Tumor Vasculature Research Articles

Enhanced brightness and photostability of dye-sensitized Nd-doped rare earth nanocomposite for in vivo NIR-IIb vascular and orthotopic tumor imaging

Rare-earth doped nanoparticles (RENPs) have shown promise in biomedical imaging, particularly within the NIR-IIb region, due to their deep tissue penetration and minimal light scattering. However, challenges such as low extinction coefficients, narrow excitation spectra, and prone to quenching in aqueous environments limit their effectiveness. To overcome these obstacles, we developed a novel dye-sensitized, onion-like Nd-doped RENP nanocomposite to enhance NIR-IIb imaging performance. The onion-like Nd-RENP nanocomposite markedly enhances emission intensity at 1525 nm within the NIR-IIb range by reducing quenching and improving spectral overlap. The integration of an IR783-containing micellar layer further stabilizes the NIR dye, mitigating quenching and photobleaching. In vivo imaging studies demonstrated a 75-fold increase in luminance and a 9-fold improvement in photostability compared to free NIR dyes in aqueous solutions. Time-dependent in vivo studies confirmed the nanocomposite’s capability for prolonged imaging of vascular and tumor tissues, maintaining high-resolution images for over an hour. Additionally, the nanocomposite supported successful 3D imaging reconstruction of biological tissues. The dye-sensitized onion-like Nd-RENP nanocomposite presents a significant advancement in NIR-IIb imaging, providing enhanced brightness and photostability. Its ability to maintain clear and stable imaging over extended periods suggests potential applications in dynamic vascular and tumor-targeted imaging. This innovation holds promise for future biomedical imaging technologies, particularly in areas requiring high-resolution and long-duration monitoring.Graphical

Constitutional Mismatch Repair Deficiency: Scoping Review of a Cancer-Predisposition Syndrome With Distinctive Cutaneous Findings.

Constitutional mismatch repair deficiency (CMMRD) is a rare but severe hereditary cancer predisposition syndrome caused by biallelic pathogenic variants in one of the mismatch repair genes (MLH1, MSH2, MSH6, or PMS2). The condition mainly presents in childhood, with cancers primarily affecting the hematological, brain, and gastrointestinal systems, along with cutaneous features typical of neurofibromatosis type 1. This scoping review aims to explore the clinical characteristics of CMMRD. A systematic search of medical databases resulted in the inclusion of 127 articles. PMS2 is the most affected gene, followed by MSH6, MLH1, and MSH2. Blood and brain malignancies occur in early childhood for all genetic variants, with the age of onset progressively decreasing from PMS2 to MSH6, to MLH1 and MSH2. Gastrointestinal tumors typically present in late adolescence in individuals with PMS2 variants, at slightly younger ages in those with MSH6 variants, and are rarely reported in MLH1 and MSH2 cases. Patients with CMMRD present with café-au-lait macules that are fewer in number and larger than in patients with neurofibromatosis type 1. Additional dermatological findings include hypopigmented patches and intertriginous freckling. PMS2 and MSH6 pathogenic variants are linked to the broadest spectrum of cutaneous manifestations, including vascular tumors, various nevi, and pilomatricomas. Despite its rarity and diverse clinical manifestations, advancements in diagnostic criteria, genetic testing, and surveillance protocols have significantly improved survival rates and cancer management in CMMRD patients.

Quantifying the tumour vasculature environment from CD-31 immunohistochemistry images of breast cancer using deep learning based semantic segmentation

