Although testicular germ cell tumors (TGCTs) most commonly affect younger men, there has been an increase in their incidence among men older than 45 years in the past 2 decades. We sought to characterize differences in clinicopathologic features, management patterns, and survival outcomes for TGCTs by age at diagnosis.

The Surveillance, Epidemiology, and End Results database was used to identify all patients aged 15 to 70 years who were diagnosed with TGCTs by orchiectomy between 2004 and 2021. Comparative statistics assessed differences in clinicopathologic characteristics and management patterns between younger (15-44) and older (45-70) patients. The Kaplan-Meier method and log-rank test were used to evaluate cancer-specific survival (CSS) by age group.

A total of 34,738 patients were included in the analysis, of whom 5719 (16.5%) were in the older age group. Older patients were more likely to present with seminoma (78.7% vs. 49.9%, P < 0.001) and clinical stage I disease (72.9% vs. 70.0%, P < 0.001) compared to younger patients. Among stage I patients, there were no significant differences in histology-specific management patterns by age. Overall, 1,052 (3.0%) deaths were attributable to testicular cancer over a median follow-up of 7.4 years. Five-year CSS surpassed 96% for patients with clinical stage I and stage II disease, irrespective of histology or age group; however, for patients with stage III disease, older age was associated with statistically significant worse CSS compared to younger age, both for seminoma (86.0% vs. 92.2%, P < 0.001) and non-seminoma (65.7% vs. 81.6%, P < 0.001).

Older men with TGCTs present with higher rates of seminoma and stage I disease compared to younger men. Among patients with stage III disease, CSS is worse in those who are older at diagnosis. Understanding how age influences TGCT phenotype and outcomes can help inform age-specific management strategies.

Appendiceal tumors are uncommon, and their coexistence as collision tumors is exceedingly rare, with fewer than 20 cases reported to date. The objective is to report a multi-center case series and literature review of appendiceal collision tumors, providing a comprehensive summary of clinicopathological features and outcomes. Electronic records from five tertiary centers (2016-2024) were searched. Cases with appendiceal collision tumors composed of a neuroendocrine tumor (NET) and a second component of low- or high-grade appendiceal mucinous neoplasm (LAMN/HAMN) or adenocarcinoma were included. Additional cases with the same diagnostic combinations were identified through a PubMed literature search since 2000. Clinical, pathologic, and survival data were collected and analyzed. Thirty-three cases were identified, including 17 multi-institutional and 16 literature-derived cases, with an estimated incidence of 0.11% among appendectomies. Most tumors consisted of localized NET and LAMN. Gastrointestinal (GI) symptoms were present in 62.5-65.6% of cases, and tumors were identified by imaging in 53.1-75.0%. Outcome tracks the higher-stage and grade component. Patients with localized tumors had excellent outcomes (2-year progression-free survival [PFS] and overall survival [OS]: 100%). In contrast, cases with metastatic LAMN/HAMN had 2-year PFS 66.7% and OS 100%, while those with metastatic adenocarcinoma had 2-year PFS 0% and OS 66.7%. This study represents the largest series and literature review of appendiceal collision tumors to date. These rare tumors most often consist of localized NET and LAMN, typically present with GI symptoms, are often detected by imaging. The prognosis is dictated by the component of higher stage and grade.

Pancreatic cystic lesions (PCLs) are increasingly detected due to the widespread use of cross-sectional imaging and represent a significant diagnostic challenge because of their heterogeneous biological behavior, ranging from benign lesions to neoplasms with malignant potential. Accurate characterization and risk stratification are essential to guide appropriate management and avoid unnecessary surgical interventions. Conventional imaging modalities, including computed tomography (CT), magnetic resonance (MR) imaging, and endoscopic ultrasound (EUS), remain central to the diagnostic work-up; however, their ability to reliably differentiate cyst subtypes and predict malignant transformation remains limited. In recent years, artificial intelligence (AI) and radiomics have emerged as promising approaches for improving the non-invasive characterization of PCLs by extracting quantitative imaging features beyond those appreciable through visual assessment. This narrative review summarizes the current evidence regarding CT- and MR-based radiomics and AI in pancreatic cyst characterization, focusing on their role in differentiating mucinous from non-mucinous cysts, identifying high-risk intraductal papillary mucinous neoplasms (IPMNs), and supporting clinical decision-making. The potential advantages of these techniques are discussed alongside main methodological limitations, including variability in imaging acquisition protocols, segmentation reproducibility, small and often retrospective datasets, limited external validation, and interpretability of AI-based models. Further multicenter studies, standardized radiomic pipelines, and prospective validation are required before these tools can be reliably integrated into routine clinical practice.

