Each year, approximately 1.2 million new cases of hepatitis B are recorded globally, caused by the hepatitis B virus (HBV). This underscores the persistent transmission of the disease despite widespread availability of an effective vaccine. Although current drugs can reduce the chances of severe disease, they are not curative. Physiologically relevant in vitro models of HBV infection are essential to understand the biology of HBV and to develop strategies to target the virus. Until recently, only primary human hepatocytes could be infected with HBV. The discovery of the HBV receptor, the sodium taurocholate co-transporting polypeptide, resulted in the development of several immortalised cell lines that are infectable by HBV. These have made significant contributions to hepatitis B research. However, 2-D cell culture models fail to fully capture the complexity of the liver and HBV infection. The recent development of 3-D culture technologies offers new possibilities for modelling all the steps of HBV replication in cell culture and mimicking the liver microenvironment. This review discusses recent progress in developing models of HBV infection in 3-D cell culture and their contributions to HBV biology research and novel drug development.

In breast cancer, one of the main objectives of neoadjuvant treatment, regardless of the specific breast cancer subtype, is to downstage the disease in both the breast and the lymph nodes, thereby allowing surgical de-escalation. In patients with inoperable disease, downstaging could lead to a feasible surgical resection; whereas, in patients presenting with operable disease, it could increase the eligibility for breast-conserving surgery (i.e., lumpectomy) instead of a mastectomy as well as spare some patients an axillary lymph node dissection. In patients with hormone receptor-positive (HR + ) human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer, neoadjuvant treatment modalities include chemotherapy (NCT) and endocrine therapy (NET). The 21-gene Oncotype DX Breast Recurrence Score® assay is a multigene assay that determines a Recurrence Score® (RS) result (range, 0-100) based on gene expression profile within the primary tumor. The RS is a validated prognosticator and predictor of benefit from adjuvant CT. Beyond its validation, it has shown clinical utility in 3 prospective randomized clinical trials in the adjuvant setting (TAILORx, RxPONDER, and WSG PlanB). In these studies, all assays were performed on surgical excision samples. This review focuses on the utility of the 21-gene assay in patients with HR + HER2-negative early-stage breast cancer in the neoadjuvant setting. It discusses the analytical validation of performing the assay on core biopsies, its clinical validation as a tool to guide neoadjuvant treatment decisions (primary surgery, NET, or NCT), the association of the RS result with clinical outcomes, the impact of the RS results on neoadjuvant treatment decisions in real-life clinical practice, the inclusion of the assay in the neoadjuvant setting in clinical-practice guidelines, access of patients worldwide to this approach, and potential directions for additional studies examining the role of the RS in other steps in the clinical pathway of HR + HER2-negative early-stage breast cancer.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor. The aim of this study was to elucidate the role of microenvironment and intrinsic T-type calcium channels (Cav3) in regulating GBM. METHODS: We grafted syngeneic GBM cells into Cav3.2 knockout mice to assess the role of microenvironment T-Type calcium channels on GBM growth. We grafted syngeneic GBM cells into the hippocampus along Schafer collaterals and performed electrophysiology. We used neurons from WT and Cav3.2 Knockout (KO) mice in co-culture with GBM stem cells (GSC) to assess the effects of Cav3.2 on neuron/GSC synaptic connections and tumor cell growth. We performed single-cell RNA-seq of tumors from WT and Cav3.2 KO mice to elucidate the regulation of tumors by the microenvironment. RESULTS: Cav3.2KO in the microenvironment led to significant reduction of GBM growth and prolongation of animal survival. Neuronal Cav3.2 promoted GSC growth in co-culture and neuron/GBM functional synaptic connections in vivo. scRNA-seq showed that microenvironment Cav3.2 regulates neuronal and glial biological processes. Microenvironment Cav3.2 downregulated numerous genes associated with regulating the OPC cell state in GBM tumors. Treatment of GSCs with the Cav3 blocker mibefradil downregulated genes associated with neuronal processes. The Cav3 blocker drug mibefradil synergized with temozolomide (TMZ) and radiation to reduce in vivo tumor growth and prolong animal survival. CONCLUSIONS: The data reveal a role for microenvironment Cav3 in promoting GBM progression through regulating neuronal and glial processes. Targeting both intrinsic and microenvironment Cav3 with the inhibitor mibefradil significantly enhanced the anti-GBM effects of TMZ and radiation.

