Search Results (164)

Prostate cancer accounts for approximately 1.5 million new diagnoses and 400,000 deaths every year worldwide, and demographic projections indicate a near-doubling of both figures by 2040. Despite existing treatments, 10–20% of patients eventually progress to metastatic castration-resistant disease (mCRPC). The median overall survival (OS) after progression to mCPRC drops to 24 months, and efficacy drops severely after each additional line of treatment. Omics platforms have reached advanced levels and enable the acquisition of high-resolution large datasets that can provide insights into the molecular mechanisms underlying PCa pathology. Genomics, especially DDR (DNA damage response) gene alterations, detected via tissue and/or circulating tumor DNA, efficiently guides therapy in advanced prostate cancer. Given recent developments, we have performed a comprehensive literature search to cover recent research and clinical trial reports (over the last five years) that integrate omics along three converging trajectories in therapeutic development: (i) predicting response to approved agents with demonstrated survival benefits, (ii) stratifying patients to receive therapies in clinical trials, (iii) guiding drug development as part of drug repurposing frameworks. Collectively, this review is intended to serve as a comprehensive resource of recent advancements in omics-guided therapies for advanced prostate cancer, a clinical setting with existing clinical needs and poor outcomes. Full article

Metformin, a long-established antidiabetic agent, is undergoing a renaissance as a prototype gerotherapeutic and immunometabolic oncology adjuvant. Mechanistic advances reveal that metformin modulates an integrated network of metabolic, immunological, microbiome-mediated, and epigenetic pathways that impact the hallmarks of aging and cancer biology. Clinical data now demonstrate its ability to reduce cancer incidence, enhance immunotherapy outcomes, delay multimorbidity, and reverse biological age markers. Landmark trials such as UKPDS, CAMERA, and the ongoing TAME study illustrate its broad clinical impact on metabolic health, cardiovascular risk, and age-related disease trajectories. In oncology, trials such as MA.32 and METTEN evaluate its influence on progression-free survival and tumor response, highlighting its evolving role in cancer therapy. This review critically synthesizes the molecular underpinnings of metformin’s polypharmacology, examines results from pivotal clinical trials, and compares its effectiveness with emerging gerotherapeutics and senolytics. We explore future directions, including optimized dosing, biomarker-driven personalization, rational combination therapies, and regulatory pathways, to expand indications for aging and oncology. Metformin stands poised to play a pivotal role in precision strategies that target the shared roots of aging and cancer, offering scalable global benefits across health systems. Full article

Background: Tumor-associated macrophages (TAMs) are critical regulators of the hepatocellular carcinoma (HCC) microenvironment, yet their epigenetic heterogeneity and regulatory programs remain poorly defined. Methods: We performed integrative analysis on single-cell RNA-seq and ATAC-seq profiling of HCC patients to dissect TAM subtypes at high resolution. By correlating chromatin accessibility with gene expression, we identified cell-type-specific candidate cis-regulatory elements (CREs). TAM subsets with prognostic significance were determined through integration with HCC clinical cohorts. Pseudotime and multi-regional analyses were used to uncover regulatory trajectories underlying macrophage phenotypic transitions. The identification framework of a super-enhancer (SE) was constructed, and potential therapeutic targets were prioritized using drug–gene interaction data. Results: We delineated the regulatory landscape of TAMs in HCC, revealing cell-type-specific chromatin accessibility patterns underlying TAM heterogeneity. The 65,342 CREs linked to gene expression were identified, with distal CREs contributing most to cell-type-specific regulation. Notably, SPP1⁺ TAMs were found to be enriched in tumor cores and associated with poor prognosis in HCC. Liver-resident Kupffer cells showed progressive loss of the core transcription factors SPIC and MAFB, suggesting a potential transition into SPP1⁺ TAMs under tumor pressure. We identified 133 SPP1⁺ TAM-specific SEs and constructed a TF–SE–target gene regulatory network. Notably, 13 target genes showed higher drug–gene interaction effects, highlighting their therapeutic potential. Conclusions: This study provides the chromatin accessibility map of TAMs in HCC and reveals how distal CRE-driven transcriptional programs shape TAM states. Our findings lay the foundation for understanding the epigenetic regulation of TAM heterogeneity and nominate potential targets for TAM-directed immunotherapy in HCC. Full article

