Search Results (5,936)

Background: Microsatellite instability (MSI) and mismatch repair (MMR) deficiency are key predictive biomarkers for immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). In real-world practice, however, diagnostic pathways often involve heterogeneous testing modalities, which may lead to discordant or inconclusive results. Methods: We conducted a retrospective study of patients with mCRC who underwent at least one MSI/MMR assessment between 2015 and 2025. Diagnostic modalities included IHC, tissue-based and liquid-based MSI testing. A predefined decision algorithm classified results as conclusive or inconclusive; discordant cases underwent adjudication that integrated a pathology review, molecular features, and technical considerations. Patients were ultimately assigned to definitive MSS or definitive MSI groups. Clinical characteristics, treatment patterns, and outcomes—particularly in relation to immunotherapy—were evaluated. Results: Among 727 evaluable patients, the MSI/MMR status was conclusive in 695 (95.6%) and inconclusive in 32 (4.4%). Inconclusive cases resulted from isolated MMR protein loss, heterogeneous or equivocal staining, inter-tumoral discordance, or discrepancies between tissue- and liquid-based assays. After adjudication, 54 patients (7.4%) were classified as definitive MSI and 673 (92.6%) as definitive MSS. Definitive MSI tumors were associated with female sex, right-sided primaries, high-grade histology, nodal involvement, and BRAF V600E mutations. Among the definitive MSI patients, 31 (57.4%) received immunotherapy, achieving a complete response rate of 48.4% and an overall response rate of 71.0%. Median PFS and OS were not reached in the definitive MSI group, whereas definitive MSS patients treated with ICIs experienced significantly poorer outcomes. Conclusive and adjudicated MSI groups demonstrated comparable responses to immunotherapy. Conclusions: In real-world practice, a meaningful proportion (4%) of mCRC patients experience inconclusive MSI/MMR assessment, with important clinical implications. Both technical and biological factors contribute to diagnostic uncertainty. Integrating orthogonal testing modalities and applying structured adjudication improves classification accuracy and ensures appropriate access to immunotherapy. Full article

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article

The failure of therapy in muscle invasive bladder cancer (MIBC) is primarily attributed to tumor heterogeneity and therapy resistance. We propose a novel approach targeting interleukin-13 receptor subunit alpha 2 (IL-13Rα2), which is expressed on bladder cancer (BC) cells but absent in normal urothelial cells. We investigated the therapeutic effects of WPD101a immunotoxin (IL-13-DT390) on IL-13Rα2-expressing BC cells in relation to BC cell phenotype and functional characteristics in vitro using both 2-dimensional (2D) and 3-dimensional (3D) models. Cell phenotype and IL-13Rα2 expression were assessed using flow cytometry, immunofluorescence, and Western blot analysis. The biological effects of WPD101a were evaluated by measuring cell viability and proliferation using the MTT, sulforhodamine B (SRB), CellTiter-Glo and Live/Dead assays. Apoptosis was assessed using Annexin V/propidium iodide (PI) staining, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of CASP genes expression. We found that the reference BC cell lines TCC-SUP, JMSU-1 and UM-UC-3 express IL-13Rα2 at various level in contrast to RT-4, HCV-29 and 5637 cells. Cells expressing IL-13Rα2 were sensitive to WPD101a at lower concentrations in the 2D model (0.1 ng/mL) compared to the 3D model (1.0 ng/mL). IL-13Rα2-negative cells remain resistant to the immunotoxin. WPD101a induces apoptosis in BC cells expressing IL-13Rα2 as confirmed by the presence of apoptotic cells, increase the proportion of cells in the subG1 phase, and by the effector CASP3, CASP7, and initiator CASP8, CASP9 genes expression. This study confirmed receptor-dependent cytotoxic effects of WPD101a and the ability and specificity to inhibit growth and apoptosis induction in MIBC cells expressing IL-13Rα2. Full article