Laser interstitial thermal therapy (LITT) is a local surgical treatment for brain metastases (BM). Here, we present and discuss the main radiologic findings and challenges related to LITT-treated BM. Prior to LITT, imaging features are useful for prognostic stratification and patient selection, as well as treatment planning. During the LITT session, intra-procedural imaging is acquired immediately at the beginning of the procedure for tumor delineation, during the ablation to monitor treatment using MR thermometry, and immediately post-LITT to evaluate the ablated region. Images obtained during the LITT procedure are useful to estimate extent of ablation, either by analyzing the real-time thermometry data or by comparing pre- and post-ablation images. In the months following LITT, follow-up scans exhibit characteristic imaging patterns for responding versus progressing lesions, which should be accounted for during post-LITT surveillance. In light of these patterns, and considering the strategies adopted by previous LITT studies, we propose dedicated criteria for local radiologic response and local radiologic progression in clinical trials, by adapting the RANO-BM criteria for local therapies to a "dual baseline" framework dedicated to LITT treated BM. Finally, we provide suggestions for the adoption of standardized post-LITT imaging protocols based on the current consensus.

BACKGROUND AND STUDY AIM: Endoscopic submucosal resection (ESR) is a novel resection technique. ESR is performed with a partially insulated snare, which allows a resection close to the proper muscle layer thus resecting in the deep submucosa. This should have advantages over endoscopic mucosal resection (EMR). This pilot study aimed to compare the quality of specimens obtained by ESR versus EMR with emphasis on preservation of submucosal tissue. PATIENTS AND METHODS: In this retrospective single-center study we analyzed specimens from large flat or sessile rectal neoplasms resected by either ESR or EMR. The primary outcome was a comparison of specimen quality assessed by a validated semiquantitative histopathology score which rates specimen quality between 0-5 points. Secondary outcomes included en bloc and R0 resection rates, complications and recurrences. RESULTS: We included 35 procedures (ESR,  = 21; EMR,  = 14) with median lesion sizes of 30 × 23 mm (ESR) and 38 × 30 mm (EMR). Optimal histopathology scores were obtained in 66.6% (14/21) of ESR vs. 7.1% (1/14) of EMR specimens ( = 0.005). ESR resulted in higher en bloc rates (67% vs. 28%,  < 0.001). There was no significant difference in R0 resection, complication or recurrence rates. CONCLUSIONS: ESR provides superior specimen quality compared with EMR, allowing more accurate histopathological evaluation, particularly in neoplastic lesions with suspected submucosal invasion.

BACKGROUND: Obesity is characterized by low‑grade chronic inflammation and impaired insulin sensitivity. Maresin‑1 (MaR1), a specialized pro‑resolving mediator, plays a critical role in terminating inflammation and supporting metabolic homeostasis; however, interventional data in humans remain scarce. This study examined whether fisetin supplementation augments the effects of concurrent interval resistance-aerobic training on Maresin‑1, pro‑inflammatory markers, and insulin resistance in obese men. METHODS: In a 12‑week parallel‑group randomized controlled trial, 44 obese adult males (BMI > 30 kg/m²) completed one of four interventions: control-placebo (CP), fisetin (F) (200 mg/day), training-placebo (TP), or training-fisetin (TF). Training comprised eight resistance exercises at 60% 1RM with active rest followed by progressive aerobic bouts (50%-70% HRmax). Anthropometric and biochemical parameters, including plasma Maresin‑1, interleukin-6 (IL‑6), tumor necrosis factor-alpha (TNF‑α), fasting blood glucose (FBS), insulin, and HOMA‑IR, were assessed pre‑ and post‑intervention. RESULTS: Significant group × time interactions were observed for Maresin‑1 ( = 0.034), IL‑6 ( = 0.001), TNF‑α ( = 0.001), FBS ( = 0.001), insulin ( = 0.001), and HOMA‑IR ( = 0.001). Maresin‑1 increased in the TP ( = 0.001) and TF ( = 0.001) groups. IL‑6 decreased in T ( = 0.006), TF ( = 0.001), and F ( = 0.013) groups. TNF‑α decreased in all intervention groups (F, TP, and TF) ( = 0.002). FBS, insulin, and HOMA‑IR decreased significantly in all active arms ( = 0.003), with the greatest reductions in the TF group. CONCLUSION: Twelve weeks of concurrent interval resistance-aerobic training, especially when combined with fisetin, improved inflammatory resolution (↑Maresin‑1, ↓IL‑6, and ↓TNF‑α) and metabolic control (↓FBS, ↓insulin, and ↓HOMA‑IR) in obese men. The synergy between exercise‑induced adaptations and fisetin's anti‑inflammatory properties offers a promising non‑pharmacological strategy for mitigating obesity‑related metabolic risk.

