Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with immunotherapy yielding <10% objective response rates (ORR) due to its profoundly immunosuppressive tumor microenvironment (TME). This review integrates preclinical and clinical evidence (2018-2026) to dissect how stromal desmoplasia, myeloid dominance, T-cell exclusion, and impaired antigen presentation converge to form an immune-privileged niche. Key resistance pathways, including cGAS-STING, Hedgehog, and NF-κB, are discussed alongside emerging strategies such as CAR-T cells, mRNA neoantigen vaccines, STING agonists, CD39/CD73 blockade, and cDC1-based vaccines. Despite incremental progress, durable responses remain rare, emphasizing that single-target interventions are insufficient. We propose a "3D+R" framework, De-desmoplasia, De-adenosine, De-novo antigen, and Rational sequencing, to guide multidimensional, biomarker-driven immunotherapy design. Approaches such as timed cDC1 vaccination, patient-tuned STING agonism, and metabolic checkpoint inhibition exemplify how PDAC's immune-desert phenotype may be reshaped toward an immune-reactive state. Conceptualizing PDAC as a dynamic immune ecosystem rather than a mutation-driven entity may ultimately transform sporadic responses into durable and predictable clinical benefit.

Pheochromocytomas (PCCs) are rare neuroendocrine tumors with limited treatment options once metastasized. Progress toward effective therapies has been hindered by their rarity, disease heterogeneity, and lack of representative preclinical models. Organoids are three-dimensional, self-renewing structures that recapitulate key features of their tissue of origin, providing valuable platforms for disease modeling, drug screening, and personalized medicine. This study aimed to establish and characterize patient-derived organoid cultures of PCCs.

Epithelioid hemangioendothelioma (EHE) of bone is a malignant vascular neoplasm with a very low global prevalence. Nonspecific clinical and histopathological findings make the diagnosis of this tumor very challenging. In this case, we reported a 23-year-old male presented with persistent right buttock pain for 9 months (VAS 2-3). No other clinical findings were found. On plain radiographs, a lytic lesion was found on the right iliac wing. MRI showed iso- hyperintense lesions on both T1- and T2-weighted sequences with hemorrhagic components. A CT guided core needle biopsy was performed for further evaluation. The patient underwent wide excision with adjuvant chemotherapy. At six months post-surgery, lymph node metastases was found on PET scan without any clinical symptoms. A comprehensive interdisciplinary evaluation is required to establish the diagnosis of EHE.

Chondrosarcoma is a malignant tumor originating from cartilage-producing cells. Although rare in the hand, it is the most common primary malignant bone tumor in this location. We present a case of high-grade chondrosarcoma of the first metacarpal bone in an 85-year-old female, who presented with pain and severe limitation of hand function. Imaging studies initially suggested a giant cell bone tumor, and a tru-cut biopsy did not confirm chondrosarcoma. During the preoperative period, the tumor enlarged from approximately 10x9 cm to 15x11 cm, ultimately necessitating amputation as the treatment of choice. Histopathological evaluation revealed grade 2-3 chondrosarcoma. According to the existing literature, a hand chondrosarcoma of this size has not been previously documented. Hand chondrosarcomas, unlike those in other regions, rarely metastasize; however, despite their low metastatic potential, they may still lead to substantial morbidity. When wide resection and amputation are performed, as in our case, the risk of local recurrence is significantly reduced.

Colorectal cancer (CRC) remains a major global health challenge, with current therapeutic options often limited by drug resistance and adverse effects. Small molecules provide distinct advantages, including oral bioavailability, cost-effectiveness, and the ability to target intracellular pathways critical for tumor progression. In this study, we designed and synthesized a new series of pyrazolone derivatives with varied substitution patterns using microwave-assisted methods and evaluated their antiproliferative activity against CRC cell lines (HCT-116 and WiDr). Among these, PL-13 emerged as a potent and selective candidate, exhibiting strong cytotoxicity toward cancer cells while sparing noncancerous CRL-1459 colon cells. Functional assays, including colony formation and wound healing, confirmed its ability to inhibit cell proliferation and migration. Western blot analyses demonstrated that PL-13 induces apoptosis via the intrinsic mitochondrial pathway, as evidenced by increased levels of cleaved caspase-9 and PARP, and modulates LC3A/B expression, suggesting involvement of autophagy. Kinome profiling revealed selective binding of PL-13 to FLT3, which was validated by an IC50 value of 8.2 μM. Molecular docking further supported these findings, showing favorable binding energy (-7.98 kcal/mol) compared to regorafenib (-7.13 kcal/mol). Collectively, these results highlight PL-13 as a promising lead compound for further optimization toward CRC therapy.

