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Photobiomodulation (PBM) has widely been used to effectively treat complications associated with cancer treatment, including oral mucositis, radiation dermatitis, and surgical wounds. However, the safety of PBM against cancer still needs to be validated as the effects of PBM on cancer cells and their mechanisms are unclear. The current study investigated the wavelength-dependent PBM effects by examining four different laser wavelengths (405, 532, 635, and 808 nm) on B16F10 melanoma tumor cells. In vitro tests showed that PBM with 808 nm promoted both proliferation and migration of B16F10 cells. In vivo results demonstrated that PBM with 808 nm significantly increased the relative tumor volume and promoted angiogenesis with overexpression of VEGF and HIF-1α. In addition, PBM induced the phosphorylation of factors closely related to cancer cell proliferation and tumor growth and upregulated the related gene expression. The current result showed that compared to the other wavelengths, 808 nm yielded a significant tumor-stimulating effect the malignant melanoma cancer. Further studies will investigate the in-depth molecular mechanism of PBM on tumor stimulation in order to warrant the safety of PBM for clinical cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This pre-clinical study was designed to demonstrate how vascular disrupting agents (VDAs) should be administered, either alone or when combined with radiation in clinically relevant fractionated radiation schedules, for the optimal anti-tumor effect. CDF1 mice, implanted in the right rear foot with a 200 mm 3 murine C3H mammary carcinoma, were injected with various doses of the most potent VDA drug, combretastatin A-1 phosphate (CA1P), under different schedules. Tumors were also locally irradiated with single-dose, or stereotactic (3 × 5-20 Gy) or conventional (30 × 2 Gy) fractionation schedules. Tumor growth and control were the endpoints used. Untreated tumors had a tumor growth time (TGT5; time to grow to 5 times the original treatment volume) of around 6 days. This increased with increasing drug doses (5-100 mg/kg). However, with single-drug treatments, the maximum TGT5 was only 10 days, yet this increased to 19 days when injecting the drug on a weekly basis or as three treatments in one week. CA1P enhanced radiation response regardless of the schedule or interval between the VDA and radiation. There was a dose-dependent increase in radiation response when the combined with a single, stereotactic, or conventional fractionated irradiation, but these enhancements plateaued at around a drug dose of 25 mg/kg. This pre-clinical study demonstrated how VDAs should be combined with clinically applicable fractionated radiation schedules for the optimal anti-tumor effect, thus suggesting the necessary pre-clinical testing required to ultimately establish VDAs in clinical practice.

In gold nanoparticle-enhanced radiotherapy, intravenously administered nanoparticles tend to accumulate in the tumor tissue by means of the so-called permeability and retention effect and upon irradiation with x-rays, the nanoparticles release a secondary electron field that increases the absorbed dose that would otherwise be obtained from the interaction of the x-rays with tissue alone. The concentration of the nanoparticles in the tumor, number of nanoparticles per unit of mass, which determines the total absorbed dose imparted, can be measured via magnetic resonance or computed tomography images, usually with a resolution of several millimeters. Using a tumor vasculature model with a resolution of 500 nm, we show that for a given concentration of nanoparticles, the dose enhancement that occurs upon irradiation with x-rays greatly depends on whether the nanoparticles are confined to the tumor vasculature or have already extravasated into the surrounding tumor tissue. We show that, compared to the reference irradiation with no nanoparticles present in the tumor model, irradiation with the nanoparticles confined to the tumor vasculature, either in the bloodstream or attached to the inner blood vessel walls, results in a two to three-fold increase in the absorbed dose to the whole tumor model, with respect to an irradiation when the nanoparticles have already extravasated into the tumor tissue. Therefore, it is not enough to measure the concentration of the nanoparticles in a tumor, but the location of the nanoparticles within each volume element of a tumor, be it inside the vasculature or the tumor tissue, needs to be determined as well if an accurate estimation of the resultant absorbed dose distribution, a key element in the success of a radiotherapy treatment, is to be made., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Díaz-Galindo, Garnica-Garza. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT., Material and Methods: The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA., Results: The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment., Conclusions: VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.

Background: Ultrasound-stimulated microbubble (USMB) therapy has proven efficacy of targeting tumor vasculature and enhancing the effect of radiation in tumor xenografts. In this investigation, we studied whether this treatment enhances the sensitivity of cervical cancer to radiation., Methods: Human cervical cancer (ME-180 and SiHa) cells were treated with USMB or exposed to radiation (0, 2, 4, 6 and 8 Gy) or radiation (8 Gy) in combination with USMB. Clone formation assay and CCK-8 assay were used to analyze the proliferation capacity of cells. Apoptosis and DNA double-strand breaks were detected using flow cytometry and immunofluorescence staining of gamma-H2AX (γ-H2AX), respectively. Matrigel tubule formation was performed to evaluate the angiogenesis of human umbilical vein endothelial cells. In xenograft model of SiHa cells, tumor tissue expression of CD31 was detected by immunohistochemistry., Results: USMB and radiation synergistically restrained the growth of ME-180 and SiHa cells. USMB promoted radiation-induced apoptosis by enhancing the levels of proapoptotic proteins. Furthermore, USMB enhanced radiation-induced γ-H2AX foci to induce DNA double-strand breaks in cervical cancer cells. USMB in combination with radiation reduced the angiogenic capacity of endothelial cells in vitro. Moreover, USMB strengthened the inhibitory effect of radiation on tumor growth and angiogenesis in xenograft models., Conclusion: In conclusion, USMB exposure effectively enhanced the destructive effect of radiation on cervical cancer, suggesting that USMB might be a promising sensitizer of radiotherapy to treat cervical cancer.

