miRNAs are small molecules which influence cellular function by regulating the expression of mRNA. They control various stages of the cell’s existence, including differentiation, proliferation and finally death. In cancer cells, miRNAs can become dysregulated, enabling the cell to escape growth suppression and resist apoptosis, as well as adapt to new niches for metastasis. In breast cancer, miR-218 has been shown to play an important role, however, data is conflicting as to its oncogenic or tumour-suppressive impact. Our review aims to assess these differences and identify their potential causes. On one hand, research shows that miR-218 allows breast cancer cells to proliferate and migrate through activation of the EGFR/ErbB2 signalling pathway, as well as metastasize especially to bone tissue, by disrupting the osteogenesis-osteolysis equilibrium. However, data suggesting a tumour-suppressive function point to the role of miR-218 as an enhancer of chemo- and radiosensitivity, as well as an inhibitor of cell proliferation by acting on mTOR. Several studies correlate higher miR-218 expression with better outcomes in patients. It is also part of a subtle network of RNA regulator systems through its interplay with long-noncoding RNA. We hypothesize that these differences in the directionality of miR-218 stem mainly from the cell’s internal state, as well as interactions with its environment. Factors affecting different miRNA expression may include nutrient availability and phenotypic characteristics of the cancer. Therefore, to increase the viability of miR-218 as a therapeutic target, its exact role and context-dependence must be determined.
Breast cancer (BC) is one of the most frequently diagnosed cancer types, with severe consequences impacting almost every sphere of an individual’s life. Returning to work (RTW) is a crucial element in regaining a sense of normalcy; however, it remains a major challenge for the BC population due to a number of factors impacting employment outcomes. While the clinical impact of BC on RTW is well acknowledged and investigated, the psychosocial aspects of it have often been overlooked. Thus, the aim of this systematic review (SR) is to identify and systematically summarize the psychosocial factors associated with RTW in the BC population. Three scientific databases (PubMed, Embase, and Scopus) were searched to identify studies investigating psychosocial factors associated with RTW published from 2015 to 2025. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in the International Prospective Register of Systematic Reviews (PROSPERO). The methodological quality of the included studies was assessed using the modified Downs and Black checklist. Sixteen studies were included in this review. Our analysis identified a number of psychosocial variables significantly associated with work reintegration for this population of cancer survivors. More specifically, anxiety and depression emerged as the most prominent barriers to successful RTW. Other major determinants hindering RTW were fatigue (particularly mental and emotional) and impaired quality of life domains in emotional and social well-being. Factors positively associated with RTW included resilience, motivation, greater RTW self-efficacy, perceived support, and positive body image. This SR highlights that psychosocial factors play a crucial role in RTW outcomes among BC survivors. The findings underscore the need for a coordinated, multidisciplinary approach to optimize RTW outcomes, integrating oncological treatment, mental health support, and occupational rehabilitation in the cancer care pathway. Early psychosocial assessment within oncological care will enable the identification of vulnerable domains and guide the development of individualized survivorship care plans, tailored to optimize not only physical functioning but also psychological recovery and occupational reintegration.