BackgroundTumour vascular density assessed from CD-31 immunohistochemistry (IHC) images has previously been shown to have prognostic value in breast cancer. Current methods to measure vascular density, however, are time-consuming, suffer from high inter-observer variability and are limited in describing the complex tumour vasculature morphometry.MethodsWe propose a method for automatically measuring a range of vascular parameters from CD-31 IHC images, which together provide a detailed description of the vasculature morphology. We first used a U-Net based convolutional neural network, trained and validated using 36 partially annotated whole slide images from 27 patients, to segment vessel structures and tumour regions from which the measurements are taken. The model also segments the vascular smooth muscle, benign epithelium, adipose tissue, stroma, lymphocyte clusters, nerves and CD-31 positive leukocytes, and we applied it to an additional 21 images from 15 patients. Using these segmentations, we investigated the relationship between the various tissue types and the vasculature and studied the relationship of various vascular parameters with clinical parameters. We also performed a 3D histology analysis on a separate tumour sample as a proof of principle, providing a more comprehensive visualization of vasculature morphology compared to the standard 2D cross-section of a tissue sample.ResultsUsing two-way cross-validation, we show that vessels were accurately segmented, with Dice scores of 0.875 and 0.856, and were accurately identified, with F1 scores of 0.777 and 0.748. All vascular parameters exhibit strong (r>0.70.7$$\\end{document}]]>) and significant (p<0.001) correlations with measurements taken from the manual ground truth vessel segmentations. A significant relationship between the major/minor axis ratio, a measure of elongation, and the tumour grade was found.ConclusionOur proposed method shows promise as a tool for studying the tumour vasculature and its relationship with surrounding cells and tissue types. Furthermore, the correlation with tumour grade highlights the clinical relevance of our approach. These findings suggest that our method could have substantial implications for improving prognostic assessments and personalizing therapeutic strategies in breast cancer treatment.

Kasabach–Merritt syndrome, not only a pediatric condition: An autopsy case report and review of literature

Kasabach–Merritt syndrome (KMS), also known as hemangioma with thrombocytopenia, is a rare vascular disease characterized by thrombocytopenia, anemia, disseminated intravascular coagulation (DIC), and vascular lesions. It often occurs during infancy and the neonatal period and rarely in adults. The syndrome presents with consumptive coagulopathy initiated within a vascular tumor, mainly tufted angiomas or Kaposiform hemangioendotheliomas, and less commonly, hepatic and/or biliary hemangiomas. We report a case of a 41-year-old female with a recent diagnosis of biopsy proven biliary-type hemangioma of the liver, undergoing fertility treatment, who developed consumptive coagulopathy and disseminated intravascular coagulation shortly following a liver biopsy procedure, and ultimately demised. Based on the review of the literature, we present the first adult case of KMS where the diagnosis was made post-mortem. Given the rarity of this condition, particularly in the adult population, we believe our case adds value to the field of critical care medicine, coagulopathies, and forensic medicine.

Sustained Nitric Oxide Release Using Hybrid Magnetic Nanoparticles for Targeted Therapy: An Investigation via Electron Paramagnetic Resonance

This research describes the development and thorough characterization of a novel, versatile, and biocompatible hybrid nanocarrier of the NO-releasing agent NOC-18, with a specific focus on optimizing the purification process. In this study, we focused on the sustained release of NO using biocompatible and diagnostic hybrid magnetic nanoparticles (hMNPs) containing cerium-doped maghemite (CM) NPs, embedded within human serum albumin (HSA) protein. A comprehensive study was conducted using electron paramagnetic resonance (EPR) alongside the Griess assay to evaluate NO release from the chosen NO donor, NOC-18, and to assess the limitations of the molecule under various reaction conditions, identifying the optimal conditions for binding NOC-18 with minimal NO loss. Two types of particles were designed: In-hMNPs, where NOC-18 is encapsulated within the particles, and Out-hMNPs, where NOC-18 is attached onto the surface. Our results demonstrated that In-hMNPs provided a sustained and prolonged release of NO (half-life, 50 h) compared to the rapid release for the Out-hMNPs, likely due to the strong bonds formed with cerium, which helped to stabilize the NO molecules. These results represent a promising approach to designing a dual-function agent that combines contrast properties for tumor MRI with the possibility of increasing the permeability of tumor vasculature. The employment of this dual-function agent in combination with nanotherapeutics could improve the latter’s efficacy by facilitating their access to the tumor.

Analysis of prognostic factors and establishment of a recurrence risk prediction model for papillary thyroid carcinoma based on BRAF stratification.