ObjectiveThis study aimed to investigate the clinical diagnostic performance of a combined classification model incorporating magnetic resonance imaging (T1WI-CE) habitat and human epididymis protein 4 (HE4) for differentiating borderline ovarian tumors (BOTs) from malignant epithelial ovarian tumors (MEOTs).MethodsA retrospective analysis was conducted on 127 patients with pathologically confirmed ovarian tumors, including 62 with BOTs and 65 with MEOTs, all of whom underwent preoperative magnetic resonance imaging examination. Twenty habitat features, including the original images, were extracted. T1WI-CE was used to extract 2395 radiomics features from two habitat subregions. Feature selection was performed using correlation analysis and least absolute shrinkage and selection operator regression.ResultsThe combined classification model had the highest area under the curve, 0.941 in the training group and 0.880 in the test group, thus outperforming the habitat area and clinical data classification model. The DeLong test demonstrated statistically significant differences between the combined classification model and the clinical classification model, with P values of 0.041 in the training group and 0.023 in the test group. Additionally, a statistically significant difference was observed in the DeLong test results between the cystic habitat subregion (H2) and the overall habitat region.ConclusionsThe combined classification model of habitat analysis and clinical data effectively improved the diagnostic efficacy of differentiating borderline from malignant ovarian tumors. The diagnostic efficacy of the habitat subregion (H1) dominated by solid components and the habitat overall region was superior to that of the habitat subregion dominated by cystic components.

Vascular tumours and malformations encompass infantile hemangiomas (IHs) and genetically driven vascular malformations with distinct natural histories and therapeutic vulnerabilities. The discovery that the non-selective beta-blocker propranolol induces rapid regression of proliferating IHs established the first widely adopted systemic pharmacologic therapy in vascular anomaly care and provided a clinical proof-of-concept that targeting lesion-specific endothelial biology can alter disease course. In parallel, recurrent somatic variants affecting PI3K/AKT/mTOR (e.g., PIK3CA, TEK/TIE2, AKT1) and RAS/MAPK (e.g., KRAS, NRAS) signalling have reframed many malformations as mosaic disorders amenable to targeted inhibition with agents such as sirolimus, alpelisib, AKT inhibitors and MEK inhibitors. This review synthesizes translational mechanisms, clinical evidence and safety considerations for beta-blockers and emerging targeted therapies, emphasizing lesion phenotype, timing of intervention and molecular stratification as determinants of response. We highlight current limitations, including toxicity, durability and pathway escape, and outline future directions for precision therapy and genotype-guided trial design in vascular anomalies.

The lncRNA NEAT1 is overexpressed in multiple myeloma (MM) plasma cells and plays a key role in MM pathogenesis. NEAT1 is involved in ceRNA network in several cancers; however, data in MM are virtually absent. This study identified a NEAT1-driven ceRNA network involving 96 miRNAs and 40 target genes, selected as concurrently downregulated in NEAT1-KD AMO1 cells and upregulated in NEAT1-overexpressing AMO1 cells (AMO1-OVX). The co-expression of NEAT1 and the targets was validated in MM patients (GSE116294, GSE13591, GSE6477, CoMMpass), and in NEAT1-KD NCI-H929, LP1, and KMS27 cell lines, showing for all targets a consistent downregulation, resembling that of NEAT1. The functional implication of the ceRNA network was explored by functional enrichment analyses of the 40 targets, identifying 78 significant gene sets, 17 of which were found significantly enriched by GSEA analysis in at least one experimental condition among NEAT1-KD LP1, NCI-H929, and KMS27 cells, AMO1-OVX cells, or the extreme quartiles of NEAT1 expression in the CoMMpass dataset. Noteworthy, the cell cycle gene set was validated in 5 out of 6 conditions tested, suggesting that in MM the impact of NEAT1 upregulation on the cell cycle, experimentally demonstrated in our earlier publications, may be attributable, at least partially, to ceRNA mechanisms.

