Tumor Vessels Research Articles

Therapeutic efficacy of ECs Foxp1 targeting Hif1α-Hk2 glycolysis signal to restrict angiogenesis

Endothelial cells (ECs) rely on glycolysis for energy production to maintain vascular homeostasis and the normalization of hyperglycolysis in tumor vessels has recently gained attention as a therapeutic target. We analyzed the TCGA database and found reduced Foxp1 expression in lung carcinoma. Immunostaining demonstrated reduced expression more restricted at tumor vascular ECs. Therefore, we investigated the function and mechanisms of Foxp1 in EC metabolism for tumor angiogenesis required for tumor growth. EC-Foxp1 deletion mice exhibited a significant increase of tumor and retinal developmental angiogenesis and Hif1α was identified as Foxp1 target gene, and Hk2 as Hif1α target gene. The Foxp1-Hif1α-Hk2 pathway in ECs is important in the regulation of glycolytic metabolism to govern tumor angiogenesis. Finally, we used genetic deletion of EC-Hif1α and RGD-peptide nanoparticles EC target delivery of Hif1α/Hk2-siRNAs to knockdown gene expression which reduced the tumor EC hyperglycolysis state and restricted angiogenesis for tumor growth. This study advances our understanding of EC metabolism for tumor angiogenesis, and meanwhile provides evidence for future therapeutic intervention of hyperglycolysis in tumor ECs for suppression of tumor growth.

Blood vessel wall shear stress determines regions of liposome accumulation in angiogenic vasculature.

Nanoparticles used for drug delivery often require intravenous administration exposing them to fluid forces within the vasculature, yet the impact of blood flow on nanoparticle delivery remains incompletely understood. Here, we utilized transgenic zebrafish embryos to investigate the relationship between the accumulation of fluorescently labeled PEGylated liposomes and various hemodynamic factors (such as flow velocity, wall shear stress (WSS), and flow pattern) across a wide range of angiogenic blood vessels. We reconstructed 3D models of vascular structures from confocal images and used computational fluid dynamics to calculate local WSS, velocities, and define flow patterns. The spatial distribution of fluorescently labeled liposomes was subsequently mapped within the same 3D space and correlated with local hemodynamic parameters. Through the integration of computational fluid dynamics and in vivo experimentation, we show that liposomes accumulated in vessel regions with WSS between 0.1-0.8 Pa, displaying an inverse linear correlation (R2 > 0.85) between time-averaged wall shear stress and liposome localization in vivo. Interestingly, flow pattern did not appear to impact liposome accumulation. Collectively, our findings suggest the potential of stealth liposomes for passive targeting of low-flow vasculature, including capillaries and intricate angiogenic vasculature resembling that of tumor vessel networks.

Tumor necrosis factor receptor 2 promotes endothelial cell-mediated suppression of CD8+ T cells through tuning glycolysis in chemoresistance of breast cancer

BackgroundT cells play a pivotal role in chemotherapy-triggered anti-tumor effects. Emerging evidence underscores the link between impaired anti-tumor immune responses and resistance to paclitaxel therapy in triple-negative breast cancer (TNBC). Tumor-related endothelial cells (ECs) have potential immunoregulatory activity. However, how ECs regulate T cell activity during TNBC chemotherapy remains poorly understood.MethodsSingle-cell analysis of ECs in patients with TNBC receiving paclitaxel therapy was performed using an accessible single-cell RNA sequencing (scRNA-seq) dataset to identify key EC subtypes and their immune characteristics. An integrated analysis of a tumor-bearing mouse model, immunofluorescence, and a spatial transcriptome dataset revealed the spatial relationship between ECs, especially Tumor necrosis factor receptor (TNFR) 2+ ECs, and CD8+ T cells. RNA sequencing, CD8+ T cell proliferation assays, flow cytometry, and bioinformatic analyses were performed to explore the immunosuppressive function of TNFR2 in ECs. The downstream metabolic mechanism of TNFR2 was further investigated using RNA sequencing, cellular glycolysis assays, and western blotting.ResultsIn this study, we identified an immunoregulatory EC subtype, characterized by enhanced TNFR2 expression in non-responders. By a mouse model of TNBC, we revealed a dynamic reduction in the proportion of the CD8+ T cell-contacting tumor vessels that could co-localize spatially with CD8+ T cells during chemotherapy and an increased expression of TNFR2 by ECs. TNFR2 suppresses glycolytic activity in ECs by activating NF-κB signaling in vitro. Tuning endothelial glycolysis enhances programmed death-ligand (PD-L) 1-dependent inhibitory capacity, thereby inducing CD8+ T cell suppression. In addition, TNFR2+ ECs showed a greater spatial affinity for exhausted CD8+ T cells than for non-exhausted CD8+ T cells. TNFR2 blockade restores impaired anti-tumor immunity in vivo, leading to the loss of PD-L1 expression by ECs and enhancement of CD8+ T cell infiltration into the tumors.ConclusionsThese findings reveal the suppression of CD8+ T cells by ECs in chemoresistance and indicate the critical role of TNFR2 in driving the immunosuppressive capacity of ECs via tuning glycolysis. Targeting endothelial TNFR2 may serve as a potent strategy for treating TNBC with paclitaxel.