Predicting the likelihood of papillary thyroid carcinoma (PTC) recurrence is crucial for improving patient outcomes. The association between the BRAF V600E (BRAF) mutation and PTC recurrence remains controversial. Our goal was to determine prognostic features of PTC patients and construct models for predicting recurrence risk according to BRAF mutation status. A total of 811 PTC patients whose clinical information and survival data were available were included in this study. Independent prognostic variables of PTC identified by screening via LASSO-Cox regression analysis were then used to construct nomograms. The performance of the predictive models was assessed according to the C-index, ROC curve, validation curve, and decision curve analyses. Kaplan-Meier curves were used to analyze differences between patients grouped according to prognostic factors and relapse risk. Multivariate Cox regression analysis demonstrated that extrathyroidal extension (ETE), vascular tumor thrombus, and lymph node yield (LNY) were correlated with recurrence-free survival (RFS) in the BRAF mutation-negative group, while extranodal extension (ENE), number of metastatic lymph node (NMLN), pathological stage, and vascular tumor thrombus were correlated with RFS in the BRAF mutation-positive group. The mutation-stratified predictive models demonstrated better performance than the model without stratification, as indicated by the greater C-index values (0.880 vs. 0.859 vs. 0.753), AUC values (1-year AUC: 0.946 vs. 0.947 vs. 0.758; 3-year AUC: 0.889 vs. 0.871 vs. 0.760; 5-year AUC: 0.845 vs. 0.793 vs. 0.758), and net clinical benefit. The calibration curves at 1 year, 3 years, and 5 years showed good consistency. The bootstrap internal validation had good AUC values exceeding 0.8 and showed a well-fitting calibration curve. Significant differences in RFS were observed between the low-risk and high-risk groups (P < 0.001). Stratifying patients based on their BRAF mutation status can facilitate the development of better and more targeted postoperative management strategies. Nomograms for BRAF mutation positive and negative patients were developed to precisely and consistently predict recurrence risk in PTC patients.

Tumor vascularity as a predictor of FGFR inhibitor response in FGFR2-fused intrahepatic cholangiocarcinoma.

638 Background: Fibroblast growth factor receptor 2 (FGFR2) fusion is a well-established mutation in intrahepatic cholangiocarcinoma (iCCA), accounting for approximately 10% of cases. Current treatments, including pemigatinib, infigratinib, and futibatinib, have shown promising results with response rates of less than 40%. Most patients experience progression within 6-8 months, and reliable biomarkers to predict treatment response are still lacking. This study aimed to assess the clinical outcomes of FGFR inhibitors in patients (pts) with FGFR2-fused iCCA, while investigating tumor vascularity as a potential predictor of treatment efficacy. Methods: We retrospectively analyzed data from 134 pts treated at MD Anderson Cancer Center between 2009 and 2024, focusing on 73 pts with comprehensive clinical data. The cohort included pts treated with futibatinib (n=16), infigratinib (n=16), pemigatinib (n=36), and derazantinib (n=5). Tumor vascularity was assessed via Hounsfield units (HU) from CT images, including a mathematical parameter to calculate a ratio of hypervascular tumor rim thickness to tumor diameter. Transcriptomic analysis of 11 pts was performed to explore mRNA expression related to tumor vasculature. Kaplan-Meier analysis for progression-free survival (PFS) and ANOVA for statistical comparisons were applied. Results: The median age was 60 years, and 41 pts were female. For FGFR2-fused iCCA, median PFS for first-line gemcitabine-based chemotherapy with or without immunotherapy was 4.07 months [3.0-5.1]. Among FGFR inhibitors, mPFS was 7.07 months [95% CI: 5.10-8.16], with no significant difference in outcomes between FGFR inhibitors. 59 pts had comparable CT images and were grouped into 3 groups based on K-means clustering: Group 1 (n=30) had mPFS of 3.07 months [2.03-4.10]; Group 2 (n=22), mPFS of 9.10 months [8.2-11.2]; Group 3 (n=7), mPFS of 34.03 months [18.2-37.6]. Group 1 had the most hypovascular tumors (the lowest HU in the periphery of tumors), while Group 3 had the most hypervascular tumors (p=0.017). The HU ratio of the hypervascular tumor rim thickness to tumor diameter showed a trend, with the highest ratio in Group 3 and the lowest in Group 1 (p=0.09). Transcriptomic analysis revealed a trend toward higher VEGF/VEGFR gene expression in hypervascular tumors. Eight pts received second-line FGFR inhibitors, with mPFS of 5.0 months [2.1-8.3]. Conclusions: Pts with FGFR2-fused iCCA have a shorter PFS on first-line chemotherapy, and PFS outcomes for FGFR inhibitors were consistent with existing data. Tumor vascularity, as assessed by CT imaging, may be a valuable predictor of response to FGFR inhibitors. This study suggests that hypervascular tumors may have better outcomes, warranting further investigation in a larger cohort to confirm these findings and establish tumor vascularity as a predictive biomarker for FGFR inhibitor therapy.

