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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.

Daily online adaptive radiation therapy (OART) allows the creation of individualized safety margins based on daily optimized treatment planning, taking into account daily anatomy variations. The goal of our work was to compare the protocols and safety margins of a non-adapted, image- guided radiation therapy (IGRT), a published Danish and the National Institute of Oncology of Hungary (NIO) protocol in the first eight bladder cancer patients treated with OART. Three cone beam CTs (CBCT) were taken during the first three fractions: after patient positioning, after adaptation, and at the end of treatment. Bladder contours, extensions and margins were established on all CT images (n=512). Intraadaptational, intrafractional and interfractional changes were examined. Regarding PTV, a mean reduction of 12.2% could be achieved using the Danish, and 34.1% using the NIO protocol compared to IGRT. Healthy tissue irradiated by the prescribed dose could be reduced. The target volume miss is decreased as well. PTV could be reduced and optimized, increasing healthy tissue protection using OART.

Optimizing the treatment of metastatic prostate cancer is important for reducing mortality. Therefore, it is essential, among others, to know the predictive markers of abiraterone acetate (AA) treatment in metastatic castration-resistant prostate cancer (mCRPC). We aimed to clarify the predictive factors of AA treatment of mCRPC patients, and particularly the predictive role of comorbidities and co-medication based on meta-analysis of published data. Meta-analysis of the results of multivariate analysis found in 120 publications examining at least 100 cases. Besides clear predictors of progression-free and overall survival, opioid use, pain, cerebrovascular diseases, dyslipidemia, statin treatment, bisphosphonate/antiresorptive treatment and metabolic syndrome significantly affect the risk of progression and survival. Since the analysis of comorbidities is based on relatively few observations, further studies are needed to clarify the predictive impact of comorbidities and co-medication in order to improve the effectiveness of treatment in mCRPC in an individualized manner.

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. 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. Rapid clinical improvement occurred without significant adverse effects. Serum calcitonin levels normalized within four weeks, and imaging revealed marked tumor regression. 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.

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. 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. 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. Our results highlight that both hypoxia and therapeutic pressure modulate tumor progression in a complex, context-dependent manner.

To evaluate the efficacy and safety of high-dose-rate interstitial VAPBI in women undergoing conservative surgery for low-risk, early invasive breast cancer. Between December 2018 and December 2024, 28 patients were enrolled in this prospective, non-randomized trial. Targeted radiotherapy of the tumor bed was delivered using thin plastic catheters placed at the surgical site, through which a high-dose-rate Ir-192 source was administered. Prescribed doses were 4×6.25 Gy (25 Gy total) or 3×7.45 Gy (22.35 Gy total), delivered over two consecutive working days. With a median follow-up of 60 months (range: 9-84), local recurrence was observed in 2 patients (7.1%). One patient (3.6%) died of liver metastases, and another (3.6%) from a second primary tumor. The 5-year local control rate was 93.7% (95% CI: 88.1-99.4). Late toxicity was limited to grade 1 fibrosis in 6 patients (21.4%) and grade 1 pain in 2 patients (7.1%); no grade ≥2 toxicities occurred. Cosmetic results were excellent or good in all cases. Reducing interstitial treatment duration from 5 to 2 days appears safe and more convenient for patients.

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.

To investigate the effect of a model-based calculation algorithm that takes into account tissue inhomogeneities and real scattering conditions, on dose-volume parameters in brachytherapy for head and neck tumours. We recalculated the treatment plans of twentyfour patients treated with brachytherapy using the modelbased Advanced Collapsed Cone Engine (ACE) algorithm. High-dose volumes in the target and volumes irradiated with lower doses were determined. We calculated the doses to the organs at risk for the small volumes receiving high doses and the average doses. The conventional calculation algorithm calculated higher doses than ACE for almost all parameters. The difference was less than 1% for V100 and D90. Among the volumes enclosed by the isodose surfaces, the difference was greater between the high-dose volumes and the low-dose volumes. The doses to the mandible were 2-3% lower with ACE, while the doses to the skin were 4-7% lower. The difference to the salivary glands was between 5-8%, while the doses to the spinal cord were the same. When treating head and neck tumours, the traditional calculation algorithm overestimates the doses to the target volume and organs at risk. The introduction of the new calculation algorithm into clinical practice is not yet recommended.

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.

Following the groundbreaking discoveries of X-rays, radium, and radioactivity, Hungarian radiotherapy has a 130-year history. Initially, external beam irradiation was performed by radiologists, while radium therapy was performed by representatives of manual surgical professions. Oncoradiology, and later radiotherapy, became an independent medical discipline in 1970. In this summary, we review the history of Hungarian radiotherapy, whose continuous development was significantly slowed down by the two world wars, but the dedicated experts in the field of radiation oncology (including physicians and physicists) ensured that today Hungarian cancer patients have access to the most modern radiotherapy procedures without waiting lists. Of course, within the framework of the National Cancer Control Programme significant funding will be required in the coming period to maintain and develop human resources and radiotherapy equipment.