Purpose: Tumor oxygenation is one of the key features influencing the response of cells to radiation and chemo therapies. This study presents a novel in silico tumor model simulating realistic 3D microvascular structures and related oxygenation maps, featuring regions with different levels and typologies of hypoxia (chronic, acute and anemic). Such model, if integrated into a treatment planning system, could allow evaluations and comparisons of various scenarios when deciding the therapy to administer., Methods and Materials: Spherical tumors between 0.6 and 1.5 cm in diameter encompassed uniformly by vascular trees generated starting from pseudo-fractal principles were simulated with a voxel resolution of 10 µm. The approach ensures a continuous transition from a well-perfused rim to a core with poor vascularization. The oxygen diffusion equation in the tumor is solved by a finite difference method. Several quantities, such as the fractal dimension (FD), the microvascular density (MVD) and the hypoxic fraction (HF) were assessed and compared., Results: Different tumors with various degrees of chronic hypoxia were simulated by varying the tumor size and the number of bifurcations in the vascular networks. The simulations showed that for the case of chronically hypoxic tumors, in well-oxygenated volumes FD = 2.53 ± 0.07, MVD = 3460 ± 2180 vessels/mm 3 and HF = 4.0 ± 3.4%, while in hypoxic volumes FD = 2.34 ± 0.09, MVD = 365 ± 156 vessels/mm 3 , HF = 49.8 ± 18.3%. The superimposition of acute or anemic hypoxia accentuated the oxygen deprivation in the core of the volumes., Conclusions: Tumors varying in diameter and extension of their vasculature were simulated, showing features that define two distinctive subvolumes in terms of oxygenation. The model could be regarded as a testbed for simulations of key radiobiological features governing the tumor response to radio- and chemotherapy and thus for treatment outcome simulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: To investigate the synergic effect and underlying mechanism of Endostar, a recombinant human endostatin used for anti-angiogenesis, in radiotherapy for cervical cancer., Methods: The Cell Counting Kit-8 (CCK-8) assay and plate cloning experiment were first employed to analyze the proliferation of HeLa and SiHa cervical cancer cells and human umbilical vein vascular endothelial cells (HUVECs). Flow cytometry was used to detect apoptosis and cell cycle progression. A tube formation assay was used to assess angiogenesis in vitro . The expression of gamma H2A histone family member X (γ-H2AX) and activation of the vascular endothelial growth factor receptor (VEGFR) signaling pathway were detected by immunofluorescence and western blotting, respectively. In a HeLa xenograft model, tumor tissue expression of CD31 and alpha smooth muscle actin and serum expression of VEGF-A were detected by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay, respectively., Results: The CCK-8 and plate cloning assays showed that Endostar and radiotherapy synergistically inhibited the growth of HUVECs but not HeLa and SiHa cells. The flow cytometric results showed that Endostar only promoted radiotherapy-induced apoptosis and G2/M phase arrest in HUVECs ( p < 0.05). Endostar combined with radiotherapy also significantly inhibited tube formation by HUVECs ( p < 0.05). Furthermore, Endostar inhibited the radiotherapy-induced expression of γH2AX ( p < 0.05) and phosphorylation of VEGFR2/PI3K/AKT/DNA-PK in HUVECs ( p < 0.05). IHC showed that Endostar enhanced the inhibitory effect of radiotherapy on the microvessel density in xenograft tumor tissues ( p < 0.05), as well as serum VEGF-A expression ( p < 0.05). The tumor volume in the combination therapy groups (1200 mm 3 ) was significantly lower than in the control group (2500 mm 3 ; p < 0.05)., Conclusions: Our findings provide experimental evidence and a theoretical basis for the application of Endostar in combination with irradiation for anti-cervical cancer treatment., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Obesity is a rising epidemic, the influence of which on cancer development, progression as well as its impact on current standard of care cancer treatments is profound with many facets. Obesity is emerging as a modulating factor in many cancer therapies, such as chemotherapy, radiotherapy, immunotherapy and combination therapies. It has been reported to diminish the efficacy of some treatments but has also been alluded to being protective in terms of reduced treatment toxicities, thus the evolution of the obesity paradox. The obese tumour microenvironment influences treatment response through modulation of a series of aspects, including altered adipocyte secretome, angiogenesis, hypoxia, fibrosis, free fatty acid uptake as well as a modulated immune landscape. However, the influence of these underlying mechanisms on cancer treatment response and the biological action of adipose tissue is still largely unknown. Elucidation of these facets may lead to the enhanced efficacy of current treatment options or the identification of novel methods to combat cancer in the obese tumour microenvironment., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: The long-term clinical outcome of adjuvant stereotactic radiotherapy (SRT) in neovascular age-related macular degeneration (nAMD) patients was evaluated., Methods: This case-control study included patients with unilateral nAMD, who underwent SRT complementary to standard anti-VEGF treatment. Only patients with monthly follow-up over at least three years were considered. Number of intravitreal injections, visual acuity (VA), central retinal thickness (CRT), and subfoveal choroidal thickness (SFCT) were evaluated and compared to baseline as well as to an age- and gender-matched control group, who received anti-VEGF monotherapy., Results: Twenty patients were irradiated and had complete follow-up. Cumulatively, SRT patients needed significantly less injections than non-irradiated ones over three years (14 vs. 18, p ​= ​0.014), while median VA did not show statistically significant changes (0.4 logMAR at baseline to 0.65 logMAR at final follow-up, p ​= ​0.061). CRT remained steady, but SFCT showed a continuous thinning of almost 50 ​μm (p ​= ​0.031) in irradiated patients over three years. Multiple linear regression analysis revealed that SFCT and VA at time of irradiation are significant prognostic factors of VA change in SRT patients over the following three years (F(2,17) ​= ​23.946, p<0.001, R 2 of 0.738)., Conclusions: SRT significantly reduced the cumulative anti-VEGF treatment burden over three years, however, this was mainly driven by the results of the first year after irradiation. A thinner SFCT at time of irradiation was associated with poorer visual outcome. While further research and investigation are warranted to elucidate the underlying pathogenesis, SFCT could be a potential biomarker when evaluating a patient's suitability for SRT., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2021 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Background: p-Boronophenylalanine ( 10 BPA) is a powerful 10 B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of 10 BPA must be administered over a few hours. Here, we report BNCT efficacy after rapid, ultralow-dose administration of either tumor vasculature-specific annexin A1-targeting IFLLWQR (IF7)-conjugated 10 BPA or borocaptate sodium ( 10 BSH)., Methods: (1) IF7 conjugates of either 10 B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of 10 B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7- 10 B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/He mice and YTS-1 tumor bearing nude mice., Results: Intravenous injection of IF7C conjugates of either 10 B drugs into MBT2 bladder tumor-bearing mice promoted rapid 10 B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10-20 mg/kg) doses of IF7- 10 B drug-mediated BNCT significantly suppressed tumor growth in a mouse model of human YTS-1 bladder cancer, with increased Anxa1 expression in tumors and infiltration by CD8-positive lymphocytes., Conclusions: We conclude that IF7 serves as an efficient 10 B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.

Rosacea is a skin inflammatory condition accompanied by cutaneous signs such as oedema, flushing, erythema, telangiectasia and pustules. Generally, rosacea is triggered by ultraviolet B (UVB) exposure. When exposed to UVB, skin epidermis thickens and produces elevated levels of pro-inflammatory cytokines, especially keratinocyte-related VEGF, a potent angiogenic factor. The upregulations of VEGF expression and its secretion promote the formation of new blood vessels and exacerbates rosacea. In this study, radiofrequency (RF) irradiation reduced keratinocyte proliferation in the epidermal layer, the expressions of pro-inflammatory cytokines, angiogenesis-related inflammatory factors and VEGF in our UVB-induced model of rosacea in vitro and in vivo. RF irradiation attenuated VEGF-induced angiogenesis-associated processes such as tube formation, cell migration and endothelial cell proliferation. Notably, blood vessel densities in the skins of UVB-treated mice and rosacea patients were significantly decreased by RF irradiation. These results provide experimental and molecular evidence regarding the effectiveness of RF irradiation for the treatment of rosacea., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Intervertebral disc (IVD) degeneration with chronic low back pain is associated with neo-vascularisation into the deeper IVD regions. During this process, endothelial cells (ECs), which are primarily responsible for angiogenesis, interact with the adjacent annulus fibrosus (AF) cells, which are the first line of defence against the invasion of vascular structures into deeper IVD regions. However, the accumulation of inflammatory and catabolic enzymes that results from this interaction promotes matrix degradation and an inflammatory response. Thus, regulating the production of these mediators and catabolic enzymes could ameliorate IVD degeneration. Photobiomodulation (PBM) therapy is a non-invasive stimulation known to have biologically beneficial effects on wound healing, tissue repair, and inflammation. Here, we examined the effects of PBM, administered at various wavelengths (645, 525, and 465 nm) and doses (16, 32, and 64 J/cm 2 ), on EC-stimulated human AF cells. Our results show that PBM selectively inhibited the EC-mediated production of inflammatory mediators, catabolic enzymes, and neurotrophins by human AF cells in a dose- and wavelength-dependent manner. These results suggest that PBM could be a superior and advanced treatment strategy for IVD degeneration.

