Search Results (295)

Central nervous system metastases involving the brain parenchyma and leptomeninges are common in non-small cell lung cancer, especially cases with EGFR mutations. Here, we examine treatment options for EGFR-mutated non-small cell lung cancer patients with central nervous system metastases, highlighting the efficacy of third-generation EGFR-targeted tyrosine kinase inhibitors. Furthermore, we examine the interplay of this modality with chemotherapy or radiation in resistant cases. Full article

Background/Objectives This systematic review and network meta-analysis aimed to determine the most effective therapeutic exercise modality for improving quality of life (QoL) in patients with advanced-stage cancer. Specifically, the study compared the effects of aerobic training, strength training, and combined aerobic and strength training on QoL outcomes. Methods A systematic literature search was conducted in PubMed, Embase, Cochrane Reviews, and the Cochrane Central Register of Controlled Trials up to 24 February 2023. The review adhered to PRISMA guidelines. Included studies were randomized controlled trials (RCTs) involving adult patients with advanced-stage cancers (e.g., pancreatic, colorectal, lung, breast, prostate, gastrointestinal, gynecological, hematological, head and neck, melanoma, or cancers with bone metastases). The primary outcome was post-intervention QoL, while the secondary outcome assessed was the dropout rate across exercise modalities. Results Aerobic training demonstrated the greatest improvement in QoL with a standardized mean difference (SMD) of 0.30 (95% CI: 0.00 to 0.61), followed by strength training (SMD = 0.13; 95% CI: −0.41 to 0.66) and combined training (SMD = 0.07; 95% CI: −0.11 to 0.24). However, none of the interventions showed statistically significant superiority. Dropout rates were comparable across all exercise modalities and control groups, suggesting strong adherence and feasibility of these interventions in advanced cancer populations. Conclusions While all exercise modalities were associated with improved QoL in patients with advanced-stage cancer, no single intervention emerged as significantly superior. Aerobic exercise may offer a slight advantage, although this effect was not statistically significant. These results highlight the importance of individualized exercise prescriptions based on patient preference, functional status, and treatment context. Further research is warranted to identify patient subgroups that may benefit most from specific exercise interventions and to explore QoL subdomains such as fatigue, emotional well-being, and physical functioning. Full article

Brain metastases (BM), which most commonly originate from lung, breast, or skin cancers, remain a major clinical challenge, with standard treatments such as stereotactic radiosurgery (SRS), surgical resection, and whole-brain radiation therapy (WBRT). The prognosis for patients with BM remains poor, with a median overall survival (OS) of just 10–16 months. Although recent advances in systemic therapies, including small molecule inhibitors, monoclonal antibodies, chemotherapeutics, and gene therapies, have demonstrated success in other malignancies, their effectiveness in central nervous system (CNS) cancers is significantly limited by poor blood–brain barrier (BBB) permeability and subtherapeutic drug concentrations in the brain. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome these limitations by enhancing CNS drug penetration and selectively targeting metastatic brain tumor cells while minimizing off-target effects. This review summarizes recent preclinical and clinical developments in nanoparticle-based therapies for BM. It is evident from these studies that NPs can carry with them a range of therapeutics, including chemotherapy, immunotherapy, small molecule inhibitors, gene therapies, radiosensitizers, and modulators of tumor microenvironment to the BM. Moreover, preclinical studies have shown encouraging efficacy in murine models, highlighting the potential of these platforms to improve therapeutic outcomes. However, clinical translation remains limited, with few ongoing trials. To close this translational gap, future work must address clinical challenges such as trial design, regulatory hurdles, and variability in BBB permeability while developing personalized nanoparticle-based therapies tailored to individual tumor characteristics. Full article