Malignant neoplasms of the salivary glands are a heterogeneous group of cancers that include more than 24 malignant histological types in the salivary glands, with different genetic, morphological, and immunohistochemical features and clinical behavior.

A retrospective population-based analysis of salivary gland cancers diagnosed between 1994 and 2018 was performed, using data from the Girona and Tarragona cancer registries. Crude incidence rates, European and world-age-standardized incidence rates and incidence trends, measured as the annual percentage change, were estimated. Observed and net survival at 5 and 10 years and 10-y/5-y conditional survival were calculated. The analysis was focused on histological type.

A total of 301 cases were recorded in the provinces of Girona and Tarragona during 1994-2018, of which 51.5% were in men and 76.1% in the parotid salivary gland. The most common histology type was the squamous cell carcinoma (17.9%) followed by the mucoepidermoid carcinoma (16.9%). Incidence was 9.2 cases per 1,000,000 person-years for all salivary gland tumors. A decrease in incidence for all cases and in most of the histology types specifically, was observed. For the cohort, the 10-year observed and net survival rates were 37.3 and 55.5%, respectively. Acinar cell carcinoma was the histology with better prognosis at 10 years.

A decrease in the overall incidence of cases has been observed, which may be due to better diagnostic or registration accuracy along with changes in exposure to etiological factors such as smoking. Net survival at 10 years was 55.5% for the entire cohort.

Non-small cell lung cancer (NSCLC) continues to account for the majority of lung cancer-related mortality, primarily due to disease progression and the development of resistance to conventional chemotherapy, targeted therapies, radiotherapy, and immunotherapy. While genetic and epigenetic alterations have been extensively studied, growing evidence indicates that these factors alone are insufficient to explain therapeutic failure. Recent advances highlight tumor mechanobiology as a critical regulator of cancer progression and treatment response. In NSCLC, progressive stiffening of the extracellular matrix (ECM), driven by aberrant collagen deposition, crosslinking, and cancer-associated fibroblast activation, generates biomechanical cues that profoundly influence tumor cell behavior. These mechanical signals are transduced through integrins and cytoskeletal networks, activating downstream pathways such as focal adhesion kinase, Rho/ Rho-associated coiled-coil containing protein kinase (ROCK) signaling, and the Hippo pathway effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Sustained activation of these pathways promotes epithelial-mesenchymal transition, stemness, and immune evasion, collectively contributing to therapy resistance and tumor aggressiveness. This review provides details of current evidence linking ECM stiffness-mediated mechanotransduction to therapeutic resistance in NSCLC. Furthermore, it discusses emerging therapeutic strategies aimed at targeting tumor mechanics, including ECM normalization, inhibition of mechanosensitive signaling nodes, and cancer-associated fibroblast modulation. By integrating biomechanical regulation with molecular signaling and therapeutic perspectives, this review underscores tumor mechanics as an underappreciated but clinically relevant determinant of treatment outcome. Targeting mechanobiology-driven resistance may offer novel opportunities to enhance therapeutic efficacy and improve clinical outcomes in patients with NSCLC.

Resistance to anthracyclines and taxanes remains a major barrier to effective breast cancer treatment, particularly in aggressive subtypes such as triple-negative breast cancer. Although these agents form the backbone of systemic chemotherapy, variability in response limits long-term survival benefits and underscores the urgent need for predictive biomarkers and novel therapeutic strategies. Emerging evidence implicates Rho family small GTPases and their downstream effectors, p21-activated kinases (PAKs), as central regulators of cytoskeletal remodeling, epithelial-mesenchymal transition, and survival signaling. Aberrant activation of the Rho/PAK axis enhances tumor cell adaptability through cross-talk with PI3K/AKT, MAPK, and NF-κB pathways, promoting DNA repair, apoptosis evasion, and multidrug efflux via P-glycoprotein. These mechanisms converge to reduce chemosensitivity, drive recurrence, and worsen patient outcomes. This review synthesizes current evidence linking Rho/PAK signaling with chemotherapy resistance, discusses its potential as a predictive biomarker for patient stratification, and explores therapeutic opportunities to restore chemosensitivity. Integrating molecular insights into clinical strategies may enable more effective, personalized treatment approaches in breast cancer.