The endpoint Time to Subsequent Therapy (TTST) is an intermediate endpoint used in research and regulatory assessments. TTST denotes initiation of subsequent therapy and is a clearly definable, clinically relevant event for healthcare professionals. However, it has not been systematically established to which extent TTST is subjectively meaningful to patients. The objective of this study was to define TTST as a patient-relevant intermediate endpoint. The study examined five oncological indications (breast cancer, prostate cancer, melanoma, multiple myeloma, and non-small cell lung cancer) using a systematic literature review, analysis of case report forms used in international randomized controlled trials, review of German Federal Joint Committee (G-BA) documents, semi-structured interviews and a two-stage Delphi survey with healthcare professionals, patients, and relatives. A total of 35 individuals participated in qualitative interviews. Most of them rated TTST as particularly significant. The Delphi Survey included 264 interviewees in round one, and 117 in round two. Patient-relevance of TTST was confirmed by 81
Abstract Purpose MISSION4Sax aims to develop and pilot new concepts for cross-sectoral oncological care, data integration and networking between maximum care centres and rural practitioners in medical underserved, enabling access to guideline-based therapy, innovative surgery, and clinical trials. Methods This pilot project is an exploratory multicentre, prospective longitudinal study. It assesses the feasibility, acceptability, implementation and data-quality aspects of the proposed care model and study infrastructure, rather than to determine the effectiveness or causal impact of the interventions. It implements an interdisciplinary, cross-sectoral care model centred on a regional surgical indication tumour board at the National Center for Tumor Diseases (NCT) Dresden. Evidence-based, standardised patient care pathways are developed and piloted across three regional hospitals and two oncology practices. A database using the infrastructure of the NCT Core Unit “Registry Trial Platform”, targeted training programmes and “Flying Data Nurses” support coordination, data flow and communication. Patient-reported outcomes complement the clinical data. Routinely collected health insurance data will be used exclusively as external reference data for a descriptive comparison with the MISSION4Sax cohort; no individual-level data linkage will be performed. A mixed-methods process evaluation will be performed alongside the project. Expected outcomes The study will assess feasibility in routine care and explore access to specialised care, waiting times, coordination, pathway adherence, and clinical and patient-reported outcomes. Conclusion Strengthening cancer care infrastructure, interdisciplinary cooperation, and digital systems may support equitable access to high-value care in rural regions. The proposed tumour board, patient pathways, and trained staff may improve care quality and collaboration across sectors. Trial registration DRKS00036134 (registration date: 30 June 2025)
Female informal caregivers, who provide critical support to cancer patients, may face substantial caregiver burden that may adversely affect their participation in preventive healthcare. We aimed to evaluate their knowledge and attitudes toward breast and cervical cancer screening and its correlation with caregiver burden. A cross-sectional study was conducted at a tertiary cancer centre using a structured questionnaire, which assessed demographics, caregiving burden (using the Zarit Burden Interview), health behaviours, and cancer screening practices. Descriptive and inferential statistics were used to identify predictors of screening knowledge and attitude. 480 women caregivers were recruited with a median age of 39 years. Most caregivers were married, and over 70
POLE/POLD1 mutations are associated with DNA proofreading defects and immunotherapy response in colorectal cancer (CRC), but their comprehensive profile and clinical utility remain incompletely clarified. We enrolled 450 consecutive CRC patients to systematically characterize POLE/POLD1 mutational profiles, their associations with clinicopathological features, immunotherapy efficacy, and survival outcomes, and subsequently developed and validated an integrated prognostic nomogram. The overall POLE/POLD1 mutation frequency was 5.78
Extramedullary disease (EMD) represents an aggressive manifestation of multiple myeloma (MM) in which malignant plasma cells acquire the ability to survive independently of the bone marrow microenvironment. Based on the site of involvement, EMD is classified into extramedullary bone related (EMB) that partially depends on the bone marrow, and extramedullary extraosseous (EME) that spreads through bloodstream. EMD can affect any tissue or organ and is associated with poor clinical outcomes in patients with MM. The underlying pathogenesis of EMD remains incompletely understood, and no standardized treatment approach has been established to date. This review integrates recent advances in the molecular pathogenesis of EMD with emerging immunotherapeutic strategies, particularly CAR-T cell-based therapies, and discusses the major translational challenges and future directions for improving the management of EMD.
Hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM) carries a poor prognosis, and treatment options after failure of anti-angiogenic targeted agents combined with immune checkpoint inhibitor (ICI) remain limited. An adult patient with advanced HCC exhibited primary resistance to three sequential immunotherapy-based regimens: first-line lenvatinib plus camrelizumab (progressive lung metastases), second-line atezolizumab plus bevacizumab (rapid tumor marker surge), and third-line atezolizumab plus regorafenib (new liver and adrenal metastases within 3 months, suspicious for rapid disease progression following immunotherapy). Fortunately, fourth-line mFOLFOX6 chemotherapy (oxaliplatin, leucovorin, and fluorouracil) plus bevacizumab induced a partial response (PR) with significant tumor shrinkage and substantial declines in AFP and PIVKA-II. The case had shown a total progression-free survival (PFS) for more than 21 months until the latest follow-up in June 2026. Then, we performed 24-plex spatial tissue profiling of the primary tumor. The tumor microenvironment revealed three core features: immune-desert (lymphocytes < 5
Abstract Purpose Psychosocial stressors and mental disorders can negatively affect the success of cancer treatments. Therefore, they should be addressed by target group-oriented psycho-oncological care. This study examined possible predictors of the use of psycho-oncological care. Methods Routine data from 5217 patients of a German Comprehensive Cancer Center between 2020 and 2023 were analysed in a retrospective monocentric study. The effects of predictors (gender, age, distance to the center, subjective stress at intake, and tumor stage) on the use of psycho-oncological care (use vs. no use) and on the number of psycho-oncological care sessions lasting at least 20 min were explored using logistic and binomial regression analyses. Results Women at younger age, experiencing subjective distress, and patients with advanced-stage cancer were significantly more likely to use psycho-oncological support. Female patients, younger patients, patients who lived closer to the treating centre, patients with subjective distress, and patients at higher tumor stages attended more sessions of psycho-oncological counselling. The analyses also indicated substantial differences between different organ-specific cancer centers. Conclusion All patients should be screened for psychological distress and wish for psycho-oncological support by a structured and validated tool. Vulnerable patients, patients at risk, and those, who are hesitant to seek help, could be screened by an interview to reduce barriers.
Globally, esophageal cancer is one of the main reasons of deaths from cancer. The initiation and progression of this malignancy is the result of complex interactions between alterations in genes, epigenetic processes and components of the tumor microenvironment. Esophageal squamous cell carcinoma (ESCC) is the most frequent histological type of esophageal carcinoma in human being, which is associated with high incidence, poor prognosis and few therapeutic options. Recent investigations suggest that an enzyme that is related to lipid metabolism, namely, Platelet activating factor acetylhydrolase 1B subunit 3 (PAFAH1B3) plays a crucial role in the development of tumours among various types of cancer. Nevertheless, the exact role played by this factor in ESCC so far has not been clarified in detail. The aim of this investigation was on providing a comprehensive characterization of PAFAH1B3 expression patterns in several cancers along with its associations with survival outcomes of patients and the immune components of tumor microenvironments. Such efforts aimed to improve the understanding of the functional contributions and probable pathways of the action of this enzyme in esophageal carcinoma (ESC) particularly ESCC. Moreover, the research has focused on its value as a candidate for predicting or as the focus for interventions. Bioinformatic analyses were performed by several public databases (e.g., The Cancer Genome Atlas [TCGA] and cBioPortal). These analyses focused on the study of the expression of PAFAH1B3, copy number alterations (CNV), DNA methylation status, immune cell infiltration, and clinical outcomes in several different cancer types. Additionally, clinical ESCC tissues and in vitro assays were used to investigate the role of PAFAH1B3 in ESCC cell behavior and its potential involvement in FGFR1–PI3K/AKT signaling, and reciprocal Co-IP assays were performed to confirm the endogenous interaction between PAFAH1B3 and FGFR1. Pan-cancer analyses showed that PAFAH1B3 was overexpressed in various types of tumors, and was expressed in close correlation with copy number amplification and DNA methylation changes. Elevated expression of PAFAH1B3 was significantly associated with unfavorable clinical outcomes in a number of cancers. In ESCC, PAFAH1B3 expression correlated with clinicopathological features such as the higher expression of PAFAH1B3 was noted in advanced-stage tumors. Functional and pathway related studies showed that silencing of PAFAH1B3 significantly inhibited ESCC cell proliferation, migration and invasion. Reciprocal Co-IP assays demonstrated an endogenous interaction between PAFAH1B3 and FGFR1 in ESCC cells.Additionally, Immune landscape analysis showed a negative correlation between the expression of PAFAH1B3 and immune cell infiltration, as well as immune-related scores. Overexpression of PAFAH1B3 in ESCC may promote tumor progression through its association with FGFR1-PI3K/AKT signaling.It is also strongly associated with alterations of the tumor immune milieu. These findings suggest that PAFAH1B3 may serve as a potential biomarker and therapeutic target for ESCC, although further mechanistic and clinical validation is required.