IMPORTANCE: Risk-based breast cancer screening has emerged as a viable alternative to annual mammography. To guide implementation, knowledge is needed on the contribution of testing for pathogenic variants (PVs) beyond clinical risk factors and common genetic variants for population-based risk stratification. OBJECTIVE: To evaluate how many PV carriers in a risk-based breast cancer screening trial would have been recommended for high-risk screening based on clinical risk or clinical plus polygenic risk. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used retrospective data from the WISDOM Study, a national clinical trial of risk-based vs annual breast cancer screening, to compare screening assignments informed by PV status vs those based on a clinical risk model alone or a clinical risk model combined with a polygenic risk score. WISDOM participants aged 40 to 74 years who tested positive for a PV as part of risk-based screening were included. Data were collected from September 2016 to February 2023, with follow-up to September 2025. Data were analyzed from January to May 2026. MAIN OUTCOMES AND MEASURES: Concordance between actual (considering participants' PV status) and hypothetical screening assignments based on a clinical (Breast Cancer Surveillance Consortium) risk model or a clinical model plus polygenic risk score. RESULTS: Of 712 included women with a PV, the median (IQR) age was 53 (46-62) years. A total of 232 PVs (33%) were high penetrance, 278 (39%) were moderate penetrance, and 202 (28%) were CHEK2 low penetrance. There was little overlap between actual screening assignments based on PV status and hypothetical assignments based on a clinical model plus polygenic risk score. Among high-penetrance PV carriers (a group recommended high-risk screening with magnetic resonance imaging alternating with mammography every 6 months), 2 of 232 (0.9%) would have received the same screening assignment based on clinical plus polygenic risk. Overall, 178 of 279 PV carriers aged 40 to 49 years (63.8%) would have otherwise been recommended to defer screening until age 50 years based on clinical plus polygenic risk, whereas 385 of 433 carriers aged 50 to 74 years (88.9%) would have been recommended biennial mammography. Results were similar when comparing assignments based on a clinical model alone. CONCLUSIONS AND RELEVANCE: In this cohort study, most participants with PVs in breast cancer genes would not have been recommended for high-risk screening based on their clinical or clinical plus polygenic risk. PV testing therefore may identify different subsets of high-risk women than clinical risk factors and polygenic risk scores. These findings highlight the importance of population-based PV testing in risk-based screening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02620852.

Rare disease drugs represent a significant portion of new drug approvals, but the United States and European Union (EU) have differing approaches to Orphan Drug designations, impacting application fees and market exclusivity. This cross-sectional study analyzed the first rare disease drug approvals in the United States and EU from 2011 to 2020 using data from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) databases, describing similarities and differences in how both regions grant Orphan Drug designations. Out of 344 rare disease drug approvals, 336 (97.7%) were licensed by the FDA with Orphan Drug designations, 139 (40.4%) by the EMA with Orphan Drug designations; 131 (38.1%) were licensed with Orphan Drug designations by both the FDA and EMA, while 103 (29.9%) were approved in the EU without this designation. Additionally, 110 (32.0%) had approval from one agency only, with 102 (29.7%) by the FDA and 8 (2.3%) by the EMA. Both agencies were most consistent in granting Orphan Drug designations for advanced therapies (75.0%) and genetic diseases (55.4%). EMA approvals were lacking for tropical diseases (12.7%), while EU designations were often absent for diseases not considered distinct entities, such as subsets of cancers or pediatric indications of prevalent diseases. These findings reflect the differing regulatory frameworks and practices between the United States and the EU. Policymakers seeking to improve rare disease drug approval could prioritize incentives for the development of treatments for truly rare diseases as opposed to subsets of more common conditions for which incentives have already been established or create pathways that tackle scientific and societal challenges.

Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement). External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (AUROC: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age (p < 0.05). Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1-SD increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality. Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (HR = 3.94 [3.20-4.86] and 7.82 [2.05-29.80]), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal cancers, with over 90% of cases harboring KRAS gene mutations. These mutations not only serve as key drivers of tumorigenesis but also reshape the tumor microenvironment (TME), creating a highly immunosuppressive "cold tumor" characterized by immune cell dysfunction, a dense fibrotic stroma, and a unique metabolic state. This immunosuppressive TME contributes to the widespread resistance of PDAC to immune therapies, such as immune checkpoint inhibitors (ICIs). This review systematically elucidates the mechanisms by which KRAS mutations shape the immune-suppressive TME, with a focus on the multimodal combination strategies developed to overcome this resistance. These strategies include combinations of ICIs with chemotherapy, radiotherapy, and targeted therapies (e.g., KRAS G12C/D inhibitors, PARP inhibitors, FAK inhibitors, MEK inhibitors), as well as explorations of novel immunotherapies like CAR-T cell therapy, oncolytic viruses, and T-cell agonists. Additionally, we discuss the potential of innovative localized drug delivery technologies, such as hydrogels, intelligent nanoparticle carriers, and oral spore systems, in enhancing intratumoral drug concentrations while reducing systemic toxicity. Despite the limited efficacy of monotherapy in immune treatment, increasing preclinical and clinical evidence suggests that well-designed combination strategies, by remodeling the TME through multiple targets, hold the promise of converting "cold tumors" into "hot tumors," thereby restoring anti-tumor immune responses. Future breakthroughs in therapy will depend on the use of multi-omic biomarkers, including ctDNA, exosomes, and microbiomes, for precise patient stratification, guiding tailored immune combination therapies, and ultimately improving the survival outcomes of PDAC patients.

Breast cancer progression is increasingly recognized as a dynamic process shaped by reciprocal communication between malignant cells and the tumor microenvironment (TME). Among immune-cell populations, tumor-associated macrophages (TAMs) are major regulators of immune suppression, metabolic adaptation, angiogenesis, and therapeutic resistance. Emerging evidence indicates that extracellular vesicle (EV)-mediated transfer of long non-coding RNAs (lncRNAs) constitutes an important mechanism underlying tumor-immune communication in breast cancer. In this review, we summarize mechanistically characterized studies examining how exosomal lncRNAs regulate bidirectional signaling between breast cancer cells and macrophages and contribute to tumor progression, immune remodeling, and resistance-associated phenotypes. Tumor-derived exosomal lncRNAs modulate macrophage signaling through pathways associated with signal transducer and activator of transcription 3 (STAT3), transforming growth factor beta (TGF-β), Hippo/Yes-associated protein (YAP), hypoxia-responsive signaling, and autophagy-related remodeling, thereby promoting immunoregulatory and tumor-supportive macrophage phenotypes. Conversely, macrophage-derived exosomal lncRNAs, including hypoxia-inducible factor-1 alpha (HIF-1α)-stabilizing long non-coding RNA (HISLA), reinforce glycolytic adaptation, epithelial-mesenchymal transition, epigenetic remodeling, metastatic plasticity, and resistance to therapy in recipient tumor cells. Exosomal lncRNA signaling additionally influences γδ T cells, endothelial cells, and stromal compartments, supporting broader multicellular regulation within the TME. Collectively, current evidence supports exosomal lncRNAs as biologically important mediators of tumor-immune adaptation in breast cancer. We further discuss the translational potential of circulating exosomal lncRNAs as minimally invasive biomarkers and evaluate therapeutic strategies targeting EV biogenesis, vesicle trafficking, and oncogenic lncRNA cargo molecules. Finally, we highlight current limitations involving EV heterogeneity, lncRNA stoichiometry, and incomplete in vivo validation that remain critical barriers to clinical translation.