Metformin synergizes with PD-1 blockade to promote normalization of tumor vessels via CD8T cells and IFNγ

Tumor blood vessels are highly leaky in structure and have poor blood perfusion, which hampers infiltration and function of CD8T cells within tumor. Normalizing tumor vessels is thus thought to be important in promoting the flux of immune T cells and enhancing ant-tumor immunity. However, how tumor vasculature is normalized is poorly understood. Metformin (Met) combined with ant-PD-1 therapy is known to stimulate proliferation of and to produce large amounts of IFNγ from tumor-infiltrating CD8T lymphocytes (CD8TILs). We found that the combination therapy promotes the pericyte coverage of tumor vascular endothelial cells (ECs) to improve blood perfusion and that it suppresses the hyperpermeability through the increase of VE-cadherin. Peripheral node addressin(PNAd) and vascular cell adhesion molecule (VCAM)-1, both implicated to promote tumor infiltration of CD8T cells, were also increased. Importantly, tumor vessel normalization, characterized as the reduced 70-kDa dextran leakage and the enhancement of VE-cadherin and VCAM-1, were canceled by anti-CD8 Ab or anti-IFNγ Ab injection to mice. The increased CD8TILs were also abrogated by anti-IFNγ Ab injection. In vascular ECs, flow cytometry analysis revealed that pSTAT1 expression was found to be associated with VE-cadherin expression. Moreover, in vitro treatment with Met and IFNγ enhanced VE-cadherin and VCAM-1 on human umbilical vein endothelial cells (HUVECs). The Kaplan-Meier method revealed a correlation of VE-cadherin or VCAM-1 levels with overall survival in patients treated with immune checkpoint inhibitors. These data indicate that IFNγ-mediated cross talk of CD8TILs with tumor vessels is important for creating a better tumor microenvironment and maintaining sustained antitumor immunity.

Evaluation of a prototype metal artifact reduction algorithm for cone beam CT in patients undergoing radioembolization

Metal artifacts notoriously pose significant challenge in computed tomography (CT), leading to inaccuracies in image formation and interpretation. Artifact reduction tools have been designed to improve cone beam computed tomography (CBCT) image quality by reducing artifacts caused by certain high-density materials. Metal artifact reduction (MAR) tools are specific algorithms that are applied during image reconstruction to minimize or eliminate artifacts degrading CBCT images. The purpose of the study is to evaluate the effect of a MAR algorithm on image quality in CBCT performed for evaluating patients before transarterial radioembolization (TARE). We retrospectively included 40 consecutive patients (aged 65 ± 13 years; 23 males) who underwent 45 CBCT examinations (Allura FD 20, XperCT Roll protocol, Philips Healthcare, Best, The Netherlands) in the setting of evaluation for TARE between January 2017 and December 2018. Artifacts caused by coils, catheters, and surgical clips were scored subjectively by four readers on a 5-point scale (1 = artifacts affecting diagnostic information to 5 = no artifacts) using a side-by-side display of uncorrected and MAR-corrected images. In addition, readers scored tumor visibility and vessel discrimination. MAR-corrected images were assigned higher scores, indicating better image quality. The differences between the measurements with and without MAR were most impressive for coils with a mean improvement of 1.6 points (95%CI [1.5 1.8]) on the 5-point likert scale, followed by catheters 1.4 points (95%CI [1.3 1.5]) and clips 0.7 points (95%CI [0.3 1.1]). Improvements for other artifact sources were consistent but relatively small (below 0.25 points on average). Interrater agreement was good to perfect (Kendall’s W coefficient = 0.68–0.95) and was higher for MAR-corrected images, indicating that MAR improves diagnostic accuracy. A metal artifact reduction algorithm can improve diagnostic and interventional accuracy of cone beam CT in patients undergoing radioembolization by reducing artifacts caused by diagnostic catheters and coils, lowering interference of metal artifacts with adjacent major structures, and improving tumor visibility.