Purpose: The aim of this study is to characterize the effects of high-dose radiation therapy (HDRT) on Notch signaling components of the tumor vasculature., Methods and Materials: Human umbilical vein endothelial cells monolayers were exposed to different single fraction doses of irradiation; ribonucleic acid RNA was isolated and polymerase chain reaction was performed for Notch signaling components. The vascular response to radiation therapy was examined in a xenograft model of neuroblastoma. Tumors were treated with 0 Gy, 2 Gy, and 12 Gy single fraction doses and analyzed by double immunofluorescence staining for Notch1, Notch ligands Jagged1 and Dll4, and the endothelial cell (EC) marker endomucin. To assess the role of Notch in vivo, NGP xenograft tumors expressing Fc or Notch1- 1-24 -decoy (a novel Notch inhibitor) were treated with 0 Gy and 12 Gy. Immunofluorescence staining for endomucin and endomucin/αSMA was performed to analyze the effect of combination treatment on tumor EC and endothelial-to-mesenchymal-transition (EndMT), respectively., Results: In human umbilical vein endothelial cells monolayers doses ≥8 Gy increased expression of NOTCH1, JAG1, and Notch target genes HEY1 and HEY2 as early as 6 hours after irradiation. In vivo, 12 Gy significantly increased Notch1 and Jagged1 in tumor ECs compared with 0 Gy or 2 Gy after 72 hours. Combining HDRT with Notch inhibition using the Notch1- 1-24 -decoy resulted in a greater loss of EC coverage of tumor vessels than HDRT alone at 6 hours and 72 hours post treatment. Notch inhibition reduced EndMT induced by HDRT, as indicated by diminished αSMA staining in ECs., Conclusions: HDRT induced Notch1 expression and increased Notch1 signaling in the endothelial component of tumor vasculature, which was not observed with lower doses. This increase in Notch1 activation might protect tumor vessels from HDRT induced damage and regulate EndMT process., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to investigate the molecular mechanism of miRNA-9-5p in cervical cancer., Patients and Methods: The expression level of microRNA-9-5p (miR-9-5p) in cervical cancer (CC) tissues and cell lines was examined by quantitative Real Time-Polymerase Chain Reaction. Cells were transfected with Lipofectamine 3000. Cell proliferation was measured by Cell Counting Kit-8 (CCK-8). Invasion assays were performed in 24-well transwell chambers system with 8 μm pores. Cell invasion was evaluated by transwell assay. Western blot was used to detect the changes of epithelial-mesenchymal transition (EMT) and SOCS5. The effects of miR-9-5p on tubule formation were examined under different doses of γ radiation. Immunohistochemistry assay was used to analyze the protein expression of SOCS5. Fluorescence microscopy analysis was used to measure autophagosomes after cells treated with γ irradiation., Results: From the Cancer Genome Atlas (TCGA) database, the expression of miR-9-5p was significantly higher in cervical cancer patients than in the negative ones, and it was verified in 22 paired of lymph node-positive patient tissues and negative. The overexpression of miR-9-5p promoted proliferation and invasion of cervical cancer cells in vitro and primary tumor growth in vivo. MiR-9-5p reduced the tubule generation after the radiation dose of 4Gy. Besides, we identified SOCS5 as the target of miR-9-5p, and the overexpression of SOCS5 could inhibit miR-9-5p mimics from promoting tubule formation., Conclusions: MiR-9-5p could promote proliferation and invasion of CC cells in vitro and in vivo. MiR-9-5p could affect angiogenesis and radiosensitivity of CC cells by targeting SOCS5.

Aberrant increase in angiogenesis contributes to the progression of malignant solid tumors. An alternative anti‑angiogenesis therapy is critical for cancer, since the current anti‑angiogenesis drugs lack specificity for tumor cells. In the present study, the effects and mechanisms of low‑intensity pulsed ultrasound (LIPUS) on human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMECs) were investigated, and the therapeutic potential of this technology was assessed. HUVECs and HMECs were treated with LIPUS (0.5 MHz; 210 mW/cm2) for 1 min and cultured for 24 h. Flow cytometry and Cell Counting Kit‑8 assays demonstrated that LIPUS treatment at a dose of 210 mW/cm2 promoted apoptosis and decreased the viability in HUVECs and HMECs. Real‑time cell analysis also revealed that LIPUS did not affect the proliferation or migration of HUVECs. An endothelial cell tube formation assay indicated that LIPUS treatment inhibited the angiogenic ability of HUVECs and HMECs. Furthermore, LIPUS increased the protein levels of the apoptosis‑associated cleaved Caspase‑3 and decreased the B‑cell lymphoma‑2 levels. LIPUS increased the phosphorylation of p38 mitogen‑activated protein kinase (MAPK), and the levels of endoplasmic reticulum (ER) stress‑associated markers, including activating transcription factor‑4 (ATF‑4) and phosphorylated eukaryotic initiation factor 2α (eIF2α). The p38 inhibitor SB203580 reversed the pro‑apoptotic and anti‑angiogenic effects of LIPUS in cells. Finally, inhibition of p38 decreased the LIPUS‑induced elevation of p‑eIF2α and ATF‑4 levels. Taken together, these results suggested that LIPUS promoted apoptosis and inhibited angiogenesis in human endothelial cells via the activation of p38 MAPK‑mediated ER stress signaling.

In order to evaluate the role of angiogenesis in 90 Y-radioembolization for colorectal cancer liver metastasis an overview was provided of angiogenic growth factors and their function, the angiogenic mechanisms in colorectal cancer, the role of hypoxia, and the advances in antiangiogenic therapy. Last, the use of circulating angiogenic growth factors in 90 Y-radioembolization was reviewed. Two literature searches were conducted. A search query in PubMed on angiogenesis in colorectal cancer, and a systematic search in PubMed (Medline), Embase, and the Cochrane Library (October 2018) with synonyms for "radioembolization" and "angiogenic growth factor." The first search yielded 3 relevant publications on the role of angiogenic growth factors in colorectal cancer, hypoxia, and antiangiogenic therapy. The second search yielded two prospective studies on circulating angiogenic factors and their relationship with response and survival after 90 Y-radioembolization for colorectal cancer liver metastases. Rises in circulating angiogenic growth factors after radioembolization were seen in both studies. High baseline values of Ang-2 and IL-8 correlated with shorter survival and post 90 Y-radiembolization rises in Ang-2 and HGF correlated with early progression. Various angiogenic growth factors play a role in the development and progression of colorectal cancer. Several factors show correlation with poor outcomes after 90 Y-radioembolization and might be used for patient selection in the future, however, validation in larger comparative studies is required., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Patients with hepatocellular carcinoma (HCC) and gross vascular invasion (GVI) have poor outcomes with systemic therapy such as sorafenib. Both external beam radiation therapy (EBRT) and transarterial radioembolization (TARE) have been utilized for this patient population. We sought to compare outcomes using dual modality radiation (EBRT+TARE) versus EBRT alone in patients with HCC and GVI., Materials and Methods: Between 2011 and 2017, 45 patients with HCC and GVI were treated with EBRT±TARE at our institution. Progression-free survival (PFS) and overall survival (OS) were assessed and compared using Kaplan-Meier method and log-rank test. Univariable and multivariable Cox proportional hazards regression was used to assess the impact of the variables stage, etiology of cirrhosis, Child-Pugh (CP) score, and Karnofsky Performance Score (KPS) on PFS and OS., Results: Patient characteristics were well-balanced except for KPS (80 vs. 90) and CP score. Median OS for patients receiving EBRT+TARE was 263 days (95% confidence interval [CI]: 167, -) versus 193 days (95% CI: 51, 262) for EBRT alone (P=0.049). However, this did not hold up on MVA. When EBRT and TARE were delivered within 2 months as planned (n=12), median PFS was 218 days (95% CI: 44, -) for dual modality radiation versus 63 days (95% CI: 38, 137) for EBRT alone (P=0.048). When EBRT and TARE were delivered within 6 months, the difference in PFS was no longer seen (P=NS), because some patients received TARE as a salvage therapy., Conclusions: Dual modality radiation with EBRT and TARE may be associated with improved OS in patients with HCC and GVI. Dual modality radiation may be associated with improved PFS in patients with HCC and GVI compared with EBRT alone when EBRT and TARE are delivered within 2 months of each other as part of a planned dual modality treatment strategy. However, since this is a retrospective study with inherent selection bias, these findings need further validation in a prospective clinical trial for patients with HCC and GVI.