Pheochromocytomas and Paragangliomas (PPGL) are rare neuroendocrine tumors with favorable prognosis, although a significant subset (20-25%) progress to metastasis, worsening patient prognosis. For metastatic cases, pharmacological interventions become essential, yet most tumors show poor response to treatment. While clinical trials are ongoing, there is no established treatment for metastatic PPGL. Like other neuroendocrine tumors, PPGL exhibit high membrane expression of somatostatin receptors, and despite Peptide Receptor Radionuclide Therapy, PRRT, strategies have successfully been implemented, trials with cold somatostatin analogs were abandoned prematurely due to inconsistent results. To investigate this issue and identify potential therapeutic tools, we widely profiled somatostatin receptors expression in PPGL and conducted a comprehensive functional screening on wild-type and SDHB knockdown PPGL cell lines of native and synthetic somatostatin analogs. Results revealed that pheochromocytomas and paragangliomas similarly display a predominant SSTR2 and SSTR1 expression regardless of molecular cluster. Treatment with somatostatin, cortistatin, octreotide or pasireotide did not exert clear antitumoral effects on model cell lines. Notably, the selective SST2 agonist BIM-23120 significantly reduced cell proliferation and induced apoptosis in an SST2-dependent manner, but only in SDHB knocked-down PPGL cells. Indeed, only SDHB KD cells showed stronger membrane-enriched SST2 and clear receptor internalization upon BIM-23120 treatment. Molecular analysis revealed a generalized dephosphorylation affecting key proliferation, growth and cell survival pathways in response to BIM-23120 (unlike when treating with octreotide). Altogether, our results provide novel information on the status of the somatostatin system in PPGL and identify new potential therapeutic tools selectively targeting somatostatin receptors on this refractory tumor.

This study investigated patients whose initial diagnosis was de novo Stage IV gastric cancer, a population with extremely poor prognosis and limited evidence regarding how longitudinal nutritional changes evolve over time in advanced disease. We examined the trajectories of hemoglobin (Hgb), body mass index (BMI), and the prognostic nutritional index (PNI) as well as descriptively explored differences in nutritional trajectories between survival-defined groups based on one-year survival.

Hepatocellular carcinoma (HCC) represents a critical oncological challenge demanding innovative therapeutic interventions. miRNA has been known to play an important role in cancer inhibition to control HCC's development and progression by regulating cell proliferation and apoptosis. The major hurdle is to deliver the miRNA at the site of tumor. Metallic nanoparticles with modified surface can be used to solve this problem. In the current study, gold-nanoparticles (Au NPs) were prepared, and their surface was modified with PEG moiety to facilitate the attachment of miRNA. For the first time, the modified gold NPs were loaded with miR-199a. Our findings revealed that, when cells treated with gold bare (80 nM) for 24 h, a low cytotoxicity was obtained (11.11 ± 2.25%). When cells treated with nanocomplex miRNA- PEG -Au NPs (80 nM) for 24 h, a significantly increased cellular cytotoxicity was obtained (55.7 ± 4.55%). Also, the prepared nanocomplex exhibits a promising potential in suppressing tumor cell proliferation and significantly enhancing apoptosis in a concentration and time dependent manner. These results underscore the transformative potential of targeted nanomaterial-based miRNA delivery as a sophisticated therapeutic modality in cancer management. In conclusion, Au NPs are excellent carriers for miRNA where they increase the cellular uptake, exerting a promising anticancer effect on HCC cells, representing a new approach in developing precision therapeutics for hepatocellular carcinoma.

Osteosarcoma is a highly malignant bone tumor which primarily affects the juvenile population and is characterized by high rate of recurrence and metastasis. RNA editing has emerged as a key process in cancer progression. Herein, we investigated the role of RNA editing enzyme ADAR2 (Adenosine Deaminase Acting on RNA 2) in osteosarcoma. We demonstrated that ADAR2 expression increases during osteoblast differentiation and inversely correlates with the aggressiveness of osteosarcoma cells. Interestingly, the overexpression of ADAR2 in osteosarcoma cell lines reduces their tumoral properties and promotes their differentiation in osteoblast-like cells, as shown by gene expression analysis and mineralization assays. These results were also confirmed by in vivo experiments; indeed, intratibial injection of ADAR2-overexpressing osteosarcoma cells in NSG mice resulted in less aggressive tumors compared to mice injected with pEmpty or pInactive ADAR2 E/A vector-transfected cells. To elucidate the mechanisms by which ADAR2 overexpression induces osteogenic terminal differentiation of osteosarcoma cells, we performed RNA-seq analysis of Saos-2 cells and identified IGFBP7 (Insulin-like Growth Factor Binding Protein 7) as the most highly edited transcript in ADAR2-overexpressing cells. We showed that the editing activity of ADAR2 on IGFBP7 abolishes its proliferative effect on osteosarcoma cells and triggers terminal differentiation. Overall, our results indicate that ADAR2 acts as a tumor suppressor in osteosarcoma and may represent a novel therapeutic target for this aggressive pediatric tumor.