Amelioration of breast cancer therapies through normalization of tumor vessels and microenvironment: paradigm shift to improve drug perfusion and nanocarrier permeation.

Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.

Tumor Vessel Normalization via PFKFB3 Inhibition Alleviates Hypoxia and Increases Tumor Necrosis in Rectal Cancer upon Radiotherapy.

Novel therapies to better treat colorectal cancer are necessary to improve patient outcomes. Therefore, in this study, we evaluated the combination of a metabolic inhibitor (3PO) and standard radiotherapy in different experimental settings. We have observed that the addition of 3PO increased radiation effects, ultimately improving tumor cell response to therapy.

A bright Ce-based downshifting luminescence nanoprobe for NIR-IIb vessel imaging

Nanomaterials with unique emission in the second near-infrared window (NIR-II, 1000–1700 nm) are regarded as the promising probes for visualization of tumor vessels and cerebrovascular architecture, because of their superior features such as deep tissue penetration and large imaging resolution. Herein, the new Ce-based fluoride nanoparticles (NPs) with high-efficiency NIR-IIb emission were explored for high-resolution vascular imaging and tumor associated vessel detection. Under the same synthesis conditions, the Ce-based fluoride present the preferential formation CeF3 host and low upconversion (UC) emission, but possess more strong (1.45 times) NIR-IIb downconversion (DC) emission centered at 1525 nm under the irradiation of a 980 nm laser, which is significantly different from the traditional NaYF4:Yb/Er host. Through the efficient cross relaxation between Ce3+ and Er3+, intense NIR-IIb luminescence from Er3+ with high quantum yields were achieved, which make sure the entire mouse body and brain blood vessel imaging with supernal resolution (47.6 μm) were demonstrated. Moreover, the optical imaging in NIR-IIb region guided tumorous vascular visualization was successfully achieved. Therefore, the explored CeF3 NPs with boosting NIR-IIb emission can be employed as new diagnostic bio-probes used in high spatial resolution tumorous vessel detection.

Modulating Tumor Immunity by Targeting Tumor Fibrotic Stroma and Angiogenic Vessels for Lung Cancer Treatment.

Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Both activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin αvβ3. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence here that the depletion of CAFs and the elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD4+ Treg and Myeloid-derived suppressor cells (MDSCs), increases CD8+ T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the Programmed Death Ligand 1 (PDL-1) levels in the stroma areas surrounding the tumors, and thus strongly increases the delivery of anti-PDL-1 antibody to the target cancer cells. The impact of ProAgio on tumor immunity provides strong synergistical effects of checkpoint inhibitors on lung cancer treatment.

Combined expert-in-the-loop—random forest multiclass segmentation U-net based artificial intelligence model: evaluation of non-small cell lung cancer in fibrotic and non-fibrotic microenvironments