Background: The tumor immune microenvironment, particularly the role of cytotoxic CD8+ T lymphocytes, is crucial in cancer progression but remains poorly understood in pituitary neuroendocrine tumors (PitNETs). The significance of CD8+ cell infiltration varies across PitNET subtypes, suggesting a complex interplay with tumor cell lineage. This study aimed to characterize the distribution of CD8+ tumor-infiltrating lymphocytes across different PitNET subtypes defined by the current WHO classification and to explore their association with clinicopathological features. Methods: We conducted a retrospective study on 40 surgically resected PitNETs. All cases were classified based on immunohistochemical expression of pituitary hormones and lineage-specific transcription factors (PIT-1, TPIT, SF-1). CD8+ lymphocyte density was quantified using immunohistochemistry and calculated as cells/mm². Exploratory statistical analysis was performed based on non-parametric tests to compare CD8+ cell density across tumor subtypes and with parameters like tumor size, invasiveness (Knosp grade), and proliferation index (Ki-67). Findings are to be treated as observational trends. Results: The highest density of CD8+ lymphocytes was observed in plurihormonal PIT-1-positive tumors [17.61 cells/mm² (IQR: 17.61–60.36)], followed by somatotroph [13.2 (6.6–15.72)] and mammosomatotroph [13.83 (0–21.38)] tumors. A difference in CD8+ density was found between PIT-1-positive and PIT-1-negative tumors (n1 = 34, n2 = 6, U = 49.5, p_exact = 0.050, r = 0.33); the medium effect size indicates a possible lineage-related trend. Another difference was observed between SF-1-positive and SF-1-negative tumors (p = 0.025), with SF-1 lineage tumors showing the lowest infiltration. No correlations were found between CD8+ density and tumor size, Knosp grade, or Ki-67 index. Conclusions: The distribution of intratumoral CD8+ T lymphocytes in PitNETs is highly heterogeneous and appears to be strongly dictated by the transcription factor-defined tumor lineage rather than by traditional clinicopathological markers of aggressiveness. PIT-1 lineage tumors harbor a more active immune microenvironment, while SF-1 lineage tumors are relatively ‘immune-poor’. These findings highlight the immunological diversity of PitNETs and support further investigation of the tumor immune landscape. Collaborative multi-institutional studies are required to validate these trends. Full article

Glioblastoma (GB) is the most aggressive primary central nervous system tumor in adults and the most common malignant primary brain tumor, representing approximately 50.9% of all malignant CNS tumors, with a median overall survival of approximately 14.6 months despite standard multimodal treatment, consisting of surgical resection, concurrent radiotherapy, and temozolomide (TMZ), followed by adjuvant TMZ (Stupp protocol). Tumor recurrence is inevitable and attributed to diffuse infiltration of neoplastic cells into the brain parenchyma, marked intratumoral heterogeneity, the presence of glioma stem cells, and the protection conferred by the BBB. Flavonoids are plant-derived polyphenolic compounds with more than 8000 identified. They have attracted growing interest as potential therapeutic agents because of their capacity to modulate multiple oncogenic signaling pathways and their favorable toxicity profile. Here we synthesize the preclinical evidence on the main flavonoids with documented activity in GB models, with emphasis on quercetin, apigenin, luteolin, and EGCG, while distinguishing glioblastoma-specific evidence from indirect findings derived from other experimental systems. We analyze their underlying molecular mechanisms, including induction of apoptosis through the intrinsic and extrinsic pathways, inhibition of cell proliferation and angiogenesis, suppression of migration and invasion, epigenetic modulation, and, particularly, the capacity to target the glioma stem cell population. We also examine the limited oral bioavailability and restricted penetration across the BBB, as these factors remain major barriers to translational development. We conclude with an analysis of emerging nanotechnological strategies, targeted delivery systems, and synergistic combinations with conventional chemotherapeutic agents, together with a cautious assessment of the current clinical evidence, which remains insufficient to support the use of flavonoids outside controlled clinical trials. Full article