Objectives: Hepatocellular carcinoma (HCC) associated with major vascular invasion is an advanced stage disease with an extremely poor prognosis and low survival rate. Our study evaluated the survival benefit of radiotherapy (RT) in HCC patients with major vascular invasion through Surveillance, Epidemiology, and End Results database., Methods: We analyzed 3181 HCC patients with major vascular invasion cases diagnosed from 2004 to 2013. Patients (N = 308) who underwent RT and patients (N = 2873) who did not receive RT were compared. We successfully analyzed patients using propensity score matching (PSM). Kaplan-Meier and Cox-regression analyses were applied to assess prognosis., Results: The median survival time in radiation-treated group was longer compared to the control group (7 months vs 3 months; P < 0.001) in the overall sample and 3 months longer compared to the control group (7 months vs 4 months; P < 0.001) in a PSM cohort. Cox-regression analyses showed that radiation-treated patients in propensity-matched sample had a significantly lower risk of mortality (HR: 0.625, 95% CI: 0.522-0.749, P < 0.001) compared with untreated patients. The radiation-treated groups had better survival rate than untreated group. Subgroup analysis revealed that the survival time of patients in radiation-treated group was significantly longer than that in the untreated group (P < 0.001 and P = 0.026, respectively). The subgroup analysis also revealed that RT provides a survival benefit regardless of race, marital status, and tumor size after PSM., Conclusions: Radiotherapy provides improves survival in HCC patients with major vascular invasion, especially for tumor(s) confined to one lobe and not on surface of liver., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Pancreatic ductal adenocarcinoma has dismal prognosis. Most patients receive radiation therapy (RT), which is complicated by respiration induced organ motion in upper abdomen. The purpose of this study is to report our early clinical experience in a novel self-gated k-space sorted four-dimensional magnetic resonance imaging (4D-MRI) with slab-selective (SS) excitation to highlight tumor infiltrating blood vessels for pancreatic RT., Methods: Ten consecutive patients with borderline resectable or locally advanced pancreatic cancer were recruited to the study. Non-contrast 4D-MRI with and without slab-selective excitation and 4D-CT with delay contrast were performed on all patients. Vessel-tissue CNR were calculated for aorta and critical vessels (superior mesenteric artery or superior mesenteric vein) encompassed by tumor. Respiratory motion trajectories for tumor, as well as involved vessels were analyzed on SS-4D-MRI. Intra-class cross correlation (ICC) between tumor volume and involved vessels were calculated., Results: Among all 4D imaging modalities evaluated, SS-4D-MRI sampling trajectory results in images with highest vessel-tissue CNR comparing to non-slab-selective 4D-MRI and 4D-CT for all patients studied. Average (±standard deviation) CNR for involved vessels are 13.1 ± 8.4 and 3.2 ± 2.7 for SS-4D-MRI and 4D-CT, respectively. The ICC factors comparing tumor and involved vessels motion trajectories are 0.93 ± 0.10, 0.65 ± 0.31 and 0.77 ± 0.23 for superior-inferior, anterior-posterior and medial-lateral directions respectively., Conclusions: A novel 4D-MRI sequence based on 3D-radial sampling and slab-selective excitation has been assessed for pancreatic cancer patients. The non-contrast 4D-MRI images showed significantly better contrast to noise ratio for the vessels that limit tumor resectability compared to 4D-CT with delayed contrast. The sequence has great potential in accurately defining both the tumor and boost volume margins for pancreas RT with simultaneous integrated boost.

Introduction: Increased levels of endoglin may represent a new reagent of active neovascularization and angiogenesis process in various cancer types. The prognostic value of tumor CD105 (endoglin) expression in cervical squamous cell cancer (CSCC) patients treated with radical radiotherapy (RT) ± chemotherapy was investigated., Materials and Methods: CD105 (endoglin) expression was assessed by immunohistochemical methods in seventy patients, who were treated with radical RT ± chemotherapy for CSCC. The prognostic effects of CD105 on patient and treatment characteristics, local-regional control, and survival were assessed., Results: The median follow-up was 24 (5-99) months for the whole cohort. The median CD105 microvessel density was 55.5 (range; 12-136). Age (≤61 vs. >61 years; P = 0.015), lymph node metastasis status (absent vs. present; P = 0.028), International Federation of Gynecology and Obstetrics stage (Ib-IIa vs. IIb-IVa; P = 0.036), cycles of concurrent chemotherapy (1-3 vs. 4-6 cycles; P = 0.001), and hemoglobin levels (≤10 g/dL vs. >10 g/dL; P = 0.006) appeared to associate significantly with overall survival on univariate analysis., Discussion: No correlation was identified between the tumor CD105 (endoglin) expression and survival in CSCC patients treated with radical RT ± chemotherapy., Competing Interests: There are no conflicts of interest

Background: High-dose radiotherapy (>8-10 Gy) causes rapid endothelial cell death via acid sphingomyelinase (ASMase)-induced ceramide production, resulting in biologically significant enhancement of tumor responses. To further augment or solicit similar effects at low radiation doses, we used genetic and chemical approaches to evaluate mechano-acoustic activation of the ASMase-ceramide pathway by ultrasound-stimulated microbubbles (USMB)., Methods: Experiments were carried out in wild-type and acid sphingomyelinase (asmase) knockout mice implanted with fibrosarcoma xenografts. A cohort of wild-type mice received the ASMase-ceramide pathway inhibitor sphingosine-1-phosphate (S1P). Mice were treated with varying radiation doses, with or without a priori USMB exposure at different microbubble concentrations. Treatment response was assessed with quantitative 3D Doppler ultrasound and immunohistochemistry at baseline, and at three, 24, and 72 hours after treatment, with three to five mice per treatment group at each time point. All statistical tests were two-sided., Results: Results confirmed an interaction between USMB and ionizing radiation at 24 hours (P < .001), with a decrease in tumor perfusion of up to 46.5% by three hours following radiation and USMB. This peaked at 24 hours, persisting for up to 72 hours, and was accompanied by extensive tumor cell death. In contrast, statistically nonsignificant and minimal tumor responses were noted in S1P-treated and asmase knockout mice for all treatments., Conclusions: This work is the first to confirm the involvement of the ASMase-ceramide pathway in mechanotransductive vascular targeting using USMB. Results also confirm that an acute vascular effect is driving this form of enhanced radiation response, and that it can be elicited at low radiation doses (<8-10 Gy) by a priori USMB exposure.