BackgroundThe tumor microenvironment (TME) plays a key role in lung cancer initiation, proliferation, invasion, and metastasis. Artificial intelligence (AI) methods could potentially accelerate TME analysis. The aims of this study were to (1) assess the feasibility of using hematoxylin and eosin (H&E)-stained whole slide images (WSI) to develop an AI model for evaluating the TME and (2) to characterize the TME of adenocarcinoma (ADCA) and squamous cell carcinoma (SCCA) in fibrotic and non-fibrotic lung.MethodsThe cohort was derived from chest CT scans of patients presenting with lung neoplasms, with and without background fibrosis. WSI images were generated from slides of all 76 available pathology cases with ADCA (n = 53) or SCCA (n = 23) in fibrotic (n = 47) or non-fibrotic (n = 29) lung. Detailed ground-truth annotations, including of stroma (i.e., fibrosis, vessels, inflammation), necrosis and background, were performed on WSI and optimized via an expert-in-the-loop (EITL) iterative procedure using a lightweight [random forest (RF)] classifier. A convolution neural network (CNN)-based model was used to achieve tissue-level multiclass segmentation. The model was trained on 25 annotated WSI from 13 cases of ADCA and SCCA within and without fibrosis and then applied to the 76-case cohort. The TME analysis included tumor stroma ratio (TSR), tumor fibrosis ratio (TFR), tumor inflammation ratio (TIR), tumor vessel ratio (TVR), tumor necrosis ratio (TNR), and tumor background ratio (TBR).ResultsThe model’s overall classification for precision, sensitivity, and F1-score were 94%, 90%, and 91%, respectively. Statistically significant differences were noted in TSR (p = 0.041) and TFR (p = 0.001) between fibrotic and non-fibrotic ADCA. Within fibrotic lung, statistically significant differences were present in TFR (p = 0.039), TIR (p = 0.003), TVR (p = 0.041), TNR (p = 0.0003), and TBR (p = 0.020) between ADCA and SCCA.ConclusionThe combined EITL—RF CNN model using only H&E WSI can facilitate multiclass evaluation and quantification of the TME. There are significant differences in the TME of ADCA and SCCA present within or without background fibrosis. Future studies are needed to determine the significance of TME on prognosis and treatment.

Temperature-sensitive nanogels combined with polyphosphate and cisplatin for the enhancement of tumor artery embolization by coagulation activation

Transcatheter arterial chemoembolization (TACE) is the first-line therapy for hepatocellular carcinoma (HCC). However, the exacerbated hypoxia microenvironment induces tumor relapse and metastasis post-TACE. Here, temperature-sensitive block polymer complexed with polyphosphate–cisplatin (Pt–P@PND) was prepared for the enhancement of tumor artery embolization by coagulation activation. After supra-selective infusion into the tumor vessels, Pt–P@PND nanogels performed efficient embolization of tumor arteries by sol–gel transition at body temperature. Meanwhile, coagulation cascade was evoked to form blood clots in the peripheral arteries inaccessible to the nanogels by released PolyP. The blood clots-filled hydrogel networks composed of gel and clots showed a denser structure and higher modulus, thereby achieving long-term embolization of all levels of tumor arteries. Pt–P@PND nanogels efficiently inhibited tumor growth and reduced the expression of HIF-1α, VEGF, CD31, and MMP-9 on VX2 tumor-bearing rabbit model. The released Nitro-Pt stimulated the immunogenic cell death of tumor cells, thus enhancing the antitumor immune response to suppress tumor relapse and metastasis post-TACE. It is hoped that Pt–P@PND nanogels can be developed as a promising embolic agent with procoagulant activity for enhancing the antitumor immune response through a combination of embolism, coagulation, and chemotherapy. Statement of significanceClinical embolic agents, such as Lipiodol and polyvinyl alcohol (PVA) microspheres, are limited by their rapid elimination or larger size, thus lead to incomplete embolization of trans-catheter arterial chemoembolization (TACE). Herein, temperature-sensitive Pt-P@PND nanogels were developed to achieve long-term embolization of all levels of tumor arteries by gel/clot generation. The released Nitro-Pt induced immunogenic cell death in tumor cells, which improved the antitumor immune microenvironment by the maturation of DCs and lymphocytic infiltration. Pt-P@PND nanogels successfully inhibited tumor growth and activated an antitumor immune response to curb the recurrence and metastasis of residual tumor cells both in VX2 tumor-bearing rabbit model and 4T1 tumor-bearing mouse model. These findings suggested that Pt-P@PND could be developed as an ideal embolic agent for clinical TACE treatment.

Gasless transoral endoscopic thyroidectomy in a primary substernal goitre patient: First case.

For most primary substernal goitre (SG) surgeries, sternotomy is required because the blood supply vessels of tumours come from the mediastinum. However, sternal dehiscence may lead to several surgical complications. We reported an older patient who underwent simultaneous removal of a primary SG and parathyroid adenoma through a gasless transoral endoscopic approach. The patient recovered well with no hoarseness, post-operative bleeding or other complications after the operation. To the best of our knowledge, this is the first reported case of gasless transoral endoscopic parathyroid adenoma and primary SG resection in the real world. We found that gasless transoral endoscopic surgery is feasible in patients with small primary SG and parathyroid adenoma.