Normalization of tumor vasculature by imiquimod: proposal for a new anticancer therapeutic indication for a TLR7 agonist

Imiquimod (IMQ), a drug from aminoquinoline group, is the toll-like receptor 7 (TLR7) agonist. It acts as an immunostimulant and radio-sensitizing agent. IMQ stimulates both innate and adaptive immune response. Despite studies conducted, there are no unambiguous data showing how IMQ affects the condition of tumor blood vessels. Tumor vasculature plays the main role in tumor progression. Formation of abnormal blood vessels increases area of hypoxia which recruits suppressor cells, blocks tumor infiltration by CD8+ T lymphocytes, inhibits efficacy of chemoterapeutic drug and leads to cancer relapse. Normalization is a type of therapy targeted at abnormal tumor blood vessels. Here, we demonstrated that 50 µg of IMQ inhibits the growth of melanoma tumors more efficiently, compared to other tested doses and the control group. Dose escalation did not improve the therapeutic antitumor potential of TLR7 agonist. A dose of 50 µg of IMQ most effectively reduced tumor blood vessel density. Imiquimod normalized tumor vasculature both structurally (by reducing vessel tortuosity and increasing pericyte coverage) and functionally (by improving tumor perfusion) in a dose-dependent manner. Hypoxia regions in tumors of treated mice were significantly reduced after IMQ administration. A dose of 50 µg of IMQ had also the greatest impact on the changes in tumor-infiltrating T lymphocytes levels. TLR7 agonist inhibited angiogenesis in treated mice. Functional vascular normalization by IMQ increases the effectiveness of low dose of doxorubicin. Higher dose of IMQ showed worse effects than lower doses including decreased tumor perfusion, increased tumor hypoxia and immunosuppression. This knowledge may help to optimize the combination of the selected IMQ dose with e.g. chemotherapy or radiotherapy to elicit synergistic effect in cancer treatment. To conclude, we outline IMQ repurposing as a vascular normalizing agent. Our research results may contribute to expanding the therapeutic indications for the use of IMQ in anticancer therapy in the future.

Repeated sequential administration of pegylated emulsion of SU5416 and liposomal paclitaxel enhances anti-tumor effect in 4T1 breast cancer-bearing mice.

To improve vascular normalization strategy for intractable triple-negative breast cancer 4 T1, we examined the anti-tumor effects of repeated sequential administration of polyethylene glycol (PEG)-modified emulsion of SU5416 (PE-SU5416), a vascular endothelial growth factor (VEGF) receptor-2 kinase inhibitor, and PEG-modified liposomal paclitaxel (PL-PTX) in mice bearing 4 T1 cells. Three sequential administrations (Seq × 3) of PE-SU5416 and PL-PTX exhibited significantly higher anti-tumor activity than a single sequential administration (Seq × 1). The tumor vasculatures were structurally normalized until after two PE-SU5416 (PE-SU5416 × 2) or sequential (Seq × 2) administrations, while the improvement in vascular function, such as oxygen supply, blood flow, and PEG-liposomal distribution, was evident until after three administrations of PE-SU5416 (PE-SU5416 × 3) and Seq × 3. Although some discrepancies between the structural and functional improvement in tumor vasculatures were observed after PE-SU5416 × 3 and Seq × 3, cancer-associated fibroblasts (CAFs) and collagen levels were significantly reduced after PE-SU5416 × 2, PE-SU5416 × 3, Seq × 2, and Seq × 3, suggesting that a possible decrease in interstitial fluid pressure due to the reduction in CAFs and collagen would have compensated for vascular function. Furthermore, PE-SU5416 × 2, PE-SU5416 × 3, Seq × 2, and Seq × 3 significantly decreased tumor growth factor-β (TGF-β), an activator of CAFs, in tumor tissues, suggesting that the reduction in TGF-β levels by PE-SU5416 suppresses CAF activation.

Basement membranes in lung metastasis growth and progression.

