Tumor Vasculature Research Articles

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.

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.

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.

Lack of ST2 aggravates glioma invasiveness, vascular abnormality and immune suppression

Abstract Background Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, characterized by aggressive growth and a dismal prognosis. Interleukin-33 (IL-33) and its receptor ST2 have emerged as regulators of glioma growth, but their exact function in tumorigenesis have not been deciphered. Indeed, previous studies on IL-33 in cancer have yielded somewhat opposing results as to whether it is pro- or anti-tumorigenic. Methods IL-33 expression was assessed in a GBM tissue microarray and public databases. As in vivo models we used orthotopic xenografts of patient-derived GBM cells, and syngenic models with grafted mouse glioma cells. Results We analyzed the role for IL-33 and its receptor ST2 in non-malignant cells of the glioma microenvironment and find that IL-33 levels are increased in cells surrounding the tumor. Protein complexes of IL-33 and ST2 are mainly found outside of the tumor core. The IL-33-producing cells consist primarily of oligodendrocytes. To determine the function for IL-33 in the tumor microenvironment, we used mice lacking the ST2 receptor. When glioma cells were grafted to ST2-deficient mouse brains, the resulting tumors exhibit a more invasive growth pattern, and are associated with poorer survival, compared to wild-type mice. Tumors in ST2-deficient hosts are more invasive, with increased expression of extracellular matrix remodeling enzymes and enhanced tumor angiogenesis. Furthermore, the absence of ST2 leads to a more immunosuppressive environment. Conclusions Our findings reveal that glia-derived IL-33 and its receptor ST2 participates in modulating tumor invasiveness, tumor vasculature and immunosuppression in glioma.

Soluble PD-L1 and Serum Vascular Endothelial Growth Factor-B May Independently Predict Prognosis in Patients with Advanced Non-Small Cell Lung Cancer Treated with Pembrolizumab

Background: Previous preclinical data have shown that the dynamic cross-talk between abnormal tumor vasculature and immune cell factors in the tumor microenvironment may exert a critical role in the progression and treatment resistance of non-small cell lung cancer (NSCLC). In the clinical setting, a variety of blood-based angiogenesis- and immune-related factors are being increasingly investigated as potential biomarkers of prognosis or treatment response in immunotherapy-treated NSCLC. We herein aimed to evaluate the clinical relevance of the peripheral blood levels of vascular endothelial growth factor-A and -B (VEGF-A and VEGF-B, respectively), soluble programmed cell death-1 (sPD-1), and programmed cell death-ligand 1 (sPD-L1) in patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs). Methods: Consecutive patients with advanced-stage, non-oncogene-addicted NSCLC, eligible to receive ICIs at the Oncology Unit of Sotiria Athens General Hospital, were prospectively recruited. A group of sex- and age-matched healthy controls was also enrolled for the evaluation of the potential diagnostic significance of the examined biomarkers. Serum levels of all biomarkers were measured using ELISA, both before and after treatment, and were correlated with standard clinicopathological features of patients, treatment response, progression-free survival (PFS), and overall survival (OS). Results: A total of 55 patients and 16 healthy controls were included in the final analysis. The mean age of patients and controls was 66.5 years (SD = 8.0 years) and 65.4 years (SD = 9.1 years), respectively. The majority of patients (65.5%) received pembrolizumab in combination with chemotherapy, while the remaining patients received pembrolizumab monotherapy. ROC curve analysis showed that VEGFB and sPD-1 were the only markers with a significant diagnostic value. Higher pre-treatment values of sPD-L1 (HR = 1.68; p = 0.040) and sPD-1 (HR = 10.96; p = 0.037) as well as higher post-treatment values of VEGF-B (HR = 2.99; p = 0.049) were all significantly associated with a reduced OS in univariate Cox regression analysis. The adverse prognostic significance of higher pre-treatment values of sPD-L1 (HR = 2.10; p = 0.014) and higher post-treatment values of VEGFB (HR = 3.37; p = 0.032) was further confirmed in multivariate analysis. Conclusions: Our study results suggest that serum levels of sPD-L1 and VEGF-B may independently predict prognosis in ICI-treated advanced-stage NSCLC.

Management of intercostal artery pseudoaneurysm following posterior pedicle screw insertion: illustrative case.