Purpose: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of the CDK4/6 inhibitor abemaciclib in non-small cell lung cancer (NSCLC) cells in vitro and in vivo Experimental Design: IR enhancement by abemaciclib in a variety of NSCLC cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by γH2AX analysis. Global metabolic alterations by abemaciclib and IR combination were evaluated by LC/MS mass spectrometry and YSI bioanalyzer. Effects of abemaciclib and IR combination in vivo were studied by xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry. Results: Abemaciclib enhanced the radiosensitivity of NSCLC cells independent of RAS or EGFR status. Enhancement of radiosensitivity was lost in cell lines deficient for functional p53 and RB protein. After IR, abemaciclib treatment inhibited DNA damage repair as measured by γH2AX. Mechanistically, abemaciclib inhibited RB phosphorylation, leading to cell-cycle arrest. It also inhibited mTOR signaling and reduced intracellular amino acid pools, causing nutrient stress. In vivo , abemaciclib, when administered in an adjuvant setting for the second week after fractionated IR, further inhibited vasculogenesis and tumor regrowth, with sustained inhibition of RB/E2F activity, mTOR pathway, and HIF-1 expression. In summary, our study signifies inhibiting the CDK4/6 pathway by abemaciclib in combination with IR as a promising therapeutic strategy to treat NSCLC. Conclusions: Abemaciclib in combination with IR enhances NSCLC radiosensitivity in preclinical models, potentially providing a novel biomarker-driven combination therapeutic strategy for patients with NSCLC. Clin Cancer Res; 24(16); 3994-4005. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The implementation of novel cancer immunotherapies in the form of immune checkpoint blockers represents a major advancement in the treatment of cancer, and has renewed enthusiasm for identifying new ways to induce antitumor immune responses in patients. Despite the proven efficacy of neutralizing antibodies that target immune checkpoints in some refractory cancers, many patients do not experience therapeutic benefit, possibly owing to a lack of antitumor immune recognition, or to the presence of dominant immunosuppressive mechanisms in the tumor microenvironment (TME). Recent developments in this field have revealed that local radiotherapy (RT) can transform tumors into in situ vaccines, and may help to overcome some of the barriers to tumor-specific immune rejection. RT has the potential to ignite tumor immune recognition by generating immunogenic signals and releasing neoantigens, but the multiple immunosuppressive forces in the TME continue to represent important barriers to successful tumor rejection. In this article, we review the radiation-induced changes in the stromal compartments of tumors that could have an impact on tumor immune attack. Since different RT regimens are known to mediate strikingly different effects on the multifarious elements of the tumor stroma, special emphasis is given to different RT schedules, and the time after treatment at which the effects are measured. A better understanding of TME remodeling following specific RT regimens and the window of opportunity offered by RT will enable optimization of the design of novel treatment combinations.

Glioblastoma multiforme (GBM) is a fatal cancer with varying life expectancy, even for patients undergoing the same standard therapy. Identification of differentially expressed genes in GBM patients with different survival rates may benefit the development of effective therapeutic strategies. In the present study, key pathways and genes correlated with survival in GBM patients were screened with bioinformatic analysis. Included in the study were 136 eligible patients who had undertaken surgical resection of GBM followed by temozolomide (TMZ) chemoradiation and long-term therapy with TMZ. A total of 383 differentially expressed genes (DEGs) related to GBM survival were identified. Gene Ontology and pathway enrichment analysis as well as hub gene screening and module analysis were performed. As expected, angiogenesis and migration of GBM cells were closely correlated with a poor prognosis. Importantly, the results also indicated that cell dormancy was an essential contributor to the reduced survival of GBM patients. Given the lack of specific targeted genes and pathways known to be involved in tumour cell dormancy, we proposed enriched candidate genes related to the negative regulation of cell proliferation, signalling pathways regulating pluripotency of stem cells and neuroactive ligand-receptor interaction, and 3 hub genes (FTH1, GRM1 and DDIT3). Maintaining persistent cell dormancy or preventing tumour cells from entering dormancy during chemoradiation should be a promising therapeutic strategy.

Purpose: Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy., Methods: The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with 177 Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 177 Lu only, TRC105 only, 177 Lu-DTPA-IgG (a nonspecific antibody), 177 Lu-DTPA-TRC105 low-dose, and 177 Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of 177 Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose 177 Lu-DTPA-TRC105., Results: Biodistribution studies indicated steady uptake of 177 Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses., Conclusion: 177 Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and the fastest growing malignancy in the United States. With a 5-year survival rate below 12%, effective therapies for HCC are needed. Current treatments for HCC include microwave and radiofrequency ablation, high intensity focused ultrasound, liver transplant, surgical resection, and localized embolizations. However, each of these approaches has some limitation, making it imperative to develop improved methods for sensitizing tumors prior to therapy. We hypothesized that the use of ultrasound-triggered microbubble destruction (UTMD), which sensitizes tumors to radiotherapy by inducing vascular endothelial cell apoptosis, will selectively sensitize malignant tissue to radiotherapy and improve outcomes. To test this, 18 nude rats were inoculated in the right liver lobe with Hu7.5 HCC cells and after tumor formation, received 5 Gy radiotherapy, UTMD, or UTMD prior to radiotherapy. Compared to radiotherapy alone, there was a 170% reduction in tumor growth 7 days post treatment and a 3.2X improvement in median survival time when radiotherapy was combined with UTMD. These results indicate that UTMD is an effective adjunct when combined with radiotherapy to treat HCC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Vascular disrupting agents (VDAs) damage tumor vasculature and enhance tumor radiation response. In this pre-clinical study, we combined radiation with the leading VDA in clinical development, combretastatin A-4 phosphate (CA4P), and compared the effects seen in tumors and relevant normal tissues., Material and Methods: Radiation was applied locally to tissues in CDF1 mice to produce full radiation dose-response curves. CA4P (250 mg/kg) was intraperitoneally (i.p.) injected within 30 minutes after irradiating. Response of 200 mm 3 foot implanted C3H mammary carcinomas was assessed using percent tumor control at 90 days. Normal tissue effects were evaluated using early responding skin (development of moist desquamation in the foot at 11-30 days), and late responding bladder (50% reduction in reservoir function estimated by cystometry up to 9 months after treatment), and lung (20% increase in ventilation rate measured by plethysmography within 9 months). A Chi-squared test was used for statistical comparisons (significance level of p < .05)., Results: The radiation dose controlling 50% of irradiated tumors was 52 Gy. This significantly decreased to 45 Gy with CA4P. The radiation doses inducing a change in skin, bladder and lung response in 50% of mice were 31 Gy, 14 Gy and 12 Gy, respectively. CA4P had no significant effect on the radiation response of any of these normal tissues., Conclusions: VDAs significantly enhance tumor radiation response, but had absolutely no effect on the radiation response of early or late responding normal tissues.