Deciphering the spatiotemporal distribution of bacteria during breast cancer progression may provide critical insights for developing bacterial-based therapeutic strategies. Using a murine breast cancer model, we longitudinally profiled the microbiota in breast tumor tissue, mammary gland, spleen, and cecal contents at 3-, 5-, and 7- weeks post-tumor implantation through 16S rRNA gene sequencing. Breast tumor progression was associated with lung metastasis and splenomegaly, accompanied by distinct tissue-specific microbial dynamics. While alpha diversity remained stable in tumors, mammary tissue, and cecal contents, it significantly increased in the spleen (p < 0.05). Longitudinal analysis revealed a progressive rise in Firmicutes and a decline in Proteobacteria abundance within tumors, mammary tissue, and cecum, whereas the spleen microbiota displayed unique phylum-level compositional shifts. Tissue- and time-dependent microbial signatures were identified at phylum, genus, and species levels during breast tumor progression. Strikingly, the spleen microbiota integrated nearly all genera enriched in other sites, suggesting its potential role as a microbial reservoir. Gut-associated genera (Lactobacillus, Desulfovibrio, Helicobacter) colonized both cecal contents and the spleen, with Lactobacillus consistently detected across all tissues, suggesting microbial translocation. The spleen exhibited uniquely elevated diversity and compositional shifts, potentially driving splenomegaly. These results delineated the trajectory of microbiota translocation and colonization, and demonstrated tissue-specific microbial redistribution during breast tumorigenesis, offering valuable implications for advancing microbiome-targeted cancer therapies. Full article

Background: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality despite advances in treatments, necessitating more effective therapeutic strategies. Single-cell RNA sequencing (scRNA-seq) technology has revolutionized our ability to dissect the cellular complexity of cancers, which is often obscured in conventional bulk transcriptomic experiments. Methods: In this study, we performed an integrative analysis of scRNA-seq data from multiple LUAD patient cohorts to investigate cell-type-specific transcriptomic changes across disease stages. Clustering, lineage trajectory analysis, and transcriptional regulatory network reconstruction were employed to identify stage-specific gene markers and their upstream regulators. Additionally, we constructed intercellular communication networks to evaluate signaling changes within the tumor microenvironment (TME) during LUAD progression. Results: Our analysis revealed that epithelial cells from stage IV tumors exhibited a distinct transcriptional profile compared to earlier stages, a separation not observed in immune or stromal cell populations. We identified a panel of gene markers that differentiated epithelial cells across disease stages and effectively stratified patients into subgroups with distinct survival outcomes and TME compositions. Regulatory network analysis uncovered key transcription factors, including ATF3, ATF4, HSF1, KLF4, and NFIC, as potential upstream regulators of these stage-specific genes. Moreover, cell–cell communication analysis revealed a significant increase in signaling originating from epithelial cells and a concomitant decrease in immune-derived signals in late-stage LUAD. We identified several signaling pathways enriched in stage-specific crosstalk, including Wnt, PTN, and PDGF pathways, which may play critical roles in LUAD progression. Conclusions: This study provides a comprehensive single-cell resolution map of LUAD progression, highlighting epithelial-driven regulatory programs and dynamic intercellular communication within the TME. Our findings uncover novel molecular markers and regulatory mechanisms with potential prognostic and therapeutic value for more precise treatment. Full article