T-cell lymphoblastic lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (T-ALL) originate from thymic T-cell precursors, with ongoing debate on whether they are variants of the same disease or distinct entities. For 211 patients, including pediatric and adult T-ALL and T-LBL cases, targeted next-generation sequencing and SNP-arrays were performed, and single-nucleotide variants, indels and copy-number variants (CNVs) were analyzed. We aimed to assess genetic differences between T-ALL and T-LBL across age. Generally, mutational landscape analysis identified mutated PHF6 being associated with higher, NOTCH1 with lower age at diagnosis for both T-LBL and T-ALL. Association of CNVs with higher age was evident for T-ALL, but not T-LBL. Analysis of clonal evolution revealed that CNVs - especially deletions and LOH in chromosome 9 (LOH_in_9p) - were observed as first mutational event in both pediatric T-ALL and T-LBL. The sequence of genetic events, starting with LOH_in_9p followed by mutations in NOTCH1, was significantly more frequent in pediatric T-ALL and T-LBL. Detailed evaluation of the patients' individual clonal evolution indicated that the proportion of malignant cells without NOTCHMT determines the risk of relapse (hazard ratio 1.032, p = 4.65*10-5). In T-ALL, aside from MRD, validated molecular markers for risk-group stratification remain limited. Our data suggest that molecular metrics analogous to those in T-LBL may help refining risk stratification in T-ALL as well.

Glioblastomas (GBM) can recur in different ways. While local recurrence is most common, some GBM recur at distant sites or simultaneously at multiple sites. However, the consequences of different regrowth patterns for the clinical course and the factors that might influence regrowth patterns or different modalities of recurrence remain unclear. We wondered (1) whether a more accurate analysis of regrowth patterns helps to detect subgroups of GBM patients, (2) if evaluation of relapse patterns correlates with differences in survival, and (4) whether we can identify predictors for distinct regrowth patterns. Therefore, we retrospectively collected demographic data, as well as tumor- and patient-characteristics, from 251 patients treated at two institutions and characterized their recurrence patterns by analyzing Magnetic Resonance Imaging data. We observed distinct differences in patients' overall and progression-free survival with respect to multicentric and multifocal recurrences, further supporting the hypothesis that these recurrences develop differently. Several tumor relapse patterns were associated with patients' progression-free and overall survival (e.g., unifocal local and multicentric recurrences; p < 0.05), even when other known prognostic factors were taken into account. TTFields were associated with prolonged progression-free survival (mPFS 7.2 months vs. 4.8 months, p = 0.03). They were predictive of a higher frequency of non-local recurrence patterns (OR 0.16, p = 0.02) and longer time to development of a local recurrence after subtotal tumor resection (mPFS 11.1 months vs. 5.2 months; p = 0.01). This can be interpreted as a sign of improved local control.

The RHO GTPase family regulates cytoskeleton-dependent processes, including proliferation and migration. Although their dysregulation is well described in solid tumors, little is known about their role in hematologic malignancies. We investigated the expression of ten RHO GTPase genes in bone marrow samples from patients with acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) and analyzed TCGA AML data for prognostic associations. RHOBTB2, RND2, and RHOQ were differentially expressed compared with healthy controls. RHOBTB2 was elevated in both MDS and AML and associated with inferior overall and disease-free survival, including in intermediate-risk AML. Our findings reveal distinct dysregulation patterns of RHO GTPases in myeloid malignancies and confirm RHOBTB2 as a candidate prognostic marker in AML with a potential oncogenic role. These data support further investigation into the functional roles of RHO GTPases in leukemogenesis and their utility as emerging biomarkers in hematologic cancers.