Breast cancer (BC) poses a substantial impact on the global health landscape, thereby demanding the creation of novel therapeutic approaches aimed at enhancing patient outcomes. The objective of this article is to conduct an analysis of the potential benefits and drawbacks related to the application of siRNA-based therapy in the context of BC, along with its targeting capabilities. This paper commences by highlighting the imperative need for pioneering treatment methodologies in response to the substantial incidence of BC. This section of the article examines the molecular mechanisms underlying small interfering RNA (siRNA), with a particular emphasis on its role in selectively suppressing cancer-associated genes involved in tumor initiation and progression. The efficacy of therapies utilizing siRNA is reliant on the presence of effective delivery mechanisms. The objective of this research is to examine the effectiveness and safety of liposomes, nanoparticles (specifically carbon nanoparticles and metal nanoparticles), as potential vehicles for delivering targeted siRNA. Moreover, the objective of this article is to investigate the potential of siRNA in the context of mitigating drug resistance and augmenting the effectiveness of treatments. Additionally, the study aims to investigate the obstacles related to delivery efficiency, potential immune responses, and the suppression of off-target genes. The present comprehensive literature review concludes with a meticulous examination of the potential transformative effects of siRNA-based therapeutic approaches for BC. The primary objective of this study is to advance the development of enhanced and personalized therapeutic interventions for BC.

BACKGROUND: Ewing sarcoma arises at both skeletal (SES) and extraskeletal (EES) sites; however, whether the anatomical origin influences outcomes in current practice remains uncertain. This study compared clinical characteristics, treatment, and survival rates of patients with SES and EES in a large nationwide Japanese cohort. METHODS: We analyzed patients diagnosed with Ewing's sarcoma between 2016 and 2019 in Japan, classified as having SES or EES, using a population-based cancer registry. Demographics, stage, treatment, hospital characteristics, and overall survival (OAS) were evaluated using chi-square tests, Kaplan-Meier estimates, and log-rank analyses. RESULTS: We identified 505 patients with ES: 211 with SES and 294 with EES. Patients with EES were significantly older than those with SES (P < .001). Chemotherapy (97.7% vs. 74.9%, P < .001) and radiotherapy (36.6% vs. 27.1%, P = .024) were administered more frequently in the SES group. Three-year OAS rate was 62.3%, 73.5% for SES, and 54.7% for EES, with significantly worse survival in EES group (P < .001). Favorable prognostic factors included younger age, localized stage, surgery, chemotherapy, treatment at certified institutions, higher hospital volume, and female sex among patients with EES. CONCLUSIONS: In this nationwide cohort, EES presented at older ages, received less chemotherapy, and demonstrated inferior survival compared to SES, despite a similar stage distribution. Patient background, hospital type, and volume influenced the outcomes. These findings underscore the need for equitable multimodal therapy delivery, particularly for patients with EES.

OBJECTIVES: Clinical studies in muscle-invasive bladder cancer (MIBC) often enroll younger and fitter patients than those treated in routine practice, limiting generalizability. We developed a simple eligibility gap (EG) score to quantify baseline eligibility differences between clinical studies and real-world cohorts. METHODS: Eight clinical studies and eight real-world datasets were analyzed. The EG score was based on three commonly reported determinants: age, Eastern Cooperative Oncology Group performance status (ECOG PS), and cisplatin eligibility, each scaled from 0 to 33.3 points (total range: 0-99.9). Higher scores indicate younger, fitter, and more cisplatin-eligible populations. Known-groups validity was assessed by comparing EG scores across prespecified study categories expected to differ in eligibility selectivity. Sensitivity analyses using alternative fixed weighting schemes and random-weight simulations were performed to examine score robustness. RESULTS: Baseline characteristics differed between clinical studies and real-world cohorts. Trial populations were generally younger, had better ECOG PS, and showed higher cisplatin eligibility than real-world cohorts. EG scores followed the expected ordering across prespecified study categories, with the highest values in cisplatin-fit trials (86), intermediate values in real-world cohorts (66), and the lowest values in cisplatin-unfit/refusal trials (44), consistent with known-groups validity. Domain-specific analyses showed larger differences in age and cisplatin eligibility than in ECOG PS. Across alternative weighting scenarios, rank correlations with the equal-weight model remained high (ρ = 0.976-0.994), and the expected category-level ordering was preserved. CONCLUSIONS: The EG score describes eligibility differences between clinical studies and real-world MIBC populations and may aid interpretation of trial evidence across heterogeneous populations.