Medulloblastoma represents a rare yet complex embryonal tumor of the posterior cranial fossa that, while predominantly affecting pediatric populations, occurs with increasing recognition among adolescents and young adults (AYAs, 15–39 years). The scarcity of medulloblastoma within this demographic creates substantial obstacles in diagnosis, treatment selection, and psychosocial management that differ markedly from established pediatric approaches. Emerging data reveal that AYA patients exhibit distinctive tumor biology, including altered molecular subgroup patterns, variable therapeutic responses, and unique survival trajectories when compared to younger patients. Current investigations examining autologous stem cell transplantation following intensive chemotherapy protocols in metastatic cases demonstrate encouraging preliminary results. Evidence increasingly supports adapting pediatric treatment paradigms for adult application, potentially improving therapeutic outcomes while reducing treatment burden. These cross-disciplinary approaches between pediatric and adult oncology demonstrate considerable promise for enhancing clinical results and minimizing therapy-associated morbidity, emphasizing the critical need for collaborative care models in managing this challenging malignancy across diverse age groups. Full article

Objective: The aim of this study is to present the initiation of robotic-guided (RG) spine surgery into routine clinical care at a single center with the use of intraoperative CT (iCT) automatic registration-based navigation. The workflow included iCT with automatic registration, fusion with preoperative imaging, verification of preplanned screw trajectories, RG introduction of K-wires, and the insertion of pedicle screws (PSs), followed by a control iCT scan. Methods: All patients who underwent RG implantation of pedicle screws using the Cirq^® robotic arm (BrainLab, Munich, Germany) in the thoracolumbar spine at our department were included in the study. The accuracy of the pedicles screws was assessed using the Gertzbein–Robbins scale (GRS). Results: In total, 108 patients (60 female, mean age 68.7 ± 11.4 years) in 109 surgeries underwent RG PS placement. Indications included degenerative spinal disorders (n = 30 patients), spondylodiscitis (n = 24), tumor (n = 33), and fracture (n = 22), with a mean follow-up period of 7.7 ± 9 months. Thirty-seven cases (33.9%) were performed percutaneously, and all others were performed openly. Thirty-three operations were performed on the thoracic spine, forty-four on the lumbar and lumbosacral spine, thirty on the thoracolumbar, one on the cervicothoracic spine, and one on the thoracolumbosacral spine. The screws were inserted using a fluoroscopic (first 12 operations) or navigated technique (latter operations). The mean operation time was 228.8 ± 106 min, and the mean robotic time was 31.5 ± 18.4 min. The mean time per K-wire was 5.35 ± 3.98 min. The operation time was lower in the percutaneous group, while the robot time did not differ between the two groups. Robot time and the time per K-wire improved over time. Out of 688 screws, 592 were GRS A screws (86.1%), 54 B (7.8%), 22 C (3.2%), 12 D (1.7%), and 8 E (1.2%). Seven screws were revised intraoperatively, and after revision, all were GRS A. E screws were either revised or removed. In the case of D screws, screws located at the end of the construct were revised, while so-called in-out-in screws in the middle of the construct were not revised. Conclusions: Brainlab’s Cirq^® Robotic Alignment Module feature enables placement of pedicle screws in the thoracolumbar spine with high accuracy. A learning curve is shown through improvements in robotic time and time per K-wire. Full article

Ductal carcinoma in situ (DCIS) is the most common form of non-invasive breast cancer and a recognized precursor to invasive ductal carcinoma (IDC). Although DCIS itself is confined to the milk duct and not immediately life-threatening, its potential for progression to invasive disease necessitates careful clinical management. The increased detection of DCIS due to advancements in imaging and widespread screening programs has raised critical questions regarding its classification, prognosis, and optimal treatment strategies. While most cases exhibit indolent behavior, others harbor molecular characteristics that drive malignant transformation. A key challenge lies in distinguishing low-risk DCIS, which may never progress, from aggressive cases requiring intervention. Tumor microenvironment dynamics, immune cell infiltration, and molecular alterations, including hormone receptor (HR) status, human epidermal growth factor 2 (HER2) expression, and genetic mutations, play crucial roles in determining disease trajectory. This review explores the biological and molecular mechanisms underlying DCIS progression, with an emphasis on myoepithelial cells, tumor-infiltrating lymphocytes, and microenvironmental factors. By integrating recent findings, this article aims to refine risk stratification approaches and guide future strategies for personalized DCIS management. Improved prognostic biomarkers and targeted therapeutic interventions could help optimize treatment decisions, balancing the need for effective cancer prevention while minimizing overtreatment in low-risk patients. Full article