Background: Gastric cancer is a major global health concern. Although sex- and gender-based differences have been described, they are not yet well established, and the available evidence is often inconsistent. This systematic review aims to explore these differences in the incidence, clinicopathological characteristics, risk factors, treatment, and survival of gastric cancer, thereby contributing to healthcare equity. Methods: A systematic search was conducted in the main medical bibliographic databases (PubMed, Embase and Web of Science) in February 2026 following the PRISMA 2020 guidelines. Studies on gastric cancer were selected based on predefined inclusion and exclusion criteria. The results were synthesized qualitatively according to incidence, clinicopathological characteristics, risk factors, treatment outcomes, and survival. Due to the heterogeneity and predominantly observational design of the included studies, no meta-analysis or formal risk-of-bias assessment was conducted. Results: A total of 38 studies, involving more than 500,000 participants, were included. Most reported a higher incidence of gastric cancer in men, with a predominance of intestinal and well-differentiated tumors, while diffuse and poorly differentiated tumors were more common in women. Men showed higher rates of smoking, alcohol consumption, and postoperative complications. Overall survival tended to be higher in women, especially in early stages, although some studies described worse outcomes among young women. Conclusions: This review highlights relevant sex- and gender-related differences in gastric cancer and underscores the need to systematically incorporate these variables into future research to advance towards more personalized medicine. The available evidence was limited by the predominance of retrospective observational studies and heterogeneity across study designs and reported outcomes. Full article

While chimeric antigen receptor (CAR)-T-cell therapies have shown significant effectiveness in hematological malignancies, their efficacy in solid tumors remains limited by the hostile tumor microenvironment (TME) and antigen heterogeneity. Recently, CAR-Macrophage (CAR-M) therapy has emerged as a paradigm-shifting approach, leveraging the innate capability of macrophages to deeply infiltrate tumors and their plasticity to reverse immunosuppression. Unlike T cells, CAR-Ms not only mediate direct phagocytosis but also initiate epitope spreading, effectively bridging innate and adaptive immunity. This review critically examines the trajectory of CAR-M therapy from biological rationale to clinical reality. We dissect the engineering evolution of CAR constructs, arguing for macrophage-specific signaling domains (e.g., FcRγ, Megf10) over traditional T-cell designs. Crucially, we address the major bottlenecks in clinical translation, including the manufacturing challenges of non-expanding primary macrophages and the emerging shift toward induced pluripotent stem cell (iPSC)-derived platforms. Furthermore, we evaluate current clinical trial landscapes and discuss next-generation strategies such as in vivo programming via lipid nanoparticles (LNPs) and synthetic logic-gating to enhance safety. Ultimately, overcoming manufacturing constraints and optimizing delivery systems will be pivotal for CAR-M to evolve from a niche therapy into a standard-of-care modality for solid tumors. Full article

Introduction: Neuroinflammation is a key feature of both Alzheimer’s disease (AD) and glioblastoma, although it leads to different outcomes in each disorder. In AD, chronic activation of microglia and astrocytes by amyloid-β and tau contributes to neuronal injury and cognitive decline. In glioblastoma, tumor cells exploit inflammatory pathways to create an immunosuppressive microenvironment that supports tumor growth. This review compares the shared and distinct neuroinflammatory mechanisms in AD and glioblastoma and highlights their therapeutic relevance. Materials and Methods: This study was conducted as a narrative review based on a PubMed search performed by three reviewers. English-language articles on AD, glioblastoma, and neuroinflammatory pathways were included, covering original studies, reviews, meta-analyses, and experimental and clinical reports. Keywords included neuroinflammation, microglia, astrocytes, tumor-associated macrophages, inflammasomes, NLRP3, NF-κB, HIF-1α, cytokines, blood–brain barrier, and miRNAs. Due to study heterogeneity, findings were synthesized descriptively. Results: AD and glioblastoma share major neuroinflammatory mechanisms, including microglial and astrocytic activation, cytokine signaling, inflammasome activity, blood–brain barrier dysfunction, hypoxia-related changes, and miRNA regulation. In AD, these pathways promote chronic inflammation, synaptic loss, and neurodegeneration, with NLRP3, NF-κB, and M1-like microglial polarization playing central roles. In glioblastoma, similar pathways are redirected toward tumor progression through tumor-associated macrophages, reactive astrocytes, angiogenesis, immune evasion, and therapy resistance. Key overlapping mediators include IL-1β, TNF-α, NF-κB, HIF-1α, GSK-3β, and selected miRNAs. Conclusions: AD and glioblastoma are connected by common neuroinflammatory pathways, but these processes result in neurodegeneration in AD and tumor support in glioblastoma. Understanding these shared and divergent mechanisms may guide the development of biomarkers and targeted therapies focused on microglia, inflammasomes, cytokines, and immune reprogramming in both diseases. Full article