Glioblastoma (GBM) is the most common primary malignant astrocytoma characterized by extensive invasion, angiogenesis, hypoxia, and micrometastasis. Despite the relatively leaky nature of GBM blood vessels, effective delivery of antitumor therapeutics has been a major challenge due to the complications caused by the blood-brain barrier (BBB) and the highly torturous nature of newly formed tumor vasculature (blood tumor barrier-BTB). External beam radiotherapy was previously shown to be an effective means of permeabilizing central nervous system (CNS) barriers. By using targeted short-ranged radionuclides, we show for the first time that our targeted actinium-225-labeled α v β 3 -specific liposomes ( 225 Ac-IA-TLs) caused catastrophic double stranded DNA breaks and significantly enhanced the permeability of BBB and BTB in mice bearing orthotopic GBMs. Histologic studies revealed characteristic α-particle induced double strand breaks within tumors but was not significantly present in normal brain regions away from the tumor where BBB permeability was observed. These findings indicate that the enhanced vascular permeability in these distal regions did not result from direct α-particle-induced DNA damage. On the basis of these results, in addition to their direct antitumor effects, 225 Ac-IA-TLs can potentially be used to enhance the permeability of BBB and BTB for effective delivery of systemically administered antitumor therapeutics. Mol Cancer Ther; 16(10); 2191-200. ©2017 AACR ., (©2017 American Association for Cancer Research.)

In patients undergoing radiotherapy for cancer, radiation dose to healthy tissue can occur, causing microvascular damage. Monocytes that have been shown to promote tissue revascularization comprise the subsets: CD11b + Ly6G - 7/4 hi /monocytes hi and CD11b + Ly6G - 7/4 lo /monocytes lo . We hypothesized that monocytes were implicated in postirradiation blood vessel formation. C57Bl6 mice underwent localized colorectal irradiation and were sacrificed at different times after exposure. Bone marrow, spleen, blood and colon were collected. Fourteen days postirradiation, colons expressed proangiogenic actors and adhesion molecules. Monocytes hi , which were the main subset of infiltrating monocytes, mobilized to the blood from spleen and bone marrow, peaking at day 14 postirradiation, and were associated with lymphocyte Th1 polarization. At day 28 postirradiation, angiographic score and capillary density increased by ∼1.8-fold, and then returned to nonirradiated levels at day 60. Clodronate-mediated depletion of circulating monocytes prior to irradiation resulted in a ∼1.4-fold decrease in angiographic score and capillary density compared to the nontreated control. Histological analysis of the colon in clodronate-treated mice revealed a massive decrease of macrophage and lymphocyte infiltration as well as reduced collagen deposition in crypt area at day 21. However, late depletion of monocytes from day 25 postirradiation had no effect on fibrotic process. These findings demonstrate a central role for monocyte/macrophage activation in the orchestration of a neovascularization mechanism after localized colorectal irradiation.

The purpose of this paper is to assess the relationship between gene polymorphism in angiogenesis-related genes and radiation responses in nasopharyngeal carcinoma (NPC) patients. The genotypes of 180 NPC patients were analyzed by Sequenom MassARRAY. The response evaluation criteria in solid tumours were used for assessing efficacies, and the criteria of the Radiation Therapy Oncology Group or European Organization for Research & Treatment of Cancer were utilized for evaluating acute toxic reactions in response to radiation. Statistical methods included chi-square test, uni- and multivariate logistic regression analyses. Genotypic carriers of rs1800541 GT were at an elevated risk of developing grade 3+ oral mucositis, and a genetic variant of rs5333 was a predictor for a lower occurring risk of grade 2+ radiation-induced xerostomia. EDN1 rs1800541, rs2071942 and rs5370 variants were associated with a significantly higher risk of severe myelosuppression. SNPs in such angiogenesis-related genes as EDN1 rs1800541, rs2071942 & rs5370 and EDNRA rs5333 may serve as useful biomarkers for predicting the outcomes of NPC patients., (© 2017 John Wiley & Sons Australia, Ltd.)

Antivascular therapy represents a proven strategy to treat angiogenesis. By applying synchronized ultrasound bursts and nanosecond laser irradiation, we developed a novel, selective, non-invasive, localized antivascular method, termed photo-mediated ultrasound therapy (PUT). PUT takes advantage of the high native optical contrast among biological tissues and can treat microvessels without causing collateral damage to the surrounding tissue. In a chicken yolk sac membrane model, under the same ultrasound parameters (1 MHz at 0.45 MPa and 10 Hz with 10% duty cycle), PUT with 4 mJ/cm 2 and 6 mJ/cm 2 laser fluence induced 51% (p = 0.001) and 37% (p = 0.018) vessel diameter reductions respectively. With 8 mJ/cm 2 laser fluence, PUT would yield vessel disruption (90%, p < 0.01). Selectivity of PUT was demonstrated by utilizing laser wavelengths at 578 nm or 650 nm, where PUT selectively shrank veins or occluded arteries. In a rabbit ear model, PUT induced a 68.5% reduction in blood perfusion after 7 days (p < 0.001) without damaging the surrounding cells. In vitro experiments in human blood suggested that cavitation may play a role in PUT. In conclusion, PUT holds significant promise as a novel non-invasive antivascular method with the capability to precisely target blood vessels., Competing Interests: Yannis M. Paulus, Xueding Wang, and Xinmai Yang have applied for a patent on PUT “Method and Apparatus for Removing Microvessels”.

Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation., Competing Interests: S.A., D.A.C., S.J.A. hold a patent on micro-RNAs and micro-RNA inhibitors to modulate blood vessel growth, patterning, tumour growth and malignant disease and method for making and using them. The remaining authors declare no competing financial interests.

The extent of tumor oxygenation is an important factor contributing to the efficacy of radiation therapy (RTx). Interestingly, several preclinical studies have shown benefit of combining RTx with drugs that inhibit tumor blood vessel growth, i.e. angiostatic therapy. Recent findings show that proper scheduling of both treatment modalities allows dose reduction of angiostatic drugs without affecting therapeutic efficacy. We found that whilst low dose sunitinib (20 mg/kg/day) did not affect the growth of xenograft HT29 colon carcinoma tumors in nude mice, the combination with either single dose RTx (1x 5Gy) or fractionated RTx (5x 2Gy/week, up to 3 weeks) substantially hampered tumor growth compared to either RTx treatment alone. To better understand the interaction between RTx and low dose angiostatic therapy, we explored the effects of RTx on tumor angiogenesis and tissue perfusion. DCE-MRI analyses revealed that fractionated RTx resulted in enhanced perfusion after two weeks of treatment. This mainly occurred in the center of the tumor and was accompanied by increased tissue viability and decreased hypoxia. These effects were accompanied by increased expression of the pro-angiogenic growth factors VEGF and PlGF. DCE-MRI and contrast enhanced ultrasonography showed that the increase in perfusion and tissue viability was counteracted by low-dose sunitinib. Overall, these data give insight in the dynamics of tumor perfusion during conventional 2 Gy fractionated RTx and provide a rationale to combine low dose angiostatic drugs with RTx both in the palliative as well as in the curative setting.

Photothermal treatment of tumors of the retina and choroid such as retinoblastomas, malignant melanomas, benign tumors as well as of vascular malformations can be performed by using laser radiation. A number of basic physical laws have to be taken into account in this procedure. Of particular importance thereby are: Arrhenius' law to approximate the kinetics of protein denaturation and photocoagulation, furthermore the electromagnetic radiation field, the distribution of both radiant and thermal energy induced in tumors and vascular structures, the influence of the wavelength and laser pulse duration (exposure time), as well as of the optical properties of the tissue. Strict confinement of the extent of the photothermal damage is critical since such pathological entities are frequently located close to the macula or optic nerve head.The conditions for tumor destruction are best fulfilled when using radiation in the near-infrared range of the electromagnetic spectrum such as that emitted from the diode (810 nm) and the Nd: YAG (1064 nm) laser, because of the good optical penetration properties of these radiations in tissue. Short wavelength sources of radiation, such as the argon ion (488, 514 nm) or the freqeuency-doubled Nd: YAG (532 nm) laser are less well suited for the irradiation of large vascular structures due to their poor penetration depths. However, for vascular formations with a small thickness (1 mm or less), short wavelength sources appear to be the most appropriate choice. Optical coupling of radiant energy to the eye by means of indirect ophthalmoscopic systems or positive contact lenses is furthermore of importance. Strong positive lenses may lead to severe constrictions of the laser beam within the anterior segment, that leads to high irradiance increasing the probability for structures to be damaged; with negative contact lenses, such as the -64 D Goldmann type lens, this danger is largely absent.