Efficacy of Cisplatin-CXCR4 Antagonist Combination Therapy in Oral Cancer.

Cisplatin is a platinum-based compound that is widely used for treating inoperable oral squamous cell carcinoma (OSCC) in Japan; however, resistance to cisplatin presents a challenge and innovative approaches are required. We aimed to investigate the therapeutic potential of targeting the chemokine receptor CXCR4, which is involved in angiogenesis and tumor progression, using the CXCR4 inhibitor AMD3100, in combination with cisplatin. AMD3100 induced necrosis and bleeding in OSCC xenografts by inhibiting angiogenesis. We investigated the combined ability of AMD3100 plus cisplatin to enhance the antitumor effect in cisplatin-resistant OSCC. An MTS assay identified HSC-2 cells as cisplatin-resistant cells in vitro. Mice treated with the cisplatin-AMD combination exhibited the most significant reduction in tumor volume, accompanied by extensive hemorrhage and necrosis. Histological examination indicated thin and short tumor vessels in the AMD and cisplatin-AMD groups. These results indicated that cisplatin and AMD3100 had synergistic antitumor effects, highlighting their potential for vascular therapy of refractory OSCC. Antitumor vascular therapy using cisplatin combined with a CXCR4 inhibitor provides a novel strategy for addressing cisplatin-resistant OSCC.

Probabilistic Nested Model Selection in Pharmacokinetic Analysis of DCE-MRI Data in Animal Model of Cerebral Tumor.

Best current practice in the analysis of dynamic contrast enhanced (DCE)-MRI is to employ a voxel-by-voxel model selection from a hierarchy of nested models. This nested model selection (NMS) assumes that the observed time-trace of contrast-agent (CA) concentration within a voxel, corresponds to a singular physiologically nested model. However, admixtures of different models may exist within a voxel's CA time-trace. This study introduces an unsupervised feature engineering technique (Kohonen-Self-Organizing-Map (K-SOM)) to estimate the voxel-wise probability of each nested model. Sixty-six immune-compromised-RNU rats were implanted with human U-251N cancer cells, and DCE-MRI data were acquired from all the rat brains. The time-trace of change in the longitudinalrelaxivity for all animals' brain voxels was calculated. DCE-MRI pharmacokinetic (PK) analysis was performed using NMS to estimate three model regions: Model-1: normal vasculature without leakage, Model-2: tumor tissues with leakage without back-flux to the vasculature, Model-3: tumor vessels with leakage and back-flux. Approximately two hundred thirty thousand (229,314) normalized profiles of animals' brain voxels along with their NMS results were used to build a K-SOM (topology-size: 8×8, with competitive-learning algorithm) and probability map of each model. K-fold nested-cross-validation (NCV, k=10) was used to evaluate the performance of the K-SOM probabilistic-NMS (PNMS) technique against the NMS technique. The K-SOM PNMS's estimation for the leaky tumor regions were strongly similar (Dice-Similarity-Coefficient, DSC=0.774 [CI: 0.731-0.823], and 0.866 [CI: 0.828-0.912] for Models 2 and 3, respectively) to their respective NMS regions. The mean-percent-differences (MPDs, NCV, k=10) for the estimated permeability parameters by the two techniques were: -28%, +18%, and +24%, for , and , respectively. The KSOM-PNMS technique produced microvasculature parameters and NMS regions less impacted by the arterial-input-function dispersion effect. This study introduces an unsupervised model-averaging technique (K-SOM) to estimate the contribution of different nested-models in PK analysis and provides a faster estimate of permeability parameters.

Role of transforming growth factor-β1 pathway in angiogenesis induced by chronic stress in colorectal cancer

ABSTRACT Background Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood. Methods Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or β-adrenergic receptor (β-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-β (TGF-β) receptor Type I kinase (Ly2157299) in vitro. TGF-β1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested. Results Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-β1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion. Conclusions Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.