Neurocutaneous syndromes represent a clinically and genetically heterogeneous group of disorders, with tuberous sclerosis complex (TSC), von Hippel–Lindau syndrome (VHL), and ataxia–telangiectasia (A-T) exemplifying some of the most complex entities within this category. These syndromes have traditionally been considered monogenic disorders, caused by germline mutations in tumor suppressor or regulatory genes. However, they exhibit a striking degree of phenotypic variability and divergent clinical trajectories that cannot be fully explained by their underlying genetic alterations alone. Increasingly, epigenetic regulatory mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA (ncRNA) activity, are recognized as key modulators of gene expression, cellular differentiation, and tissue-specific function. Disruption of these mechanisms has been implicated in disease pathogenesis, tumorigenesis, and neurodegeneration associated with TSC, VHL, and A-T. Aberrant epigenetic profiles may underlie the observed variability in clinical outcomes, even among individuals with identical mutations. This review consolidates current evidence on the epigenetic landscape of these syndromes, elucidating how these modifications may influence disease behavior and contribute to incomplete genotype–phenotype correlations. By integrating epigenetic insights with known molecular pathways, a more nuanced understanding of disease biology emerges, with potential implications for diagnostic stratification, prognostic assessment, and therapeutic innovation. Full article

In patients undergoing systemic treatment for cancer, symptom tracking via electronic patient-reported outcomes (ePROs) has been used to optimize communication and monitoring, and facilitate the early detection of adverse effects and to compare the side effects of similar drugs. We aimed to examine whether the patterns in electronic patient-reported outcomes, without any additional clinician data input, are predictive of the underlying cancer type and reflect tumor- and treatment-associated symptom clusters (SCs). The data were derived from a total of 226 patients who self-reported on the presence and severity (according to the Common Terminology Criteria for Adverse Events (CTCAEs)) of more than 90 available symptoms via the medidux^TM app (versions 2.0 and 3.2, developed by mobile Health AG based in Zurich, Switzerland). Among these, 172 had breast cancer as the primary tumor, 19 had lung, 16 had gut, 12 had blood–lymph, and 7 had prostate cancer. For this secondary analysis, a subgroup of 25 patients with breast cancer were randomly selected to reduce the risk of overfitting. The symptoms were aggregated by counting the days on which a particular symptom was reported, resulting in a symptom vector for each patient. A logistic regression model was trained to predict the type of the respective tumor from the symptom vectors, and the symptoms with coefficients above (0.1) were graphically displayed. The machine learning model was not able to recognize any of the patients with prostate and blood–lymph cancer, likely as these cancer types were barely represented in the dataset. The Area Under the Curve (AUC) values for the three remaining cancer types were breast cancer: 0.74 (95% CI [0.624, 0.848]); gut cancer: 0.78 (95% CI [0.659, 0.893]); and lung cancer: 0.63 (95% CI [0.495, 0.771]). Despite the small datasets, for the breast and gut cancers, the respective models demonstrated a fair predictive performance (AUC > 0.7). The generalization of the findings are limited especially due to the heterogeneity of the dataset. This line of research could be especially interesting to monitor individual treatment trajectories. Deviations in the electronic patient-reported symptoms from the treatment-associated symptom patterns could dynamically indicate treatment non-adherence or lower treatment efficacy, without clinician input or additional costs. Similar analyses on larger patient cohorts are needed to validate these preliminary findings and to identify specific and robust treatment profiles. Full article