Stereotactic Body Radiotherapy (SBRT) has emerged as a pivotal treatment modality for early-stage non-small cell lung cancer (NSCLC), offering highly precise, high-dose radiation delivery. However, several clinical challenges remain, particularly in the treatment of central or ultracentral tumors, which are located near critical structures such as the heart, bronchi, and great vessels. The introduction of MRI-guided SBRT has significantly improved targeting precision, allowing for better assessment of tumor motion and adjacent organ structures. Additionally, SBRT has demonstrated efficacy in multifocal NSCLC, providing an effective option for patients with multiple primary tumors. Recent advances also highlight the role of SBRT in locally advanced NSCLC, where it is increasingly used as a complementary approach to concurrent chemotherapy or in cases where surgery is not feasible. Moreover, the combination of SBRT with immunotherapy has shown promising potential, enhancing tumor control and immunological responses. Furthermore, SBRTs application in SCLC is gaining momentum as a palliative and potentially curative option for selected patients. This narrative review explores these evolving clinical scenarios, the technical innovations supporting SBRT, and the integration of immunotherapy, providing an in-depth look at the new frontiers of SBRT in lung cancer treatment. Despite the challenges, the ongoing development of personalized approaches and technological advancements continues to push the boundaries of SBRTs clinical utility in lung cancer. Full article

Introduction: Elderly patients with metastatic non-small-cell lung cancer (NSCLC) are underrepresented in clinical trials evaluating immune checkpoint inhibitors (ICIs). This study assesses the efficacy of first-line pembrolizumab monotherapy in patients with metastatic NSCLC aged ≥70 years with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50%. Materials and Methods: We retrospectively analyzed 381 patients with metastatic NSCLC without oncogenic driver mutations treated with pembrolizumab monotherapy between 2017 and 2023 at three academic centers in Central and Southeastern Europe. Clinical outcomes, including median time on treatment (mToT) and overall survival (mOS), were compared between patients aged ≥70 and <70 years. Results: Of 381 patients, 149 (39.1%) were aged ≥70. No significant differences in mToT (12.7 vs. 14.3 months; p = 0.125) or mOS (18.2 vs. 27.4 months; p = 0.124) were observed between older and younger groups. Good ECOG PS (0–1) was independently associated with longer mToT and mOS in older patients. Additionally, a history of smoking was linked to improved outcomes compared to never-smokers, suggesting potential immunogenic effects. Older patients were significantly less likely to receive second-line therapy after progression (p = 0.04). Conclusions: First-line pembrolizumab monotherapy is effective across all age groups and provides similar treatment efficacy in patients with metastatic NSCLC and a PD-L1 TPS ≥ 50%. Patients older than 70 with a smoking history and ECOG PS 0–1 derive the most benefit from this treatment modality. The adaptation of this treatment strategy for elderly patients is especially important, since only a minority of them are capable of receiving second-line therapy. Full article

Bardoxolone methyl, also known as CDDO-Me or RTA 402, is a synthetic oleanane triterpenoid that has garnered significant attention as a potent pharmacological activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is a master regulator of cellular redox homeostasis, controlling the expression of genes involved in antioxidant defense, detoxification, and mitochondrial function. By inducing Nrf2 and promoting the transcription of downstream antioxidant response element (ARE)-driven genes, bardoxolone methyl enhances cellular resilience to oxidative stress and inflammation. This mechanism is central not only to its cytoprotective effects but also to its emerging role in oncology. A number of studies investigated the effects of bardoxolone methyl in several malignancies including breast cancer, lung cancer, pancreatic ductal adenocarcinoma, prostate cancer, colorectal cancer, oral and esophageal squamous cell carcinoma, ovarian cancer and glioblastoma. Studies in the literature indicate that bardoxolone methyl exhibits anticancer activity through several mechanisms, including the suppression of cell proliferation, induction of cell cycle arrest and apoptosis, inhibition of epithelial–mesenchymal transition (EMT), and impairment of cancer cell stemness. Additionally, bardoxolone methyl modulates mitochondrial function, reduces glycolytic and oxidative phosphorylation capacities, and induces reactive oxygen species (ROS)-mediated stress responses. In this review, we summarize the available literature regarding the studies which investigated the effects of bardoxolone methyl as anticancer agent. Full article