High CIB1 expression in colorectal cancer liver metastases correlates with worse survival and the replacement histopathological growth pattern

To date, nearly one-quarter of CRC patients develop liver metastases (CRCLM), and its aggressiveness can be correlated to defined histopathological growth patterns (HGP). From the three main HGPs within CRCLM, the replacement HGP emerges as particularly aggressive, characterized by heightened tumor cell motility and vessel co-option. Here, we investigated the correlation between the expression of CIB1, an ubiquitously expressed gene involved in various cellular processes including migration and adhesion, and disease-free (DFS) and overall survival (OS) in primary CRC patients. Additionally, we explored the correlation between CIB1 expression and different HGP of CRCLM. Proteomic analysis was used to evaluate CIB1 expression in a cohort of 697 primary CRC patients. Additionally, single-cell and spatial RNA-sequencing datasets, along with a publicly available bulk sequencing data were used to evaluate CIB1 expression in CRCLM. In silico data was further validate by FFPE immunohistochemical stainings. We observed that high CIB1 expression is independently associated with worse DFS and OS, regardless of UICC stage, gender, or age. Furthermore, the aggressive replacement CRCLM HGP is significantly associated with high CIB1 expression. Our findings show a correlation between CIB1 levels and the clinical aggressiveness of CRC. Moreover, CIB1 may be a novel marker to stratify HGP CRCLM.

Swept-source optical coherence tomography and swept-source optical coherence tomography angiography findings in circumscribed choroidal hemangioma before and after transpupillary thermotherapy

PurposeTo investigate the swept-source optical coherence tomography (SS-OCT) and SS-OCT angiography (SS-OCTA) findings in circumscribed choroidal hemangioma (CCH) before and after treatment with transpupillary thermotherapy (TTT).MethodsThe clinical records of 21 eyes having CCH imaged with SS-OCT/SS-OCTA between September 2018 and December 2022 were evaluated.ResultsSS-OCT examination in CCH showed dome-shaped appearance (100%), choroidal shadowing (100%), expansion of choroidal structures (100%), subretinal fluid (66.7%), intraretinal edema/schisis (33.3%), retinal pigment epithelium (RPE) atrophy (19.0%), hyperreflective dots (19.0%), and epiretinal membrane (4.8%). Internal arborizing tumor vessels showing hyperreflectivity were observed in the choriocapillaris slab on SS-OCTA in all eyes. In the deep capillary plexus (DCP), flow void changes were seen in 7 eyes with intraretinal schisis/cystoid macular edema. Four CCHs > 2 mm in thickness showed outer retinal involvement due to unmasking of flow in intratumoral vessels related to RPE atrophy. Following TTT/indocyanine green-enhanced TTT (ICG-TTT) of CCH, SS-OCT findings included total/partial resolution of subretinal fluid (57.1%), complete/partial regression of the tumor (52.4%), and RPE atrophy (33.3%). After treatment; loss of choriocapillaris, decrease in tumor vascularity together with increase in the fibrous component and flow void areas were detected on SS-OCTA.ConclusionsSS-OCT/SS-OCTA are useful non-invasive tools for imaging the structural/vascular changes in CCHs managed with TTT or ICG-TTT. On SS-OCTA, hyporeflective spaces localizing to edema/schisis in the DCP and arborizing tumor vessels within a hyporeflective stromal background in the choriocapillaris slab were observed. After TTT/ICG-TTT, a decrease in tumor vessels and an increase in the fibrous component and flow-void areas inside the CCH were detected on SS-OCTA.

Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis.

Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occur through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that is dependent on Angiopoietin (Ang-2) and vascular endothelial growth factor (VEGF). In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and post-mortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcome were analyzed in BM patients. Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human brain metastases negatively correlated with survival. Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevent the outgrowth of macrometastases.

Association of combination tumor texture and vessel tortuosity with progression free survival across PD-L1 subgroups in durvalumab treated non-small cell lung cancer (NSCLC): Blinded validation results from CP1108.