Radiotherapy is a central component of solid tumor management and can enhance antitumor immunity through antigen release, immunogenic cell death, innate immune activation, and tumor microenvironment remodeling. However, radiotherapy can also induce systemic immune injury by depleting circulating lymphocytes and irradiating lymphoid organs. This review aims to examine radiation-induced lymphopenia (RIL) as a clinically relevant manifestation of systemic immune injury and its potential implications for radioimmunotherapy. This narrative review discusses the biological basis of RIL, including lymphocyte radiosensitivity, circulating blood exposure, lymphoid-organ irradiation, treatment volume, fractionation, systemic therapy, and patient immune reserve. It also summarizes clinical evidence regarding the association of severe or persistent RIL with outcomes across solid tumors and examines emerging dosimetric and biological biomarkers relevant to immune-sparing radiotherapy. Severe or persistent RIL has been associated with inferior outcomes across multiple solid tumors and may be particularly relevant in patients receiving immune checkpoint inhibitors. Emerging dosimetric biomarkers include effective dose to immune cells, estimated dose of radiation to immune cells, circulating blood dose, blood dose-volume histograms, immune dose-volume histograms, marrow dose, spleen dose, and low-dose bath metrics. Potential biological biomarkers include baseline absolute lymphocyte count, treatment-related lymphocyte decline, immune recovery kinetics, inflammatory indices, immune-cell subsets, circulating tumor DNA (ctDNA) dynamics, and plan-derived immune exposure. Together, these parameters may support a biomarker-guided framework for immune-sparing radiotherapy. RIL should not be regarded merely as a laboratory abnormality, but as a clinically relevant systemic immune injury that may reflect reduced systemic immune competence and influence radioimmunotherapy efficacy. Immune-sparing radiotherapy should not compromise target coverage or tumor control, but may provide a clinically meaningful direction for optimizing radioimmunotherapy in solid tumors.
To evaluate the clinical and translational effects of OncoTherad (MRB-CFI-1) nanoimmunotherapy and to investigate biomarkers associated with therapeutic response in patients with Bacillus Calmette-Guérin (BCG)-unresponsive pT1 non-muscle invasive bladder cancer (NMIBC). A retrospective observational cohort of 21 patients with BCG-unresponsive pT1 NMIBC treated with OncoTherad was analyzed. Tumor samples obtained before and after treatment were evaluated according to clinical outcome. Immunohistochemistry was performed to quantify human epidermal growth factor receptor 2 (HER-2), SERPINE1 mRNA-binding protein 1 (SERBP1), hyaluronic acid-binding protein 4 (HABP4), and IFN-γ expression. In parallel, high-content image-based phenotypic profiling was performed in 5637 urothelial carcinoma cells to investigate treatment-associated cellular remodeling. OncoTherad achieved a pathological complete response rate of 71.4
Metastatic thymic carcinoma is a rare and aggressive malignancy that may present with atypical clinical and biochemical features, posing significant diagnostic challenges. We report the first documented case of metastatic thymic carcinoma mimicking both pheochromocytoma and Von Hippel–Lindau (VHL) syndrome. A 54-year-old man presented with neck pain, microscopic hematuria, bilateral adrenal masses, fluctuating hypertension, and borderline elevated plasma normetanephrine, raising suspicion for pheochromocytoma. Concurrent retinal abnormalities and cerebellar lesions suggested VHL syndrome. However, serial biochemical reassessment demonstrated normalization of catecholamine metabolites, while ophthalmologic evaluation reclassified the retinal findings as hypertensive retinopathy rather than retinal hemangioblastoma. Brain imaging showed features atypical for VHL-associated hemangioblastomas. ^68Ga-DOTATATE PET/CT demonstrated no significant tracer uptake in the adrenal or cerebellar lesions but revealed increased somatostatin receptor expression in an anterior mediastinal mass with tracer-avid lymph node and skeletal metastases. Histopathological examination of an adrenal mass confirmed metastatic basaloid squamous thymic carcinoma (CK5/6-positive, p63-positive, synaptophysin-negative, chromogranin-negative), excluding a neuroendocrine origin. This case highlights the remarkable ability of metastatic thymic carcinoma to mimic endocrine and hereditary syndromes, resulting in potential diagnostic pitfalls. A systematic diagnostic approach integrating serial biochemical testing, advanced functional imaging, comprehensive clinical reassessment, and histopathological confirmation is essential to establish the correct diagnosis. Metastatic thymic carcinoma should be considered in the differential diagnosis of adrenal masses with syndromic features, even when the initial presentation strongly suggests pheochromocytoma or VHL syndrome.