Background and Objectives: The accurate segmentation of pulmonary nodules in computed tomography (CT) remains a critical yet challenging task due to variations in nodule size, shape, and boundary ambiguity. This study proposes CAAF-ResUNet (Context-Aware Adaptive Attention Fusion ResUNet), a novel deep learning model designed to address these challenges through adaptive feature fusion and edge-sensitive learning. Materials and Methods: Central to our approach is the Adaptive Attention Controller (AAC), which dynamically adjusts the contribution of channel and position attention based on contextual features in each input. To further enhance boundary localization, we incorporate three complementary boundary-aware loss functions: Sobel, Laplacian, and Hausdorff. Results: An extensive evaluation of two benchmark datasets demonstrates the superiority of the proposed model, achieving Dice scores of 90.88% on LUNA16 and 85.92% on LIDC-IDRI, both exceeding prior state-of-the-art methods. A clinical validation of a dataset comprising 804 CT slices from 35 patients at the University Medical Center of Ho Chi Minh City confirmed the model’s practical reliability, yielding a Dice score of 95.34% and a notably low Miss Rate of 4.60% under the Hausdorff loss configuration. Conclusions: These results establish CAAF-ResUNet as a robust and clinically viable solution for pulmonary nodule segmentation, offering enhanced boundary precision and minimized false negatives, two critical properties in early-stage lung cancer diagnosis and radiological decision support. Full article

Epigenetics and genome science have become central to current molecular biology research. Among the key mechanisms ensuring genomic integrity is the silencing of transposable elements in germline cells, a process essential for fertility in both sexes. A pivotal component of this silencing machinery involves PIWI-interacting RNAs (piRNAs), a distinct class of small non-coding RNAs that regulate gene expression and suppress transposable elements at both the transcriptional and post-transcriptional levels. piRNAs function in concert with PIWI proteins, whose expression is critical for proper oogenesis, spermatogenesis, and early zygote development. Disruptions in piRNA or PIWI protein pathways not only impair germline function but also contribute to genome instability, unchecked cell proliferation, and aberrant epigenetic modifications, hallmarks of tumorigenesis. Emerging evidence links the dysregulation of the piRNA/PIWI axis to the development and progression of various cancers, including lung and colorectal carcinomas. This review highlights the fundamental roles of piRNAs and PIWI proteins in reproductive biology and their increasingly recognized relevance in cancer biology. Full article

Breast cancer metastasis remains the primary driver of patient mortality, involving dynamic interactions between tumor cells and distant organ microenvironments. In recent years, tumor cell-derived extracellular vesicles (EVs) have emerged as critical information carriers, playing central roles in breast cancer metastasis by mediating organ-specific pre-metastatic niche formation, immune modulation, and tumor cell adaptive evolution. Studies have demonstrated that EVs drive the metastatic cascade through the delivery of bioactive components, including nucleic acids (e.g., miRNAs, circRNAs), proteins (e.g., integrins, metabolic enzymes), and lipids, which collectively regulate osteoclast activation, immune cell polarization, vascular permeability alterations, and extracellular matrix (ECM) remodeling in target organs such as bone, the lungs, and the liver. Molecular heterogeneity in EVs derived from different breast cancer subtypes strongly correlates with organotropism, providing potential biomarkers for metastasis prediction. Leveraging the organotrophic mechanisms of EVs and their dual regulatory roles in metastasis (pro-metastatic and anti-metastatic), strategies targeting EV biogenesis, cargo loading, or delivery exhibits translational potential in diagnostics and therapeutics. In this review, we summarize recent advances in understanding the role of breast cancer-derived exosomes in mediating metastatic organotropism and discuss the potential clinical applications of targeting exosomes as novel diagnostic and therapeutic strategies for breast cancer. Full article