AIM: Tumor hypoxia is a major driver of tumor progression and metastasis. Hypoxic adaptation is regulated by hypoxiainducible factor-1 (HIF-1), which controls the transcription of genes promoting malignant behavior. HIF-1 inhibitors have failed as monotherapies in clinical trials, highlighting the need for combination-based strategies. This study aimed to develop hypoxia-targeted combination therapies for breast and ovarian cancers. METHODS: Using established in vitro and in vivo hypoxia models, we evaluated acriflavine, a HIF-1 inhibitor, in combination with paclitaxel and an epithelial-mesenchymal transition targeting agent. RESULTS: Acriflavine exerted potent antiproliferative effects, particularly in triple-negative breast cancer cell lines, and proteomic profiling indicated modulation of migration, proliferation, and cellular metabolism. The acriflavine-paclitaxel combination showed synergistic antitumor and antimetastatic activity, which was further enhanced by rolipram. CONCLUSIONS: Overall, our findings support hypoxia-targeted combination approaches and provide a biological rationale for combining HIF-1 inhibition with immune checkpoint blockade in breast cancer.

AIM: This study aimed to investigate the role of the tumor microenvironment in two key aspects of cancer progression: regulation of tumor cell motility and development of resistance to targeted therapy. METHODS: In vitro lung adenocarcinoma cell lines were used to assess the effects of hypoxia on cell migration, proliferation, signaling pathway activity, and expression of epithelial- mesenchymal transition (EMT) markers. RESULTS: Hypoxia reduced single-cell motility and proliferation while promoting collective invasion and inducing cell line-specific EMT-related changes. Hypoxia-mimicking CoCl2 treatment failed to reproduce the effects of true hypoxic conditions. In the second part of the study, a patient- derived tumor xenograft (PDTX) model of BRAF V600E mutant melanoma was established to investigate acquired resistance to vemurafenib. Bulk RNA sequencing identified potential resistance-associated markers, however, protein- level validation was inconclusive. CONCLUSIONS: Our results highlight that both hypoxia and therapeutic pressure modulate tumor progression in a complex, context-dependent manner.

AIM: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy in which serum calcitonin plays a pivotal role in early diagnosis, surgical planning, guidance of systemic therapy, and monitoring of treatment response. This case highlights the importance of laboratory diagnostics during selpercatinib therapy in a patient with disseminated MTC harboring a rare RET pathogenic variant. METHODS: A cervical vertebral fracture in a young, asymptomatic male revealed MTC metastasis with distant dissemination and markedly elevated serum CEA and calcitonin levels. Tumor tissue and circulating DNA analysis identified the rare p.Glu632_Leu633del RET mutation. No germline alteration was detected. First-line systemic therapy comprised the selective RET tyrosine kinase inhibitor selpercatinib combined with denosumab. RESULTS: Rapid clinical improvement occurred without significant adverse effects. Serum calcitonin levels normalized within four weeks, and imaging revealed marked tumor regression. CONCLUSION: This case underscores the value of liquid biopsy detected mutations in guiding targeted therapy. Clinical, biochemical, and radiological findings support the potential use of selective RET tyrosine kinase inhibitors for this rare mutation. Serum calcitonin serves as a reliable quantitative biomarker of therapeutic efficacy.