Pedicle screw insertion in posterior spinal surgery can cause vascular injuries, including rare intercostal artery pseudoaneurysms, which are typically discovered incidentally during reimaging. Onyx embolization is an effective treatment for small artery pseudoaneurysms. A 36-year-old man who had initially presented with back pain that remained unresponsive to nonsteroidal anti-inflammatory drugs was diagnosed with a T7-8 sarcomatous lesion confirmed by magnetic resonance imaging and biopsy. He underwent a posterior resection and T5-10 stabilization with pedicle screws. After surgery, significant hemorrhage led to his transfer for digital subtraction angiography, which revealed a prominent vascular tumor blush and a pseudoaneurysm of the right T5 intercostal artery due to screw placement. The tumor and pseudoaneurysm were effectively embolized using superselective catheterization and Onyx. This report highlights the dangers of intercostal artery damage from posterior spinal screws, emphasizing the need for meticulous postoperative imaging. Onyx embolization is an effective treatment for such complications. https://thejns.org/doi/10.3171/CASE24291.

Abstract B012: Interferon- γ is required for immunotherapy induced radiosensitivity in solid tumors

Abstract Radiation therapy (RT) is the standard of care for many cancer types, however, some solid tumors fail to respond due to factors such as a hypoxic tumor microenvironment (TME). To overcome radioresistance in these solid tumors, clinical trials combining RT with immune checkpoint blockade (ICB) are ongoing, but hindered by a limited understanding of the mechanisms by which immunotherapies enhance RT response. In this study, we use EO771 breast and CT26 colorectal tumor models to investigate how anti PD-1 therapy improves radiosensitivity to varying RT regimens including single or multiple RT doses administered concurrently or sequentially. We show that concurrent administration of ICB and RT normalizes tumor vasculature, alleviates hypoxia, and increases vessel perfusion to improve immune cell infiltration in solid tumors. Furthermore, we reveal that this TME modulation was linked to stimulation of interferon-γ (IFN-γ) signaling in endothelial cells by activated CD8+ T cell responses, which results in systemic tumor control and establishes long term immunological memory in the neoadjuvant setting. Collectively, these results indicate that immunotherapy sensitizes solid tumors to RT by modulating the tumor microenvironment in an IFN-γ dependent manner, resulting in successful anti-tumor immunity. This research provides a rationale for the concurrent administration of anti PD-1 therapy and radiation therapy to treat radioresistant solid tumors. Citation Format: Annette Wu, Minjeong Kang, Daeyong Lee, Yifan Wang, Kristin M. Huntoon, Betty Y.S. Kim, Wen Jiang. Interferon- γ is required for immunotherapy induced radiosensitivity in solid tumors. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B012.

A Second Near-Infrared Window-Responsive Metal-Organic-Framework-Based Photosensitizer for Tumor Immunotherapy via Synergistic Ferroptosis and STING Activation.

Photodynamic therapy (PDT) holds promise as a cancer treatment modality due to its potential for enhanced therapy precision and safety. To enhance deep tissue penetration and minimize tissue adsorption and phototoxicity, developing photosensitizers activated by second near-infrared window (NIR-II) light shows significant potential. However, the efficacy of PDT is often impeded by tumor microenvironment hypoxia, primarily caused by irregular tumor vasculature. Fortunately, the stimulator of interferon genes (STING) pathway, known for immune activation, has been linked to vasculature normalization. In this study, we developed a nanoplatform (Fe-THBQ/SR) by loading a STING agonist (SR-717) into an iron-tetrahydroxy-1,4-benzoquinone (Fe-THBQ) metal-organic framework. Fe-THBQ was proven to be an effective NIR-II photosensitizer, generating numerous reactive oxygen species (ROS) under 1064 nm laser irradiation. These ROS downregulated heat shock protein expression, consequently promoting mild-photothermal therapy (mild-PTT), and facilitated ferroptosis by depleting glutathione (GSH)/glutathione peroxidase 4. Moreover, Fe-THBQ/SR released SR-717 upon GSH stimulation, synergizing with the ROS-mediated double-stranded DNA leakage to enhance STING activation. This process contributed to tumor vasculature normalization and hypoxia alleviation, thereby enhancing the PDT efficacy. Overall, we presented a versatile single-laser-triggered nanoplatform (Fe-THBQ/SR) for NIR-II PDT and NIR-II mild-PTT and simultaneously coupled it with the effective activation of STING to form a reinforcing cycle. These synergistic enhancements increased the immunogenicity of tumor cells, remodeled the immunosuppressive tumor microenvironment, increased T lymphocyte infiltration, and improved therapeutic outcomes.