The lung is a highly vascularized tissue that often harbors metastases from various extrathoracic malignancies. Lung parenchyma consists of a complex network of alveolar epithelial cells and microvessels, structured within an architecture defined by basement membranes. Consequently, understanding the role of the extracellular matrix (ECM) in the growth of lung metastases is essential to uncover the biology of this pathology and developing targeted therapies. These basement membranes play a critical role in the progression of lung metastases, influencing multiple stages of the metastatic cascade, from the acquisition of an aggressive phenotype to intravasation, extravasation and colonization of secondary sites. This review examines the biological composition of basement membranes, focusing on their core components-collagens, fibronectin, and laminin-and their specific roles in cancer progression. Additionally, we discuss the function of integrins as primary mediators of cell adhesion and signaling between tumor cells, basement membranes and the extracellular matrix, as well as their implications for metastatic growth in the lung. We also explore vascular co-option (VCO) as a form of tumor growth resistance linked to basement membranes and tumor vasculature. Finally, the review covers current clinical therapies targeting tumor adhesion, extracellular matrix remodeling, and vascular development, aiming to improve the precision and effectiveness of treatments against lung metastases.

Electroacupuncture normalized tumor vasculature by downregulating glyoxalase-1 to polarize tumor-associated macrophage to M1 phenotype in triple-negative breast cancer.

Triple-negative breast cancer is a particularly aggressive type of breast cancer that is closely associated with abnormal vascularization within the tumor. However, traditional anti-VEGF therapies and other treatments have limited efficacy. Tumor-associated macrophages (TAMs) induce and regulate tumor angiogenesis. In recent years, regulating TAMs polarization has become a hot topic for research with objectives to normalize tumor vasculature and improve drug delivery and the tumor microenvironment. Our previous studies have found that peritumoral electroacupuncture (EA) can regulate tumor angiogenesis, but the underlying mechanism remains unclear. In this study, we examined the phenotype of TAMs and inflammatory factors to observe the effect of peritumoral electroacupuncture on the phenotypic polarization of TAMs. Based on this, we evaluated the structure and function of tumor vasculature. Finally, we conducted a preliminary exploration of the mechanism underlying the regulation of TAMs phenotypic polarization by peritumoral electroacupuncture. In this study, we found that peritumoral electroacupuncture could promote the phenotypic polarization of TAMs toward the M1 type, thereby reducing microvascular density in tumor tissue, increasing pericyte coverage, improving the stability of the basement membrane, promoting vascular maturation, and enhancing perfusion while reducing tissue hypoxia. Peritumoral electroacupuncture can promote the phenotypic polarization of TAMs toward the M1 type, leading to normalization of tumor vascular structure and function. The mechanism may be related to the downregulation of glyoxalase-1 and subsequent activation of the MGO-AGEs/RAGE axis.

Enhancing immunotherapy efficacy in oral cancer through AKB-9778-mediated vascular normalization.

Tumor vasculature exhibit numerous abnormal features distinct from those of healthy vessels, potentially advancing tumor development by establishing an aberrant microenvironment. Therefore, vascular normalization has proven to be an effective tactic for substantially enhancing treatment efficacy across multiple tumors. However, the methods to attain vascular normalization may vary among tumor types. VE-PTP, expressed exclusively in vascular endothelial cells (ECs) and acting as a critical suppressor of vascular maturity and functionality, is upregulated in oral cancer due to hypoxia. In this study, we explored the effect and mechanism of AKB-9778, a competitive inhibitor of VE-PTP, in promoting vascular normalization of oral cancer. Initially, we showed that AKB-9778 can slow down tumor progression by fostering vascular normalization in a murine OSCC model. This was evidenced by improvements in vessel density, pericyte coverage, local hypoxia, and vascular permeability. RNA sequencing additionally indicated that the ECs of tumor vasculature exhibit abnormal alterations in adhesion molecules, and AKB-9778 treatment might facilitate vascular normalization by modulating lipid metabolism pathways, especially HSD17B7-regulated steroid biosynthesis. AKB-9778 treatment significantly up-regulated the HSD17B7 expression, thereby restoring the lipid content in tumor ECs. Moreover, this restoration of lipid metabolism mediated by HSD17B7 was associated with improved adhesion molecule expression and vascular normalization, facilitating immune cell infiltration and contributing to AKB-9778's anti-tumor effects. Finally, we verified the effects and safety of combined AKB-9778 treatment on improving the efficacy of anti-PD-1 immunotherapy. In summary, this study revealed the mechanism and potential application of AKB-9778-induced vascular normalization in patients with oral cancer.

AGX101: A TM4SF1-directed tubulin inhibitor conjugate in ongoing first-in-human trial including GI cancers.