8600 Background: Immunotherapy (IO) has shown a durable response with minimal toxicity in the treatment of metastatic NSCLC. However, only 30-50% of these patients (pts) actually respond. Despite initial optimism surrounding PD-L1 expression as a potential biomarker, IO provides benefit across PD-L1 low (<25%) and high (≥25%) status. This highlights a critical need for more effective biomarkers to guide treatment decisions. Here, we present blinded validation results of a CT-based biomarker of change in quantitative vessel tortuosity (1) (Δ-QVT) and texture radiomics (2) (Δ-Rad) between baseline (B) and 6 weeks post-treatment (TP1) for predicting response, overall survival (OS) and progression free survival (PFS) in CP1108 (NCT01693562). Methods: CT scans at B and TP1 were retrospectively analyzed from two studies (a) a multi-center training set (Str, N=110) of metastatic NSCLC pts treated with first line IO and (b) a blinded NSCLC cohort of N = 151 pts treated with Durvalumab in CP1108 study (Sv). In Sv, N=75 pts were PD-L1 high (Sv+) whereas N=65 pts were PD-L1 low (Sv-). An in-house MATLAB based algorithm was used to extract intra-tumoral, peri-tumoral texture and QVT features from up to two largest measurable tumors in each CT. A classifier (MCombo) was trained on Str to predict best overall response defined as per the RECIST v1.1 criteria using combination of Δ-QVT and Δ-Rad features. Area under the receiver operating characteristic (AUC) was used to evaluate MCombo against RECIST response whereas univariable and multivariable Cox regression models with log-rank test, hazard ratio (HR) with confidence interval (CI) and concordance index (C-index) were used to study the association of MCombo with OS and PFS in Sv, Sv+, and Sv-. Results: MCombo predicted objective response with an AUC of 0.78 in Sv and was statistically significantly associated with PFS (Table) in Sv, Sv+, and Sv-. MCombo was associated with OS in Sv, Sv+, but not in Sv-. Multivariable analysis with PD-L1 status, histological subtype, ECOG status, liver metastasis, line of therapy and sex showed independent association of MCombo across OS and PFS. Conclusions: Our results indicate that combination of radiomics and vessel tortuosity biomarker from CT is independently prognostic of response and PFS across PD-L1 levels. Prospective validation of this biomarker is needed. 1. Alilou et al. Sci Adv 2022. 2. Khorrami et al. Cancer Immunol Res 2020. [Table: see text]

Are we ready to use PSMA as a theranostic biomarker in clinical practice for patients with breast cancer?

e13114 Background: Subtype classification for breast cancer (BC) patients is important for risk-stratification. Unfortunately, this parameter is not able to discriminate perfectly between high- and low-risk disease and the identification of an accurate biomarker to determine aggressiveness is still a clinical need. Prostate-specific membrane antigen (PSMA) could be important given that it has been reported to be expressed in BC tumor cells and even more in endothelial cells of tumor vessels. Methods: We analyzed 101 BCs of whom 22 luminal A, 34 Luminal B, 22 HER2 positive and 23 triple negative (TN) BC to assess whether PSMA expression by immunohistochemistry was different in tumor subtypes and was related to ki67 expression and stromal (tumour-infiltrating lymphocytes) TILs. PSMA positivity was calculated as the number of positive vessels on 10 fields at 40X magnifications. Kruskal Wallis’s test was used to assess difference in PSMA positivity among BC subgroups and Dunn’s test was performed for post-hoc comparisons; Spearman’s rho coefficient was calculated to analyze the correlation among PSMA, KI67 and TILs. Results: The median age at diagnosis of BC patients was 66 (min-max: 25-87 years). Seventy (69.3%) patients had ER>0 and 64 (63.4%) had PgR>0. The ductal histotype was present in 92 patients (91%). The majority of the patients had grade 3 tumors (55.4%). Considering the number of positive vessels, our results showed that median PSMA was higher in TNBC compared to Luminal A, Luminal B and HER2 positive tumors (p<0.001, p=0.001 and p=0.041, respectively). Ki67 was higher in TNBC compared to Luminal A, Luminal B and HER2 positive tumors (p<0.001, p<0.001 and p=0.001, respectively). We saw a correlation between PSMA and ki67, especially in HER2 positive tumors (p<0.001), while a correlation between PSMA and TILs was observed in Luminal A (p=0.028). The analysis of PSMA expression on the lymph nodes showed the same trend observed for the primary tumors given that it was higher in TNBC compared to HER2 positive and luminal cancers. Conclusions: Our results suggest that PSMA could be used as a theranostic biomarker in BC considering that it is highly expressed in more aggressive tumors and the possibility to treat PSMA expressing patients for anti-angiogenesis and/or radionuclide treatment.