expression identifies a clinically adverse, ferroptosis-resistant, immune-remodeled phenotype in resected lung adenocarcinoma. Integrating GPX4 with clinicopathological and inflammatory variables may improve postoperative risk stratification.

Backgrounds: Despite the availability of multimodal strategies, no universally accepted guidelines exist for the management of advanced Thymic Epithelial Tumors (TETs), particularly in locally advanced thymomas. The aim of this study was to evaluate the oncological and surgical outcomes of induction therapy (IT) followed by surgery in patients with Masaoka-Koga stage III-IVA TETs. To this end, we conducted a systematic review and meta-analysis assessing surgical-pathological and survival outcomes. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was performed. Twenty-four studies published between 2003 and 2023 were included, comprising 749 patients treated with IT before surgical resection. The co-primary endpoints were Overall survival (OS) and Progression-free survival (PFS). Random-effects meta-analysis assessed pooled outcomes, while heterogeneity, publication bias, and meta-regression analyses were performed to explore potential moderators (year, histology, stage). The study was registered in Prospective Register of Systematic Reviews (PROSPERO) (CRD420251026044). Results: Of the included studies, 6 were prospective and 18 retrospective; 9 analyzed thymomas only, while 15 included both thymomas and thymic carcinomas. Regarding stage distribution, 4 studies focused on stage III, 11 on stage III-IV, 3 on stage IV, and 2 also included earlier stages. Response to IT was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) in 11 studies and World Health Organization (WHO) criteria in 4. The pooled rate of radiological response to IT, completeness of resection, 5-year OS, 10-year OS and 5-year PFS were 62.8%, 71.6%, 77.6%, 54.3% and 55.6%, respectively. Meta-regression showed histology significantly influenced 10-year OS (p-value 0.0418) as well as on PFS (p-value 0.0042) and treatment period on PFS (p-value 0.0007). Conclusions: Induction therapy followed by surgery provides acceptable long-term outcomes in advanced TETs. Histology remains a key prognostic factor, but 10-year OS has not improved over the past two decades, underscoring the need for innovative, histology-tailored therapeutic strategies to enhance survival.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is frequently diagnosed at an advanced stage and remains associated with poor survival outcomes. Durable responses to systemic therapy in metastatic disease are uncommon. We report a case of metastatic PDAC with prolonged survival and sustained response following first-line treatment with NALIRIFOX. This report describes a patient with metastatic PDAC who achieved prolonged disease control and sustained response following first-line treatment with NALIRIFOX. Case Presentation: A 64-year-old woman presented with abdominal pain, early satiety, weight loss, and markedly elevated CA 19-9 levels. Imaging demonstrated a pancreatic head mass with multiple hepatic metastases, and biopsy confirmed metastatic poorly differentiated PDAC. The patient initiated first-line therapy with NALIRIFOX as part of the NAPOLI-3 protocol and completed 20 cycles over approximately 25 months. Following an early treatment delay secondary to grade 2 neutropenia, she achieved substantial biochemical and radiographic improvement. After eight cycles, imaging demonstrated marked radiographic response with disappearance of the pancreatic lesion and marked regression of hepatic metastases. Disease stability was maintained for more than two years before progression was identified in a dominant hepatic lesion after cycle 20. Conclusion: This case highlights the potential for prolonged disease control and extended survival with NALIRIFOX in metastatic PDAC, emphasizing the meaningful clinical benefit that may be achieved in selected patients despite historically poor outcomes.

Cluster of differentiation 48 (CD48) is a glycosylphosphatidylinositol-anchored member of the signaling lymphocyte activation molecule (SLAM) family that is predominantly expressed on hematopoietic cells and regulates immune-cell communication through 2B4 (CD244) and CD2. This narrative review critically summarizes the context-dependent role of CD48 in tumor immunity, with emphasis on the distinction between activating trans-interactions and potentially inhibitory cis-interactions. Evidence from hematologic malignancies and selected solid tumors indicates that CD48 may support antitumor immunity by facilitating natural killer (NK) cells activation, CD8⁺ T-cell co-stimulation, immune synapse formation, and effector cytokine production. Conversely, loss of CD48 expression, sustained CD48-2B4 engagement, altered ligand density, and suppressive myeloid-rich tumor microenvironment (TME) may contribute to immune escape or NK cells dysfunction. Current therapeutic concepts, including anti-CD48 monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, engineered NK/T cells, and epigenetic restoration of CD48 expression, remain largely preclinical and require cautious interpretation. Major translational barriers include broad CD48 expression on normal hematopoietic populations, soluble CD48 (sCD48) interference, uncertain biomarker standardization, and the risk that forced activation in dense solid tumors may reinforce cis-inhibitory signaling rather than improve cytotoxicity. Future studies should define tumor-type-specific signaling states, quantify sCD48, integrate spatial and single-cell approaches, and evaluate rational combinations with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade in mechanism-driven models before clinical translation. This review aims to critically evaluate the dual regulatory roles of CD48 in tumor immunity, distinguish between activating trans-interactions and potentially inhibitory cis-interactions across different tumor types, and assess the translational potential and challenges of CD48-targeted immunotherapeutic strategies.