Background: The role of surgery in advanced thyroid cancer remains controversial, particularly in the setting of aggressive tumor behavior, local invasion, and limited therapeutic windows. Advanced thyroid cancer represents a heterogeneous clinical entity that includes anaplastic thyroid carcinoma as well as differentiated and poorly differentiated carcinomas with aggressive features. Methods: We conducted a retrospective case series of 10 consecutive patients who underwent surgical management for advanced thyroid cancer at a tertiary referral center over a 30-month period. Clinical presentation, surgical strategy, postoperative complications, adjuvant therapies, and outcomes were analyzed. Results: The cohort included 2 papillary, 5 poorly differentiated, and 3 anaplastic thyroid carcinomas. Most patients presented with locally invasive disease and compressive symptoms, including dysphonia and dyspnea. Complete resection (R0) was achieved in five patients and was associated with favorable outcomes, while patients with anaplastic histology experienced poor survival despite palliative interventions. Surgery provided meaningful symptom control in selected patients, particularly those with airway compromise. No perioperative mortality occurred. Conclusions: Surgical management of advanced thyroid cancer should be highly individualized and guided by tumor extent, symptom burden, and patient performance status. While surgery alone is insufficient as a standalone treatment, it plays a pivotal role when integrated within a multimodal strategy, offering both oncologic and palliative benefits. Early identification of candidates for surgical intervention and integration with systemic therapies represent key elements in the management of these complex malignancies. Full article

Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm whose sonographic profile has not been systematically characterized. We describe an index case of malignant uterine PEComa and present a PRISMA 2020-compliant systematic review (PubMed, Scopus, Cochrane Library; search 1 March 2026) of studies reporting original ultrasound data of histologically confirmed uterine PEComa. Sonographic features were coded with MUSA/IETA terminology; Clopper–Pearson 95% confidence intervals (CI) were calculated for key proportions, and malignancy subgroups were summarized descriptively. Thirty-one cases were pooled (30 from 18 studies plus our index case; median age 41 years). The profile comprised absent acoustic shadowing in all documented cases (10/10; 95% CI 69.2–100%), moderate-to-abundant vascularisation (Color Score 3–4, 91.7%), variable echogenicity (heterogeneous 56.0%) and predominantly regular margins (69.6%). Preoperative misdiagnosis occurred in 100% of cases, most often as leiomyoma (41.4%). In cases with known malignancy status (n = 17), irregular margins and cystic areas appeared more often in malignant lesions, but subgroups were too small for testing. Only 4/18 studies applied standardized terminology. Uterine PEComa shows a recurrent pattern of absent shadowing, high vascularisation and solid consistency with regular margins that may aid differential diagnosis; systematic adoption of MUSA/IETA terminology in future reports is strongly advocated. Full article