To identify clinicopathological and molecular factors influencing immune checkpoint inhibitor efficacy in urothelial carcinoma (UC). We analyzed >200 patients with locally advanced or metastatic UC treated with pembrolizumab or atezolizumab. Gene expression profiling was performed on 100 tumors, and baseline and on-treatment serum soluble PD-L1 (sPD-L1) levels were measured. Integrated clinicopathological- molecular survival model was developed. Objective response rate (ORR) and overall survival (OS) were comparable to clinical trials. Poor ECOG status, metastases, low hemoglobin, and Bellmunt risk factors independently predicted shorter OS. Gene expression analysis identified 23 genes associated with OS and additional genes linked to response; PSMB10 showed validated prognostic and predictive value. Neuronal and TCGA-luminal infiltrated subtypes had the best outcomes, and high neuronal signatures correlated with longer OS. Elevated baseline sPD-L1 predicted poor OS. Integrating clinical and molecular biomarkers improves survival stratification and may refine immunotherapy selection in UC.

Despite their undeniable effectiveness, the spectacular increase in the number of antitumor immunotherapies (IT) in recent years has resulted in a substantial organizational and financial challenge on healthcare systems, and prolonged treatments can be burdensome for patients as well. There is an ongoing debate about how long it is optimal to continue palliative IT, or it can be discontinued after 2 years without an increased risk of relapse. Conclusively, it could be especially justified in complete tumor remission, however stable disease does not preclude it, and the decision may be strengthened by chronic complications, comorbidity state, patient preference, and PET/CT negativity, double IT, and lack of prior oligo- progression. Nevertheless, all this requires individual consideration, tumor-board discussion, and it is recommended to gradually prepare patients psychologically. In summary, while maintaining the possibility of reinduction, the discontinuation of palliative IT should always be considered after 2 years application (even after 1 year in melanoma), aiming for the longest treatment-free survival of our patients and minimizing the feeling of having a chronic and incurable disease.

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 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.

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. 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. 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. 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.

Chromophobe renal cell carcinoma (chRCC) is a morphologically heterogeneous tumor type, with one of its rarest forms being pigmented microcystic chromophobe carcinoma. In our paper, we present the case of a 68-year-old man, in whom imaging studies identified a 32 mm kidney tumor. The tumor was surgically removed, and pathological analysis revealed a cystic tumor with unusual morphology, composed of eosinophilic cells. Brown pigment and hemorrhage were present in the lumen of the cysts. Immunohistochemically, the tumor showed diffuse CD117, PAX8, and E-cadherin expression, with focal positivity for CK7 and CD10. GATA3, MelanA, HMB45, cathepsin K, CK20, chromogranin A, and synaptophysin reactions were negative. Chromosome 17 monosomy could not be detected using double-labeled HER2/cen17 chromogenic in situ hybridization. The patient recovered well after the operation and is currently under oncological care. To the best of our knowledge, this is the first documented case of pigmented microcystic chromophobe carcinoma diagnosed in Hungary. The aim of this paper is primarily to raise awareness, and in the course of our work, we will review the morphological subtypes of chRCC and the differential diagnostic entities.

Squamous cell carcinoma is the most prevalent tumor type among the malignancies of the mucosal lined surfaces in the head and neck region. Most frequently the diagnosis is based on the tissue taken from the primary tumor and in some cases an involved lymph node serves as a source of samples. The pathology report plays a crucial role in the decision making which is guided by the different factors included in the report. In this article we aimed to summarize the prognostic and predictive factors regarding squamous cell carcinoma of oral and pharyngeal origin while taking into account the international standards.

As non-surgical therapies gain acceptance in head and neck tumors, the importance of imaging has increased. New therapeutic methods (in radiation therapy, targeted biological therapy, immunotherapy) need better tumor characterization and prognostic information along with the accurate anatomy. Magnetic resonance imaging (MRI) has become the gold standard in head and neck cancer evaluation not only for staging but also for assessing tumor response, posttreatment status and complications, as well as for finding residual or recurrent tumor. Multiparametric anatomical and functional MRI (MP-MRI) is a true cancer imaging biomarker providing, in addition to high resolution tumor anatomy, more molecular and functional, qualitative and quantitative data using diffusion- weighted MRI (DW-MRI) and perfusion-dynamic contrast enhanced MRI (P-DCE-MRI), can improve the assessment of biological target volume and determine treatment response. DW-MRI provides information at the cellular level about the cell density and the integrity of the plasma membrane, based on water movement. P-DCE-MRI provides useful hemodynamic information about tissue vascularity and vascular permeability. Recent studies have shown promising results using radiomics features, MP-MRI has opened new perspectives in oncologic imaging with better realization of the latest technological advances with the help of artificial intelligence.