The progression of prostate cancer is predominantly driven by androgen receptor (AR) signaling; however, its downstream effector molecules are not fully characterized. Fibromodulin (FMOD), a proteoglycan with established roles in other cancers, has recently been implicated in prostate cancer; however, the precise molecular mechanisms underlying its regulation and oncogenic function remain elusive. Here, we sought to elucidate the functional role of FMOD and its regulation by the AR and the subsequent activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling axis.

FMOD expression levels across multiple prostate cancer cell lines were quantified by qRT-PCR and Western blot analysis. To investigate its function, transient knockdown using small interfering RNA (siRNA) was Performed in LNCaP and 22Rv1 cells, while lentiviral-mediated overexpression of FMOD was established in LNCap cells, to assess cellular proliferation, migration, invasion, and cell cycle distribution in vitro. For in vivo studies, a stable FMOD-knockdown model was established using lentiviral-mediated shRNA to evaluate tumor growth in xenograft mice. Putative upstream transcription factors were predicted using the JASPAR database and validated through AR knockdown experiments. Downstream signaling pathways, specifically PI3K/AKT and epithelial-mesenchymal transition (EMT), were analyzed via Western blot.

FMOD was highly expressed in LNCaP and 22Rv1 cells. FMOD knockdown markedly suppressed cell proliferation, induced cell cycle arrest, and inhibited migration and invasion by reversing the EMT process. In vivo experiments confirmed that FMOD depletion significantly retarded tumor growth. Mechanistically, we identified FMOD as a transcriptional target positively regulated by AR. Furthermore, FMOD facilitated cancer progression by activating the PI3K/AKT signaling pathway.

Our findings delineate a critical AR-FMOD-PI3K/AKT signaling axis in prostate cancer progression. FMOD serves as a key downstream effector of AR and may represent a promising therapeutic target for clinical intervention.

Therapeutic resistance to tyrosine kinase inhibitors (TKIs) remains a major challenge in the clinical management of chronic myeloid leukemia (CML). The transcription factor STAT5A, a principal downstream effector of BCR::ABL1, has emerged as a key transcriptional regulator implicated in the development of TKI resistance. This study aims to functionally validate the role of STAT5A in TKI-resistant CML by employing CRISPR/Cas9-mediated gene knockout and assessing the downstream molecular and phenotypic alterations. We hypothesized that selective disruption of STAT5A would restore apoptotic sensitivity and TKI responsiveness in resistant CML models. Additionally, we sought to integrate bioinformatic transcriptional network analyses to confirm whether STAT5A directly regulates the genes modulated by its deletion, thus reinforcing its mechanistic relevance as a therapeutic target. STAT5A was knocked out using CRISPR/Cas9 in K562 cells and their TKI-resistant derivatives (K562/Ima-Res, K562/Pon-Res). Western blot analysis confirmed effective depletion of STAT5A protein following CRISPR/Cas9 editing, validating that the observed phenotypic and transcriptional changes were attributable to successful STAT5A knockout. Post-editing, XTT assays were performed to assess cell viability, followed by Annexin V/PI staining for apoptosis and PI-based flow cytometry for cell cycle analysis. RT-qPCR was used to quantify the expression of key genes involved in the JAK/STAT pathway (JAK2, STAT3, CISH) and apoptosis/DNA damage responses (TP53, ATM, CASP3, CASP8). In silico analyses were conducted using TRRUST and Harmonizome/ChEA3 to confirm whether the genes modulated by STAT5A deletion were direct transcriptional targets. For additional validation, expression matrices from GSE207627 and GSE208314 were reanalyzed to confirm STAT5A-centered pathway alterations in resistant CML datasets. STAT5A knockout significantly reduced cell viability and induced apoptosis across all CML cell models, accompanied by G0/G1 cell cycle arrest. RT-qPCR revealed altered expression of both JAK/STAT components (JAK2, STAT3, CISH) and apoptosis-related genes (TP53, ATM, CASP3, CASP8). Transcriptional target analysis confirmed that several of these genes-such as CDKN2B, BCL2L1, and CCND1-are direct STAT5A targets, reinforcing the functional consequences of STAT5A loss. Integration of these findings suggests that STAT5A knockout reprograms both intrinsic (CASP3, TP53, ATM) and extrinsic (CASP8, BCL2L1) apoptotic pathways, thereby restoring chemosensitivity. CISH dysregulation further suggested compensatory feedback within the signaling network. CRISPR/Cas9-mediated STAT5A disruption effectively reverses TKI resistance in CML cells by reprogramming apoptotic and proliferative signaling. These findings identify STAT5A as a mechanistically validated and clinically actionable target, supporting its potential for combination strategies with TKIs or STAT5 inhibitors such as pimozide. Integration of transcriptional network analysis supports the mechanistic basis of these effects. STAT5A emerges as a compelling therapeutic target, meriting further investigation in preclinical models and patient-derived samples to evaluate its translational potential. Future validation in patient-derived CD34⁺ CML models may advance STAT5A-based therapeutic design.