829 Background: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates (NHP), with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: Notable cancers with high TM4SF1 scoring intensity include pancreatic adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer. In esophageal cancer, 20% of patients have a TM4SF1 copy number amplification, and these have worse prognosis. In NHP, AGX101 exhibited a favorable safety profile. In preclinical efficacy studies, monotherapy demonstrated robust efficacy through each of the three MoAs in syngeneic models in mice including CT26 colon carcinoma, and human tumor xenograft models including MIA PaCa-2 pancreatic cancer. Measured by exposure, TI was large. In syngeneic mouse models including CT26, the effects of ICIs were potentiated, suggesting a potential synergistic approach in cancer therapy. The first two dose levels of AGX101 monotherapy in humans has cleared without DLTs. Three patients with pancreatic adenocarcinoma have been treated thus far. Conclusions: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing and initial outcome data will become available by the conference. Clinical trial information: NCT06440005 .

Primary Epithelioid Hemangioendothelioma of the Spine: A First in Africa. A Case Report and Literature Review.

Primary Epithelioid hemangioendothelioma of the spine is an ultra-rare malignant vascular neoplasm with no pathognomonic clinical features and as such requires a high index of suspicion and a multi-disciplinary and multimodality treatment approach.

Chemotaxis Effects on the Vascular Tumor Growth: Phase-field Model and Simulations.

In this paper, we propose a vascular tumor growth model that combines a phase-field tumor model with a phase-field angiogenesis model. By incorporating various tumor cell species, we capture the instabilities of the tumor in the presence of evolving neovasculature. The model not only considers different dynamics of tumor cell phase conversions, movement, and pressure effects but also provides a comprehensive representation of angiogenesis, encompassing chemotaxis of endothelial cells, sprouting, anastomoses, and blood flow in capillaries. This study evaluates the impact of chemotaxis on tumor cell movement in both avascular and vascular tumor growth scenarios. The results highlight the acceleration of tumor growth when angiogenesis is stimulated. Additionally, the investigation explores various initial distances of the tumor from neighboring vessels, revealing a critical threshold distance beyond which the angiogenesis factor fails to stimulate angiogenesis, resulting in the tumor maintaining a stable state. The integration of chemotaxis into the growth model induces instabilities, leading to increased nutrient availability and faster growth for the tumor. Furthermore, the study considers anti-angiogenesis therapy as an ideal approach, assuming complete inhibition of angiogenesis from the early stages. In this scenario, the tumor persists in a steady state, adhering to the avascular size limit in the absence of neovasculature. Conversely, when considering chemotaxis, anti-angiogenesis therapy loses efficiency, enabling unrestrained tumor growth towards neighboring vessels. This work sheds light on the intricate interplay among chemotaxis, angiogenesis, and anti-angiogenesis therapy in the context of vascular tumor growth, providing valuable insights for the development of targeted treatment strategies.

NGR-Modified CAF-Derived exos Targeting Tumor Vasculature to Induce Ferroptosis and Overcome Chemoresistance in Osteosarcoma.

Osteosarcoma (OS) chemoresistance presents a significant clinical challenge. This study aims to investigate the potential of using tumor vascular-targeting peptide NGR-modified cancer-associated fibroblasts (CAFs)-derived exosomes (exos) to deliver circ_0004872-encoded small peptides promoting autophagy-dependent ferroptosis to reverse chemoresistance in OS. Through combined single-cell transcriptome analysis and high-throughput sequencing, it identified circ_0004872 associated with chemoresistance. Subsequent experiments demonstrated that the small peptide encoded by this Circular RNA (circRNA) can effectively reverse chemoresistance by enhancing OS cell sensitivity to chemotherapy via the mechanism of promoting autophagy-dependent ferroptosis. Moreover, in vitro and in vivo results confirmed the efficient delivery of NGR-modified CAFs-derived exo-packaged circ_0004872-109aa to tumor cells, thereby improving targeted therapy efficacy. This study not only offers a novel strategy to overcome chemoresistance in OS but also highlights the potential application value of utilizing exos for drug delivery.

Tumor Vascular Normalization by B7-H3 Blockade Augments T Lymphocyte-Mediated Antitumor Immunity.

Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), presents unique clinical challenges and generally predicts a less favorable prognosis. Despite recent advancements in TNBC treatment, a subset of patients remains resistant to immunotherapy. B7-H3, a member of the B7 family of immune checkpoints, is correlated with poor outcomes in various cancers and is distinctively expressed in tumor vasculature, marking it as a potential biomarker for tumor-associated endothelial cells. We found high expression of B7-H3 in the endothelial cells of the postoperative tissue of TNBC patients. Elevated gene expression of CD276 (encoding B7-H3) and PECAM1 (encoding CD31) in TNBC is associated with poor prognosis. Anti-B7-H3 blockade reduces tumor burden and promotes lymphocyte infiltration in a TNBC mouse model. Additionally, anti-B7-H3 blockade promotes tumor vessel normalization and enhances programmed cell death ligand 1 (PD-L1) expression. Synergistic effects were observed when B7-H3 blockade was combined with programmed cell death protein 1 (PD-1) inhibition in the TNBC mouse model. Furthermore, anti-B7-H3 inhibits human umbilical vein endothelial cell (HUVEC) proliferation by suppression of the nuclear factor kappa-B (NF-κB) signaling pathway. Downregulation of B7-H3 expression in HUVECs promotes lymphocyte trans-endothelial migration. These findings suggest that B7-H3 represents a promising therapeutic target for TNBC, and the combination of anti-B7-H3 and anti-PD-1 therapies may have synergetic effects in treating TNBC.

Early release of circulating tumor cells after transarterial chemoembolization hinders therapeutic response in patients with hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the first-line therapeutic option for patients with intermediate-stage hepatocellular carcinoma (HCC). Tumor neovascularization allows tumor growth and may facilitate the release of circulating tumor cells (CTCs) to the bloodstream after TACE. We investigated the relationship between early release of CTCs and radiological response after TACE. Prospective, single-center study including patients with HCC undergoing a first TACE from January 2019 to June 2023. The IsoFlux® system was used to evaluate EpCAM+ CTC counts before TACE, at day 1 (D1), and at day 30 after TACE. Radiological response to TACE was assessed according to the mRECIST criteria one month after the procedure. Tumor vascularity was assessed by an interventional radiologist. In all, 48 patients with HCC undergoing TACE were included (age 64.2 ± 7.6 years, 14.6% women). CTC levels increased at D1 (114.0% [IQR 76.5%-178.0%], p = 0.019) and normalized to baseline levels in the first month after TACE (76.5% [IQR 41.3%-131.8%], p = 0.263). Higher CTC counts at baseline (p = 0.009) and at D1 (p = 0.026) were associated with tumor hypervascularity. Larger tumor size [OR: 1.9 (95% CI: 1.1-3.3), p = 0.020] and CTC increase at D1 [OR: 5.3 (95% CI: 1.3-21.0), p = 0.017] were independent predictors of non-response to TACE, especially for those patients with hypervascular lesions. A meaningful release of CTCs 24 h after TACE was associated with suboptimal tumor response one month after the procedure. Future studies should evaluate the role of CTC dynamics to select candidates for adjuvant therapy after TACE and to analyze their impact on long-term outcomes.

Phase I Clinical Trial of High Doses of Seleno-L-methionine in Combination with Axitinib in Patients with Previously Treated Metastatic Clear Cell Renal Cell Carcinoma.

Data in clear cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of HIF1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC. Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2500, 3000 and 4000 μg) were administered orally twice daily for 14 days, then once daily concurrently with axitinib 5 mg twice daily using a 3+3 design in Phase I. Patients were treated at the 4000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy. No dose limiting toxicities occurred at the 4000 μg SLM dose level. Among the 27 patients treated with 4000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1 and stabilization of tumor vasculature by SLM are time dependent. SLM (4000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.

Epithelioid hemangioma of the skull: Rare case report

Introduction: Epithelioid hemangiomas (EH) are benign vascular tumors that commonly occur in the skin, subcutis, and bone—most typically arising as nodules in the neck and head region. Pediatric cases with atypical presentations remain rare and challenging. Case Report: The following outlines the case of a 2-year-old male who presented with a bump and swelling on the left side of his head. Imaging tests identified multiple, hyperdense, and focally ring-enhancing intra-axial lesions located mainly at the gray-white matter junction of bilateral frontal left-sided parietal, left-sided occipital, and left-sided temporal lobes. In addition, multiple lytic lesions were seen in the calvarium. Pathology confirmed EH. While one lesion required surgical resection, the remaining lesions showed spontaneous regression during follow-up. Conclusion: This case highlights the diagnostic and management challenges associated with pediatric EH involving the head, including intracranial involvement. The patient’s unique presentation, age, and lesion involution expand the understanding of EH beyond its typical manifestation.