Background/Objectives: Liposarcoma is a heterogeneous soft tissue sarcoma in which anthracycline-based chemotherapy, including doxorubicin, remains a cornerstone of treatment for advanced disease. However, variable and often limited therapeutic responses highlight the need for improved understanding of disease-associated transcriptional adaptation under chemotherapeutic stress. In this study, a bioinformatics-driven transcriptomic analysis was performed to characterize gene expression alterations associated with doxorubicin treatment in liposarcoma using publicly available data from the Gene Expression Omnibus (GSE12972). Results: Differential expression analysis identified 365 significantly altered genes, including 164 upregulated and 201 downregulated transcripts in treated samples compared with untreated controls. Functional interpretation using Ingenuity Pathway Analysis identified transforming growth factor beta 1 (TGFB1), tumor necrosis factor (TNF), and SMARCA4 as prominent predicted upstream regulators associated with transcriptional programs related to extracellular matrix remodeling, inflammatory and immune modulation, epithelial-to-mesenchymal transition-like states, and chromatin-mediated transcriptional plasticity. Enriched canonical pathways included Liposarcoma tumor microenvironment-associated signaling and fibrosis-related pathways, reflecting stromal activation and immune-related transcriptional changes. Notably, fibroblast growth factor 1 (FGF1) emerged as a supportive regulatory node linked to survival- and anti-apoptotic gene expression patterns. Conclusions: Collectively, these findings provide a disease-oriented, cross-subtype systems-level view of the transcriptional changes associated with doxorubicin treatment in liposarcoma. This work is intended as a hypothesis-generating framework that may inform future functional studies and integrative approaches aimed at understanding therapeutic response and disease progression. Full article

Head and neck squamous cell carcinoma (HNSCC) remains one of the most aggressive and heterogeneous malignancies worldwide, characterized by high rates of locoregional recurrence, metastatic dissemination, and therapeutic resistance. Angiogenesis plays a central role in tumor progression by supporting vascular remodeling, hypoxia adaptation, invasion, immune evasion, and metastatic spread. In HNSCC, angiogenic activation is regulated through complex interactions involving hypoxia-inducible factors, vascular endothelial growth factor (VEGF) signaling, stromal remodeling, inflammatory pathways, and epigenetic mechanisms within the tumor microenvironment. Recent evidence has also highlighted the role of non-coding RNAs, particularly microRNAs, and exosome-mediated communication in modulating angiogenic and immune-related signaling pathways. Although antiangiogenic therapies, including monoclonal antibodies and tyrosine kinase inhibitors, have demonstrated biological activity in HNSCC, their clinical efficacy remains limited by tumor heterogeneity, adaptive resistance mechanisms, toxicity, and the lack of validated predictive biomarkers. Several emerging therapeutic strategies are under preclinical or early clinical investigation in HNSCC, including miRNA-based approaches, nanoparticle-assisted delivery systems, vascular normalization concepts, and combinations with immune checkpoint inhibitors; however, robust clinical evidence for most of these strategies remains limited, and their translation to routine practice requires further validation. This review provides a comprehensive overview of the molecular mechanisms regulating angiogenesis in HNSCC and critically discusses current and emerging pharmacological strategies targeting these pathways. Particular emphasis is placed on VEGF/VEGFR signaling, the integration of miRNA and exosome biology, resistance mechanisms, and translational perspectives for biomarker-guided personalized therapy. The novelty of this review lies in the systematic integration of miRNA- and exosome-mediated angiogenic regulation, therapeutic resistance pathways, and precision medicine strategies into a unified pharmacological framework, addressing gaps not fully covered by prior reviews focused primarily on VEGF-targeted agents. Full article