Despite the fact that radiation is one of the standard therapies in the treatment of patients with oral cancer, tumours can recur even in the early stages of the disease, negatively impacting prognosis and quality of life. We previously found that CD11b(+) bone marrow-derived cells (BMDCs) were recruited into human glioblastoma multiforme (GBM), leading to re-organization of the vasculature and tumour regrowth. However, it is not yet known how these cells contribute to tumour vascularization. In the present study, we investigated the role of infiltrating CD11b(+) myeloid cells in the vascularization and recurrence of oral squamous cell carcinoma (OSCC). In a xenograft mouse model, local irradiation caused vascular damage and hypoxia in the tumour and increased infiltration of CD11b(+) myeloid cells. These infiltrating cells showed characteristics of M2 macrophages (M2Mφs) and are associated with the promotion of vascularization. M2Mφs promoted tumour progression in recurrence after irradiation compared to non-irradiated tumours. In addition, we found that CD11b(+) myeloid cells, as well as CD206(+) M2Mφs, are increased during recurrence after radiotherapy in human OSCC specimens. Our findings may lead to the development of potential clinical biomarkers or treatment targets in irradiated OSCC patients.

Leptomeningeal dissemination of a primary brain tumor is a condition which is challenging to treat, as it often occurs in rather late disease stages in highly pretreated patients. Its prognosis is dismal and there is still no accepted standard of care. We report here a good clinical effect with a partial response in three out of nine patients and a stable disease with improvement on symptoms in two more patients following systemic anti-angiogenic treatment with bevacizumab (BEV) alone or in combination with chemo- and/or radiotherapy in a series of patients with leptomeningeal dissemination from primary brain tumors (diffuse astrocytoma WHO°II, anaplastic astrocytoma WHO°III, anaplastic oligodendroglioma WHO°III, primitive neuroectodermal tumor and glioblastoma, both WHO°IV). This translated into effective symptom control in five out of nine patients, but only moderate progression-free and overall survival times were reached. Partial responses as assessed by RANO criteria were observed in three patients (each one with anaplastic oligodendroglioma, primitive neuroectodermal tumor and glioblastoma). In these patients progression-free survival (PFS) intervals of 17, 10 and 20 weeks were achieved. In three patients (each one with diffuse astrocytoma, anaplastic astrocytoma and primitive neuroectodermal tumor) stable disease was observed with PFS of 13, 30 and 8 weeks. Another three patients (all with glioblastoma) were primary non-responders and deteriorated rapidly with PFS of 3 to 4 weeks. No severe adverse events were seen. These experiences suggest that the combination of BEV with more conventional therapy schemes with chemo- and/or radiotherapy may be a palliative treatment option for patients with leptomeningeal dissemination of brain tumors.

More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.

Human epidermal growth factor receptor family members (EGFR, HER2, HER3, and HER4) play important roles in tumorigenesis and response to cancer therapeutics. In this study, we evaluated the capacity of the dual-target antibody MEHD7945A that simultaneously targets EGFR and HER3 to modulate radiation response in lung and head and neck cancer models. Antitumor effects of MEHD7945A in combination with radiation were evaluated in cell culture and tumor xenograft models. Mechanisms that may contribute to increased radiation killing by MEHD7945A, including DNA damage and inhibition of EGFR-HER signaling pathways, were analyzed. Immunohistochemical analysis of tumor xenografts was conducted to evaluate the effect of MEHD7945A in combination with radiation on tumor growth and microenvironment. MEHD7945A inhibited basal and radiation-induced EGFR and HER3 activation resulting in the inhibition of tumor cell growth and enhanced radiosensitivity. MEHD7945A was more effective in augmenting radiation response than treatment with individual anti-EGFR or anti-HER3 antibodies. An increase in DNA double-strand breaks associated γ-H2AX was observed in cells receiving combined treatment with MEHD7945A and radiation. Immunohistochemical staining evaluation in human tumor xenografts showed that MEHD7945A combined with radiation significantly reduced the expression of markers of tumor proliferation and tumor vasculature. These findings reveal the capacity of MEHD7945A to augment radiation response in lung and head and neck cancers. The dual EGFR/HER3-targeting action of MEHD7945A merits further investigation and clinical trial evaluation as a radiation sensitizer in cancer therapy., (©2015 American Association for Cancer Research.)

Background: Minimal improvements in treatment or survival of patients with osteosarcoma have been achieved during the last three decades. Especially in the case of incomplete tumor resection, prognosis remains poor. Heavy ion radiotherapy (HIT) and modern anticancer drugs like histone deacetylase inhibitors (HDACi) have shown promising effects in osteosarcoma in vitro. In this study, we tested the effect of HIT and the combination of HIT and the HDACi suberoylanilide hydroxamic acid (SAHA) in a xenograft mouse model., Methods: Osteosarcoma xenografts were established by subcutaneous injection of KHOS-24OS cells and treated with either vehicle (DMSO), SAHA, HIT or HIT and SAHA. Tumor growth was determined and tumor necrosis, proliferation rate, apoptotic rate as well as vessel density were evaluated., Results: Here, we show that the combination of HIT and SAHA induced a significant delay of tumor growth through increased rate of apoptosis, increased expression of p53 and p21(Waf1/Cip1), inhibition of proliferation and angiogenesis compared to tumors treated with HIT only., Conclusion: HIT and in particular the combination of HIT and histone deacetylase inhibition is a promising treatment strategy in OS and may be tested in clinical trials.

Although granulocyte-colony stimulating factor (G-CSF) is commonly used to support recovery from radiation-induced side-effects, the precise effects of G-CSF on colon cancer under radiotherapy remain poorly understood. In the present study, to investigate the effects of tumor growth following radiotherapy and G-CSF administration in a murine xenograft model of colon cancer, female BALB/c mice were injected with cells of a colon carcinoma cell line (CT26) with irradiation and G-CSF, alone or in combination. Mice received 2 Gy of focal radiation daily for 5 days and intraperitoneal injection of G-CSF (100 µg/kg/day) after irradiation for 7 days. Changes in the levels of myeloperoxidase (MPO), vascular endothelial growth factor (VEGF), matrix metalloproteinase type 9 (MMP-9) and CD31 were assessed in the mouse cancer induced by injection of colon cancer cells. We observed that G-CSF increased the number of circulating neutrophils, but facilitated tumor growth. However, G-CSF treatment did not affect radiation-induced cytotoxicity and cell viability in CT26 cells in vitro. Increased levels of myeloperoxidase, a neutrophil marker and those of vascular endothelial growth factor were observed in tumors with G-CSF supplementation. In addition, we found that increased levels of CD31 and matrix metalloproteinase-9 were correlated with the enhanced tumor growth after G-CSF treatment. Therefore, these data suggest that G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions.