Psychological stress and cancer are frequently framed in causal narratives in public discourse; however, current scientific evidence does not support such assumptions. Epidemiological and prospective cohort studies indicate that psychological stress cannot be established as an independent carcinogenic factor, and population-level associations between stress and cancer incidence are consistently absent. Certain psychosocial variables, including maladaptive coping strategies or persistent high-level distress, show moderate and inconsistent associations with clinical outcomes (e.g., survival, recurrence), but these findings are heterogeneous and subject to methodological limitations. Psycho-oncological interventions effectively reduce psychological distress and improve quality of life, while direct causal effects on tumor progression remain unproven. Accordingly, psychosocial care is clinically warranted, contributing to patient well-being and adaptive coping, while clearly distinguishing these effects from biological causal pathways.

HER2-targeted therapies have improved outcomes in solid tumors, but their efficacy is often limited by resistance and tumor microenvironmental barriers. Over the past decade, the University of Debrecen Cell and Molecular Therapy Research Group has focused on developing CAR-engineered immune cell strategies to address these challenges. Our work spans advances in CAR-T cell design, including optimization of costimulatory signaling, development of modular targeting systems, and expansion toward off-the-shelf platforms such as CAR-NK cells. Collectively, these efforts highlight the potential of engineered immune cells to overcome key limitations of conventional therapies and support the continued evolution of CAR-based approaches for solid tumors.

Glucocorticoids, most commonly dexamethasone, are widely used alongside breast cancer therapy to alleviate adverse effects of chemotherapy, particularly allergic reactions and nausea. However, growing evidence shows that the activation of the glucocorticoid receptor (GR) has context-dependent effects on tumour biology, with both tumour-suppressive and tumour-promoting consequences. This review summarises the molecular basis of GR signalling in breast cancer and its prognostic relevance across molecular subtypes. Particular emphasis is placed on ligand-dependent and ligand-independent GR activation, crosstalk with the oestrogen receptor and GR-regulated transcriptional programmes associated with tumour cell migration and therapy resistance. Overall, the available evidence suggests that the use of glucocorticoids in triple-negative breast cancer is not biologically neutral. Assessment of GR using methods such as routine immunohistochemistry may add future value for patient's stratification for GR-targeted therapy and could inform more personalised supportive treatment and follow-up strategies; however, these approaches require prospective validation before clinical implementation.

Targeting the cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, also named TXNRD1) has emerged as a promising strategy to exploit redox vulnerabilities in cancer. However, both preclinical observations and recent mechanistic studies indicate that TrxR1 inhibition can have context‑dependent outcomes. This article synthesizes a mechanistic framework linking cytosolic redox buffering, proteostasis, receptor tyrosine kinase (RTK) signaling, and immune surveillance with treatment responses. It highlights the dual functional roles of the TrxR1-substrate TXNL1 (also named TRP32), discusses intracellular transcriptional crosstalk shaping treatment sensitivity, and outlines potential combination strategies with RTK modulators.

Cancer drug resistance remains one of the greatest barriers to durable therapeutic success. Here, we reframe resistance as a dynamic landscape shaped by transporter‑mediated efflux, reversible drug‑tolerant persister states, and therapy‑induced senescence. This review highlights areas where our group has made substantial contributions, with a particular focus on our own experimental and conceptual advances. We show how P‑glycoprotein (P-gp) overexpression, traditionally viewed as an obstacle sustaining cancer multidrug resistance (MDR), creates exploitable metabolic vulnerabilities, enabling the development of MDR‑selective compounds. We demonstrate that persister cells rely on transient P‑gp-mediated detoxification, revealing a therapeutic window during drug‑free intervals. We further show that senescence is not a terminal fate but a relapse‑initiating state requiring targeted intervention. Finally, we illustrate how pharmacokinetics and dosing schedules can be harnessed to reshape tumor evolution, culminating in LiPyDau, a next‑generation liposomal anthracycline with durable activity against resistant tumors. Together, these insights outline a unified strategy for anticipating, intercepting, and ultimately overcoming cancer drug resistance.