Medulloblastoma is one of the most prevalent pediatric brain tumors. Currently, existing therapies for this devastating type of cancer can only prolong survival time with severe side-effects and relapse. These therapies are not curative for almost a third of treated patients, while most survivors are condemned to a poor quality of life. The addition of immune checkpoint inhibitors (ICIs) to immune therapy has given some hope to those suffering from this type of cancer. Although ICIs provide a valuable contribution to immunotherapy, the exploitation of immune checkpoint inhibition within existing therapeutic strategies to cure Medulloblastoma remains understudied. However, the identification of the main molecular subgroups of medulloblastoma is considered one of the success stories of oncology. This advancement in molecular profiling of MB paved the way to subgroup-directed clinical trials, which may lead to efficacious immune-targeted therapy. However, this relatively new development is still hampered by a substantial biological heterogeneity of the disease and the absence of a full understanding of the various mechanisms behind its resistance to existing therapeutic modalities. The inclusion of chimeric antigen receptor (CAR) T and CAR NK cell therapy within various therapeutic strategies and ongoing clinical trials has given fresh hope those suffering from this fatal disease. However, ongoing clinical trials suggest that this highly promising therapy can be impaired by a number of serious limitations, including cytokine release syndrome, Graft-versus-host disease, the scarcity of target antigens, and severe adverse events. Some of the ongoing clinical trials also suggest that CAR NK is less prone to some of these limitations. This review also highlights the contribution of mass spectrometry-based proteomics, and the increasing role of liquid biopsy rather than tissue biopsy. Full article

Cancer remains one of the most formidable health challenges worldwide. Extensive research has shown that tumor progression is not driven solely by malignant cells but is profoundly shaped by the tumor microenvironment (TME), which influences cancer initiation, immune evasion, and metastatic spread. Consequently, the TME has become an increasingly compelling therapeutic target. Nanotechnology has transformed cancer diagnostics and therapy, with metallic nanoparticles (mNPs) gaining particular attention due to their distinctive physicochemical properties and broad therapeutic potential. However, their interactions within the TME remain insufficiently understood, particularly with the non-cancerous cellular components, such as Cancer-Associated Fibroblasts (CAFs), Tumor-Associated Macrophages (TAMs), Dendritic Cells (DCs), Natural Killer (NK) cells, and T cells. Most existing reviews emphasize nanoparticle interactions with non-cellular TME components, such as the extracellular matrix, while far less attention has been given to their effects on cellular constituents (a gap this work specifically addresses). Although several molecular pathways through which mNPs modulate TME-resident cells have been identified, these likely represent only a small portion of the underlying mechanisms explored in this review. Progress in the field is further hindered by the limited availability of physiologically relevant experimental models; current in vitro and in vivo systems often fail to capture the complexity and dynamic heterogeneity of the TME. These limitations highlight the urgent need for more comprehensive and mechanistically grounded studies to validate the TME as a viable therapeutic target for nanoparticle-based cancer interventions. In particular, deeper insights into how mNPs influence immune regulation, stromal remodeling, and metabolic reprogramming within the TME will be essential for unlocking their full therapeutic potential in oncology. Full article

Melanoma has long represented a unique challenge in oncology. In its early stages, it can often be cured with surgery alone, resulting in excellent survival outcomes. Its biology is complex and heterogeneous, often including mutations such as BRAF and NRAS, which partly explain its high immunogenicity but also its capacity to relapse. For many decades, the standard approach in resectable stage III melanoma was surgery first, followed by adjuvant therapy. In the last decade, the development of immune checkpoint inhibitors created the opportunity to treat patients before surgery. The neoadjuvant approach is based on the hypothesis that treatment of the intact tumor may enhance antitumor immune priming and activation. The first prospective neoadjuvant studies, including OpACIN and OpACIN-neo, showed high pathological response rates with ipilimumab plus nivolumab and introduced pathological response as an early marker of long-term benefit. The PRADO study showed that treatment response could guide the extent of surgery required. The SWOG S1801 trial demonstrated better event-free survival with perioperative pembrolizumab compared to adjuvant therapy alone. Lastly, the phase III NADINA trial showed that neoadjuvant ipilimumab plus nivolumab followed by response-adapted adjuvant therapy significantly improves outcomes. Biomarkers such as PD-L1, IFN-γ signature, tumor mutational burden and imaging (PET scan) appear promising to predict response, but none have been sufficiently validated for routine clinical practice. Full article