The combination of radiotherapy with sunitinib is clinically hampered by rare but severe side effects and varying results with respect to clinical benefit. We studied different scheduling regimes and dose reduction in sunitinib and radiotherapy in preclinical tumor models to improve potential outcome of this combination treatment strategy. The chicken chorioallantoic membrane (CAM) was used as an angiogenesis in vivo model and as a xenograft model with human tumor cells (HT29 colorectal adenocarcinoma, OE19 esophageal adenocarcinoma). Treatment consisted of ionizing radiation (IR) and sunitinib as single therapy or in combination, using different dose-scheduling regimes. Sunitinib potentiated the inhibitory effect of IR (4 Gy) on angiogenesis. In addition, IR (4 Gy) and sunitinib (4 days of 32.5 mg/kg per day) inhibited tumor growth. Ionizing radiation induced tumor cell apoptosis and reduced proliferation, whereas sunitinib decreased tumor angiogenesis and reduced tumor cell proliferation. When IR was applied before sunitinib, this almost completely inhibited tumor growth, whereas concurrent IR was less effective and IR after sunitinib had no additional effect on tumor growth. Moreover, optimal scheduling allowed a 50% dose reduction in sunitinib while maintaining comparable antitumor effects. This study shows that the therapeutic efficacy of combination therapy improves when proper dose-scheduling is applied. More importantly, optimal treatment regimes permit dose reductions in the angiogenesis inhibitor, which will likely reduce the side effects of combination therapy in the clinical setting. Our study provides important leads to optimize combination treatment in the clinical setting., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A viable rim of tumor cells surrounding central necrosis always exists and leads to tumor recurrence after vascular disrupting treatment (VDT). A novel necrosis targeted radiotherapy (NTRT) using iodine-131-labeled hypericin (131I-Hyp) was specifically designed to treat viable tumor rim and improve tumor control after VDT in rabbit models of multifocal VX2 tumors. NTRT was administered 24 hours after VDT. Tumor growth was significantly slowed down by NTRT with a smaller tumor volume and a prolonged tumor doubling time (14.4 vs. 5.7 days), as followed by in vivo magnetic resonance imaging over 12 days. The viable tumor rims were well inhibited in NTRT group compared with single VDT control group, as showed on tumor cross sections at day 12 (1 vs. 3.7 in area). High targetability of 131I-Hyp to tumor necrosis was demonstrated by in vivo SPECT as high uptake in tumor regions lasting over 9 days with 4.26 to 98 times higher radioactivity for necrosis versus the viable tumor and other organs by gamma counting, and with ratios of 7.7-11.7 and 10.5-13.7 for necrosis over peri-tumor tissue by autoradiography and fluorescence microscopy, respectively. In conclusion, NTRT improved the anticancer efficacy of VDT in rabbits with VX2 tumors.

Objectives: To examine the effects of combined treatment with sulfoquinovosylacylpropanediol and X-ray irradiation on the remodeling of the prostate cancer microenvironment, including angiogenic and hypoxic characteristics., Methods: Human prostate cancer cells (DU145 and PC3) were implanted subcutaneously into the right hind legs of athymic nude mice. After the tumor volume reached 100-300mm(3) , 2mg/kg/day sulfoquinovosylacylpropanediol was given intravenously from day0 to day4, and cells were exposed to 4Gy X-ray irradiation on days0 and 3 (for a total of 8Gy). Tumors were fixed and stained for pathological analyses and immunohistochemical evaluations. To analyze vascular normalization, 60mg/kg pimonidazole dissolved in saline was injected intraperitoneally., Results: Combined treatment with sulfoquinovosylacylpropanediol plus X-ray irradiation enhanced growth inhibition in DU145 xenografts. The tumor vessel density in DU145 cells significantly decreased after the combined treatment. Staining for αsmooth muscle actin in vessels was significantly increased. Pimonidazole staining, showing hypoxic lesions, was negative from 72h, but positive at 6 and 24h after the first combined treatment. In contrast, no enhancement of the microenvironment in PC3 xenografts was observed with sulfoquinovosylacylpropanediol plus X-ray irradiation., Conclusion: Sulfoquinovosylacylpropanediol could be a novel potent radiosensitizing agent targeting angiogenesis in prostate cancer., (© 2015 The Japanese Urological Association.)

Microbeam radiation therapy (MRT) is a form of cancer treatment in which a single large dose of radiation is spatially fractionated in-line or grid-like patterns. Preclinical studies have demonstrated that MRT is capable of eliciting high levels of tumor response while sparing normal tissue that is exposed to the same radiation field. Since a large fraction of the MRT-treated tumor is in the dose valley region that is not directly irradiated, tumor response may be driven by radiation bystander effects, which in turn elicit a microvascular response. Differential alterations in hemodynamics between the tumor and normal tissue may explain the therapeutic advantages of MRT. Direct observation of these dynamic responses presents a challenge for conventional ex vivo analysis. Furthermore, knowledge gleaned from in vitro studies of radiation bystander response has not been widely incorporated into in vivo models of tumor radiotherapy, and the biological contribution of the bystander effect within the tumor microenvironment is unknown. In this study, we employed noninvasive, serial observations of the tumor microenvironment to address the question of how tumor vasculature and HIF-1 expression are affected by microbeam radiotherapy. Tumors (approximately 4 mm in diameter) grown in a dorsal window chamber were irradiated in a single fraction using either a single, microplanar beam (300 micron wide swath) or a wide-field setup (whole-window chamber) to a total dose of 50 Gy. The tumors were optically observed daily for seven days postirradiation. Microvascular changes in the tumor and surrounding normal tissue differed greatly between the wide-field and microbeam treatments. We present evidence that these changes may be due to dissimilar spatial and temporal patterns of HIF-1 expression induced through radiation bystander effects.

Radiation therapy can successfully ablate tumors. However, the same ionization process that destroys a cancer can also permanently damage surrounding organs resulting in unwanted clinical morbidity. Therefore, modern radiation therapy attempts to minimize dose to normal tissue to prevent side effects. Still, as tumors and normal tissues intercalate, the risk of normal tissue injury often may prevent tumoricidal doses of radiation therapy to be delivered. This paper will review current outcomes and limitations of radiobiological modifiers that may selectively enhance the radiosensitivity of tumors as well as parallel techniques that may protect normal tissues from radiation injury. Future endeavors based in part upon newly elucidated genetic pathways will be highlighted.

Angiotensin II receptor antagonists inhibit various signaling pathways involved in the regulation of inflammation, apoptosis and angiogenesis. Radiation-induced activation of a proinflammatory cytokine network has been shown to mediate normal tissue injury induced by ionizing radiation in cancer patients, resulting in serious side effects. Hence, not only do angiotensin II receptor antagonists block inflammatory signaling both in cancer cells and in normal cells, but they are also effective in the treatment of cancer by inhibiting tumor progression, vascularization and metastasis. This review addresses the role of angiotensin II inhibitors in cancer therapy, and their potential to increase therapeutical index by protecting normal cells and sensitizing tumor cells to radiotherapy.

Ionizing radiation is a non-specific, but most widely used therapeutic method for cancer treatment. However, a minor fraction of tumor cell population manages to survive after radiation. Radiation efficacy depends on adequate oxygen supply. Rapid growing tumors cause hypoxia that upregulates many pro-survival pathways. At clinical doses, radiation activates inflammatory pathways and causes oxidative stress that plays a positive role during angiogenesis. Selective targeting of signaling mechanisms may radiosensitize tumors.