Autophagy plays a central role in cellular degradation and recycling pathways involving the formation of autophagosomes from cellular components. The Atg8 protein family, particularly LC3, is essential to this process, and dysregulation has been implicated in many diseases (including cancer). Furthermore, therapeutic strategies targeting Atg8 proteins like LC3 can be advanced by exploiting the expanding knowledge of the “LC3 interacting region” (LIR) domain to develop inhibitory ligands. Here, we report a computational approach to design novel peptides that inhibit LC3B. The LIR domain of a known LC3B binder (the FYCO1 peptide) was used as a starting point to design new peptides with unnatural amino acids and conformational restraints. Accomplishing molecular dynamics simulations and binding free energy calculations on the complex of peptide–LC3B, new promising FYCO1 analogs were selected. These peptides were synthesized and investigated by biophysical and biological experiments. Their ability to affect cellular viability was determined in different cancer cell lines (prostate cancer, breast cancer, lung cancer, and melanoma). In addition, the ability to inhibit autophagy and enhance the apoptotic activity of Docetaxel was evaluated in PC-3 prostate cancer cells. In conclusion, this research presents a rational approach to designing and developing LC3B inhibitors based on the FYCO1-LIR domain. The designed peptides hold promise as potential therapeutic agents for cancer and as tools for further elucidating the role of LC3B in autophagy. Full article

TGF-β is a central mediator of pulmonary allergic inflammation recently associated with lung metastasis of osteosarcoma. Given the controversial links between cancer and allergic diseases, this study aimed to evaluate the effects of allergic airway inflammation—particularly TGF-β—on osteosarcoma lung metastasis using a comorbidity mouse model. Osteosarcoma cells were implanted in BALB/c mice with induced allergic airway inflammation. Lung metastasis was quantified, while PCNA/TGF-β expression was assessed by immunohistochemistry and digital pathology. Bioinformatic analyses of patient datasets compared TGF-β and PCNA expression in metastatic vs. normal tissues, and their association with survival. Mice with allergic inflammation showed increased lung metastases associated with TGF-β production. In patient samples, both TGF-β and PCNA were upregulated in metastatic tissues and correlated with poor overall survival. PCNA was also linked to genes involved in cell proliferation, DNA replication, and repair. Our results show an association between allergic airway inflammation and extensive lung metastasis of osteosarcoma in a comorbidity mouse model with elevated expression of TGF-β and PCNA. Full article

Chronic inflammation plays a central role in the pathogenesis of lung diseases including asthma, long COVID, chronic obstructive pulmonary disease (COPD), and lung cancer. Lipopolysaccharide (LPS) is a potent inflammatory agent produced by Gram-negative bacteria and also found in cigarette smoke. Our earlier study revealed that the intranasal exposure of A/J mice to LPS for 7 days altered gene expression levels in alveolar Type II epithelial cells (AECIIs), which serve as precursors to lung adenocarcinoma and are also preferentially targeted by SARS-CoV-2. In the present work, we employed a comprehensive multi-omics approach to characterize changes in DNA methylation/hydroxymethylation, gene expression, and global protein abundances in the AECIIs of A/J mice following the sub-chronic exposure to LPS and after a 4-week recovery period. Exposure to LPS led to hypermethylation at regulatory elements within the genome such as enhancer regions and expression changes in genes known to play a role in lung cancer tumorigenesis. Changes in protein abundance were consistent with an inflammatory phenotype and also included tumor suppressor proteins. Integration of the multi-omics data resulted in a model where LPS-driven inflammation in AECIIs triggers epigenetic changes that, along with genetic mutations, may contribute to lung cancer development. Full article