Cancer metabolism is a central field in oncology, strongly serving as critical adaptation mechanism driving tumour progression, therapeutic response, and patient prognosis. The complexity of tumour metabolism remains difficult to mimic using conventional experimental conditions. Preclinical models, including in vitro 2D cultures and in vivo animal models, often fail to accurately reproduce the dynamic tissue alterations. Increasing evidence highlights the crucial role of the tumour microenvironment, nutrient availability, hypoxia, extracellular matrix components, and metabolic crosstalk between cancer, stromal, and immune cells in shaping tumour metabolic rewiring. Consequently, advanced 3D culture systems have gained significant attention, offering new perspectives for modelling cellular complexity and metabolic heterogeneity. This review summarises metabolic adaptation mechanisms influenced by microenvironment, and discusses the evolution of current modelling. Furthermore, through our own research in 3D bioprinting, we highlight the emerging role of 3D bioprinted models in tumour biology, cancer metabolism research and drug sensitivity studies.

Single-agent paclitaxel or cetuximab after immune checkpoint inhibitor (ICI) and chemotherapy demonstrated objective response rates (ORRs) of 21%-24% in recurrent/metastatic (R/M) head/neck squamous cell cancer (HNSCC). EGFR and MET are overexpressed in R/M HNSCC. Amivantamab, an EGFR-MET bispecific antibody, may be a rational treatment. Cohort 1 of OrigAMI-4 (NCT06385080) evaluated subcutaneous amivantamab administered every three weeks in participants with R/M HNSCC after PD-(L)1 inhibitor and platinum-based chemotherapy. Prior anti-EGFR was exclusionary. The primary endpoint was RECIST v1.1 ORR. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. In 102 participants, blinded independent central review-assessed ORR was 42% (95% CI, 32-52); the complete response rate was 15%. Median DoR was not reached (NR; 95% CI, 6.9-NR); 56% of responses lasted ≥6 months. Investigator-assessed ORR was 47% (95% CI, 37-57). At a median follow-up of 11.8 months (range, 1.1-21.9), median PFS and OS were 6.8 months (95% CI, 5.2-8.3) and 12.5 months (95% CI, 10.2-16.8), respectively. Adverse events were consistent with previous experience with no new safety signals. Treatment-related discontinuations were low (8%). Amivantamab demonstrated greater antitumor activity in participants previously exposed to ICI and chemotherapy than what has been reported for paclitaxel or cetuximab.

PURPOSE: The incidence of young-onset colorectal cancer is increasing, and affected patients experience distinct challenges. Patients with young-onset colorectal cancer may benefit from a dedicated care coordinator that systematically assesses their unmet needs and facilitates referrals to multidimensional specialty support services. METHODS: In this pragmatic trial, we assigned newly diagnosed colorectal cancer patients aged <50 years who presented to a tertiary academic institution between 2023-2025 to standard care vs. standard care plus additional encounter(s) with a dedicated young-onset colorectal cancer care coordinator. Patient-reported concerns and distress were collected at initial presentation. The primary endpoint was utilization frequency of support services. Multivariable regression identified predictors of service utilization. RESULTS: Among 1,250 patients with young-onset colorectal cancer (mean age 42.8±6.0 years; 45.4% female), 46.3% had rectal cancer. Emotional concerns were most common (41.0%), followed by physical (36.1%), practical (27.8%) and social (9.4%) concerns. Overall, clinically significant distress (distress score ≥4) was reported by 27.4%. The young-onset colorectal cancer coordinator successfully established contact with 604 individuals. Unmet service needs were reported by 39.1% in the intervention group, of whom 80.5% subsequently accessed corresponding support services. Patients who established contact with the young-onset colorectal cancer coordinator were more likely to access support services (72.5% vs.44.7%, p<0.001). On multivariable analysis, coordinator contact (aOR 1.48, 95%CI 1.22-1.80), rectal cancer diagnosis (aOR 1.36, 95%CI 1.13-1.62), and clinically significant distress (aOR 1.23, 95%CI 1.01-1.50) predicted greater multidimensional service utilization. CONCLUSION: Patients with young-onset colorectal cancer experience substantial emotional concerns and unmet needs. Proactive integration of a dedicated care coordinator was associated with significantly increased utilization of multidimensional support services. This pragmatic trial supports a personalized, needs-driven care delivery model, that integrates patient-reported outcomes as the basis for patient-centric cancer care.