IntroductionHead and neck squamous cell carcinoma (HNSCC) is characterized by metabolic reprogramming and poor prognosis. While lactate accumulates in HNSCC, how upstream RNA regulation coordinates lactate-associated epigenetic alterations during tumor progression remains unclear.MethodsWe integrated TCGA-HNSCC analyses, paired clinical specimens, and in vitro functional assays with mechanistic readouts including RIP-qPCR and LDHA 3'UTR luciferase reporters. Lactate was quantified in culture supernatants, H4K8la was assessed by immunoblotting and tissue IF, and H4K8la CUT&Tag was performed as an exploratory chromatin profiling assay.ResultsIGF2BP3 was upregulated in HNSCC and associated with adverse survival in public datasets. IGF2BP3 silencing inhibited proliferation, migration, and invasion. Mechanistically, IGF2BP3 bound LDHA mRNA and promoted LDHA expression via an m⁶A-site-dependent LDHA 3'UTR mechanism, increasing lactate and H4K8la; exogenous lactate partially restored H4K8la under pH-matched conditions. Exploratory H4K8la CUT&Tag suggested increased H4K8la signal at the E2F2 locus with enrichment of cell-cycle programs upon lactate treatment.ConclusionThese findings support an IGF2BP3-LDHA-lactate-H4K8la axis linking post-transcriptional regulation to metabolic and chromatin remodeling in HNSCC.

This study aims to evaluate the cost-effectiveness of atezolizumab plus bevacizumab as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC) in Malaysia, compared with the current standard treatments in the Malaysian Ministry of Health (MOH) to inform public healthcare decision‑making.

A cost-effectiveness analysis was conducted from the MOH perspective, following the national pharmacoeconomic guidelines (2019). The study compared atezolizumab plus bevacizumab with sorafenib and lenvatinib, respectively, using a partitioned survival model to project health outcomes and costs over a lifetime horizon. Clinical efficacy data were sourced from published trials and network meta-analyses. Cost inputs reflected local healthcare resource use and prices, using 2024 Malaysian Ringgit values inflated via the Consumer Price Index for Health. Costs and outcomes were discounted at 3% annually. Deterministic and probabilistic sensitivity analyses were performed to assess the impact of key parameter uncertainties on the results.

Atezolizumab plus bevacizumab provided the highest quality-adjusted life years (QALYs) and life years compared to sorafenib and lenvatinib. Sorafenib was dominated by lenvatinib due to lower QALYs and higher costs and excluded from further analysis. Compared to lenvatinib, atezolizumab plus bevacizumab yielded 0.873 additional QALYs and RM 44,863 additional cost, resulting in an incremental cost-effectiveness ratio (ICER) of RM 51,399 per QALY gained (∼0.906 GDP/capita at Malaysia's 2024 GDP/capita RM 56,734).

Atezolizumab plus bevacizumab is cost-effective compared to lenvatinib and sorafenib across willingness-to-pay (WTP) values of one to three times Malaysia's GDP per capita. These findings provide evidence to inform public health policy that expanding funding and adoption of atezolizumab plus bevacizumab is likely to improve health outcomes cost-effectively.