Bone metastases represent a critical complication in oncology, frequently indicating advanced malignancy and substantially reducing patient quality of life. This review provides a comprehensive analysis of the complex interactions between tumor cells and the bone microenvironment, emphasizing the relevance of the “seed and soil” hypothesis, the RANK/RANKL/OPG signaling axis, and Wnt signaling pathways that collectively drive metastatic progression. The molecular and cellular mechanisms underlying the formation of osteolytic and osteoblastic lesions are examined in detail, with a particular focus on their implications for bone metastases associated with breast, prostate, lung, and other cancers. A central component of this review is the categorization of pathological biomarkers into four types: diagnostic, prognostic, predictive, and monitoring. We provide a comprehensive evaluation of circulating tumor cells (CTCs), bone turnover markers (such as TRACP-5b and CTX), advanced imaging biomarkers (including PET/CT and MRI), and novel genomic signatures. These biomarkers offer valuable insights for early detection, enhanced risk stratification, and optimized therapeutic decision-making. Furthermore, emerging strategies in immunotherapy and bone-targeted treatments are discussed, highlighting the potential of biomarker-guided precision medicine to enhance personalized patient care. The distinctiveness of this review lies in its integrative approach, combining fundamental pathophysiological insights with the latest developments in biomarker discovery and therapeutic innovation. By synthesizing evidence across various cancer types and biomarker categories, we provide a cohesive framework aimed at advancing both the scientific understanding and clinical management of bone metastases. Full article

Lung cancer brain metastasis (LCBM) is a major contributor to cancer-related mortality, with a median survival of 8–16 months following diagnosis, despite advances in therapeutic strategies. The development of clinically relevant animal models is crucial for understanding the metastatic cascade and assessing therapies that can penetrate the blood–brain barrier (BBB). This review critically evaluates five primary LCBM modeling approaches—orthotopic implantation, intracardiac injection, stereotactic intracranial injection, carotid artery injection, and tail vein injection—focusing on their clinical applicability. We systematically compare their ability to replicate human metastatic pathophysiology and highlight emerging technologies for personalized therapy screening. Additionally, we analyze breakthrough strategies in central nervous system (CNS)-targeted drug delivery, including microparticle targeted delivery systems designed to enhance brain accumulation. By incorporating advances in single-cell omics and AI-driven metastasis prediction, this work provides a roadmap for the next generation of LCBM models, aimed at bridging preclinical and clinical research. Full article

Background: Racotumomab-alum is an anti-idiotype vaccine targeting the NeuGcGM3 tumor-associated ganglioside. Clinical trials in advanced cancer patients have demonstrated low toxicity, high immunogenicity and clinical benefit. The goal of this study was to identify circulating biomarkers of clinical outcome. Methods: Eighteen patients with stage IIIb/IV non-small-cell lung cancer (NSCLC) were injected with racotumomab-alum as switch maintenance therapy after first-line chemotherapy. Treatment was administered until severe performance status worsening or toxicity. The frequencies of innate and adaptive lymphocytes were assessed by flow cytometry. Circulating factors were measured using multi-analyte flow assay kits. Results: The median overall survival was 16.5 months. Twenty-seven percent of patients were classified as long-term survivors. Patients with lower baseline frequencies of CD4+Tregs and central memory (CM) CD8+T cells displayed longer survival rates. Furthermore, higher baseline frequencies of NKT cells and a high CD8+T/CD4+Treg ratio were associated with longer survival. Interestingly, patients with significantly lower levels of effector memory (EM) CD8+T cells survived longer. The levels of NKT cells and terminal effector memory (EMRA) CD8+T cells were higher in long-term survivors in comparison with short-term survivors in post-immune samples. As expected, the ratio of CD8+T/CD4+Tregs showed significantly higher values during treatment in patients with clinical benefits. Regarding serum factors, pro-tumorigenic cytokines significantly increased during treatment in poor survivors. Conclusions: In advanced NSCLC patients receiving racotumomab-alum vaccine, longer survival could be associated with a unique profile of circulating lymphocyte subsets at baseline and during treatment. Additionally, certain pro-tumor-related cytokines increased in short-term survivors. These results should be confirmed in larger randomized clinical trials. This clinical trial was registered in the Cuban Clinical Trials Register (RPCE00000279). Full article