Breast cancer brain metastasis (BCBrM) remains one of the most lethal manifestations of breast cancer. Its response to immunotherapy is severely limited by the blood-brain barrier, which restricts immune cell infiltration and antigen presentation, thereby creating an immunosuppressive microenvironment. To overcome these barriers, recent studies have focused on novel immune checkpoints, including the Lymphocyte-Activated Gene 3-Galectin 3 (LAG3-LGALS3) and T-Cell Immunoreceptor with Ig and ITIM Domains-Nectin Cell Adhesion Molecule 2 (TIGIT-NECTIN2) axes, as well as on the reprogrammed metastatic ecosystem driven by immunosuppressive cells such as Forkhead Box P3-positive (FOXP3⁺) Regulatory T (Treg) cells, Lysosomal-Associated Membrane Protein 3-positive (LAMP3⁺) tolerogenic dendritic cells (DCs), C-C Motif Chemokine Ligand 18-positive (CCL18⁺) M2-like macrophages, Regulator of G-Protein Signaling 5-positive (RGS5⁺) cancer-associated fibroblasts (CAFs), Galectin 1-positive (LGALS1⁺) and TANK-Binding Kinase 1-positive (TBK1⁺) microglia, and phosphorylated Signal Transducer and Activator of Transcription 3-positive (pSTAT3⁺) reactive astrocytes. In addition, targeted inhibition of tumor-derived N-acetyltransferase 8-like (NAT8L) and metabolites N-Acetylaspartate (NAA), suppression of the N-Methyl-D-Aspartate Receptor (NMDAR) signaling pathway in tumor cells, and interventions against γ-Aminobutyric Acid (GABA)ergic reprogramming in BCBrM cells. Moreover, targeted interventions against distinct immune escape pathways-such as the Ubiquitin-Conjugating Enzyme E2T (UBE2T)/Cell Division Cycle 42 (CDC42)/Cluster of Differentiation 276 (CD276) and C-C Motif Chemokine Ligand 2-C-C Motif Chemokine Receptor 2/C-C Motif Chemokine Receptor 4 (CCL2-CCR2/CCR4) axes-have shown promise in reshaping the immune microenvironment and enhancing the efficacy of conventional immunotherapy. Collectively, this perspective outlines evolving strategies in immune checkpoint modulation, cellular ecosystem reprogramming, and neuroimmune intervention, providing a forward-looking framework to enhance the efficacy of immunotherapy in BCBrM.

Tuberous sclerosis complex (TSC) is a genetic disorder that affects multiple organs, particularly the brain, and is associated with neurologic impairments such as cognitive deficits and seizures. There are relatively few prior studies investigating brain metabolites in TSC. The aim of this study was to investigate neurochemical alterations in TSC, focusing on cortical/subcortical glioneuronal tubers as well as normal-appearing regions, and comparing them with matched healthy control subjects.

Video-assisted thoracoscopic surgery (VATS) lobectomy is a commonly employed surgical technique for the management of operable early stage non-small cell lung cancer (NSCLC). This procedure, however, is dependent on the patient's ability to tolerate surgery. In light of this, stereotactic ablative radiotherapy (SABR) has emerged as a viable alternative treatment strategy for patients who are inoperable or who refuse surgery. Considering the lack of randomised controlled trials and the increased risk of bias in observational cohort studies, this study protocol proposes an emulated target trial design to investigate the causal effect of SABR, in comparison to VATS, on overall survival in operable early stage NSCLC patients.

Primary chest wall tumors are rare malignant neoplasms, most commonly sarcomas, for which complete surgical resection is the main curative therapy. Surgical resection conferred substantial survival benefit compared with nonoperative management. Histology-specific differences were notable, with chondrosarcoma demonstrating favorable long-term survival and high-grade soft tissue sarcomas having poorer prognosis. Adjuvant radiotherapy improved local control in high-risk soft tissue sarcomas, while systemic therapy was essential for chemosensitive histologies. In conclusion, multi-institutional data underscore the central role of complete surgical resection in achieving optimal oncologic outcomes for primary chest wall tumors, with adjunctive therapy reserved for selected high-risk patients.

We describe a case of febrile neutropenia in a patient with metastatic non-small cell lung cancer, occurring after 36 cycles of nivolumab therapy. A bone marrow aspirate was performed which showed myeloid maturation arrest without a clear alternative cause, supporting an immune-mediated mechanism. The patient responded well to broad-spectrum antibiotics and granulocyte colony-stimulating factor (G-CSF), with successful rechallenge until other immune-related toxicities led to discontinuation. While uncommon, haematological immune-related adverse events are potentially life-threatening, with neutropenia reported in <1% of patients treated with immune checkpoint inhibitors. This case demonstrates three important points: (1) neutropenia may occur even late in the course of treatment with immunotherapy, highlighting the persistent need for vigilance; (2) bone marrow biopsy and the careful review of medications are essential to differentiate immune-mediated from chemotherapy or other drug-related cytopenias; and (3) management requires urgent recognition, antimicrobial cover, and G-CSF, and caution in the consideration of rechallenge.