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) represent a rare and varied class of neoplasms, characterized by diverse clinical presentations and prognostic trajectories. Accurate and prompt diagnosis is vital to inform and optimize therapeutic decisions. Ultrasound, including standard B-mode imaging and advanced methods such as contrast-enhanced ultrasound (CEUS) and endoscopic ultrasound (EUS), serves as a key component in the diagnostic evaluation of these tumors. B-mode US and CEUS provide non-invasive, accessible methods for early detection and characterization. On B-mode imaging, GEP-NETs typically present as well-defined, hyperechoic, or iso-echoic lesions, while CEUS highlights their characteristic vascularity, marked by arterial-phase hyperenhancement and venous-phase washout. Compared to CT and MRI, ultrasound offers real-time, dynamic imaging without ionizing radiation or nephrotoxic contrast agents, making it particularly advantageous for patients requiring frequent monitoring or with contraindications to other imaging modalities. CT and MRI are widely regarded as the preferred methods for staging and surgical planning due to their detailed anatomical visualization. However, ultrasound, especially CEUS, provides a significant adjunctive role in both early detection and the follow-up on GEP-NETs. This analysis delves into the strengths, challenges, and innovations in ultrasound technology for diagnosing pancreatic NETs, focusing on its contribution to comprehensive imaging strategies and its impact on patient care decisions. Full article

Structural biomarkers determined by X-ray scattering of the tissues can complement conventional diagnostics and provide a pathway for early detection of diseases. In the present study, mouse models were utilized to observe the progression of prostate cancer. We induced cancer in the left lobe of the mouse prostate, whilst the right lobe was left uninoculated. The mice were sacrificed at increasing systematic time points, and lobe samples were subsequently analyzed using X-ray scattering. Control samples were also collected from healthy mice sacrificed at the same time points. This investigation revealed that the ratio between the X-ray scattering peaks associated with the lipids and water can serve as a structural biomarker of cancer, and this biomarker develops as the tumor advances. The obtained cancer trajectory can serve as a baseline for the determination of the disease stage, and the biomarker movement along the trajectory can be evidence of the healing or disease progression. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) exhibit considerable heterogeneity, complicating the prediction of disease progression and treatment response. Consequently, researchers are actively investigating reliable biomarkers to forecast disease trajectories and inform therapeutic decisions. This study examines the role of BAG3, a protein involved in cell survival and stress response, as a potential predictive marker in HNSCC. The objective is to analyze BAG3 expression across various HNSCC types and correlate it with disease-free survival (DFS), aiming to elucidate the influence of BAG3 positivity on cancer progression. Methods: A multi-institutional retrospective study was conducted by analyzing BAG3 expression by immunohistochemistry in 104 tissue samples from patients with head and neck squamous cell carcinoma (HNSCC). The data were then correlated with DFS to assess the impact of BAG3 positivity on prognosis. Results: Immunohistochemical analysis of primary tumor samples collected from therapy-naive patients showed that BAG3 positivity was widespread across different head and neck cancer sites, with no significant correlation to sex, smoking status, HPV infection, tumor location, grade, or TNM parameters. However, BAG3 high positive patients had shorter DFS (median 23.2 months) compared to BAG3-negative patients (median 31.3 months). Cox analysis revealed that BAG3 high expression by IHC was associated with a more than 3-fold increased risk of disease recurrence. Conclusions: This study is the first to explore BAG3 as a biomarker for HNSCC recurrence. While preliminary findings suggest a link between BAG3 positivity and increased recurrence risk, further research is needed to validate these results. Prospective studies could help establish BAG3’s prognostic value and potentially lead to more personalized treatment approaches for HNSCC. Full article

Cancer progression is a complex, multi-stage development process characterized by dynamic changes at the molecular level. Understanding these changes may provide new insights into tumorigenesis and potential therapeutic targets. This study focuses on the evolutionary transcriptomics of cancer, specifically analyzing the Transcriptome Age Index (TAI) across different pathological stages. By examining various cancers at four distinct pathological stages, we identify a significant «hourglass» pattern in TAI indices of ductal carcinoma of the breast, bladder carcinoma, and liver carcinoma, suggesting a conserved evolutionary trajectory during tumor development. The results reveal that early and late stages of these cancers exhibit higher TAI values, indicative of more novel gene expression, while intermediate stages show a dip in TAI, reflecting a more ancient evolutionary origin of expressed genes. This «hourglass» pattern underscores the evolutionary constraints and innovations at play during tumor progression. Our findings contribute to the growing body of evidence that evolutionary principles are deeply embedded in cancer biology, offering new perspectives on the dynamics of gene expression in tumors. Full article