Melanoma is a highly malignant cancer that poses a significant global health burden, yet there is limited ability to predict prognosis or immunotherapy efficacy for melanomas. Emerging evidence highlights the role of RNA modification regulators (m6A, m1A, m5C, and m7G) in modulating oncogenesis and immune responses. We comprehensively profiled 84 regulators of RNA modification (m6A/m1A/m5C/m7G) across multiple melanoma cohorts. Unsupervised clustering was performed to identify RNA modification-based subtypes, followed by WGCNA to reveal key modules. We developed the RMODscore prognostic model using LASSO and multivariate Cox regression and validated the model in several independent melanoma immunotherapy cohorts. Finally, we explored the association of RMODscore with immune signatures and drug sensitivity. We found significant differences in survival among three different RNA modification subtypes and identified the ME13 module as significantly associated with these subtypes using the WGCNA method. Our newly constructed 10-gene RMODscore model showed strong predictive performance in the TCGA cohort and four independent immunotherapy datasets. A high RMODscore was associated with poor survival, immune-cold phenotypes, and resistance to checkpoint blockade. Functional analysis revealed that tumors with high RMODscore values exhibited upregulation of proliferation-related pathways, whereas tumors with low RMODscore values exhibited greater immune activation. In addition, the RMODscore predicted sensitivity to ERK and JNK inhibitors, suggesting potential drug repurposing strategies. This study presents a novel RNA modification-based prognostic risk score as a robust prognostic tool for melanoma which may provide potential prognostic stratification value. These findings highlight the potential of RNA modification signatures for prognostic stratification and may provide preliminary insights for future therapeutic strategy exploration in patients with melanoma.
Nutritional status significantly impacts the prognosis of patients with hepatocellular carcinoma (HCC). Computed tomography (CT) has become a key tool for assessing body composition (BC), with abnormal patterns increasingly linked to reduced survival. However, BC is dynamic and may change during treatment, potentially affecting treatment outcomes. This study explores how BC affects survival and dose-limiting toxicities (DLTs) in patients with advanced HCC receiving first-line treatment, as well as changes in BC over the course of treatment. This retrospective study included patients with advanced HCC who received first-line systemic therapy. The Lumbar skeletal muscle index and adipose tissue indices were measured via CT analysis at baseline and at the best response. Cox regression and generalized linear models were used for analysis. The study included 113 patients treated with tyrosine kinase inhibitors (70
The understanding of cancer has evolved from a group of mutated cancerous cells to a complex ecosystem comprising many cellular and non-cellular components. Tumor-associated macrophages (TAMs) are one of the most abundant immune cells in the tumor microenvironment (TME). They actively contribute to cancer outcomes in two ways, either promoting its development and progression or stimulating immune response to combat tumor. Recently, TAMs have been recognized not only as prognostic markers for the outcome of anti-cancer therapy, but also as major players in shaping treatment response. It was also established that therapeutic agents may affect TAMs’ phenotype, and in consequence modulate tumor’s behavior. Therefore, reprogramming of TAMs in order to enhance tumor infiltration and overcome immune suppression is also currently a hot topic in preclinical research. In this review, we discuss the interactions between chemotherapeutic agents and tumor-associated macrophages and their potential consequences for tumor response.
