Monoclonal Vascular Endothelial Growth Factor Research Articles

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

Hemophilic arthropathy can cause recurrent hemarthroses and severe damage to the synovium and articular cartilage. Previous studies have shown that vascular endothelial growth factor (VEGF) plays an essential role in neoangiogenesis. Bevacizumab, a monoclonal VEGF inhibitor, is used clinically to prevent angiogenesis. However, its effects on hemophilic arthropathy are unknown. Using a hemophilic arthropathy rabbit model, we asked: Does an intra-articular injection of bevacizumab (1) inhibit VEGF, (2) decrease signal intensity in dynamic contrast-enhanced MRI (DCE-MRI) as an assessment of capillary permeability and neoangiogenesis, (3) reduce cartilage damage, (4) reduce synovial changes, and (5) affect macroscopic changes during the development of hemophilic arthropathy? Twenty-five male New Zealand rabbits were divided into four groups. Eight knees from four rabbits were used as the control group. We used an established animal model for hemophilic arthropathy in the remaining 21 rabbits. Animals were assigned randomly to three groups with seven rabbits in each group. One group was used to establish mild arthropathy, and the other two were used to establish severe arthropathy. Autologous blood from the rabbits' ears was injected into the right and left knees twice per week for 8 weeks to represent mild arthropathy and for 16 weeks to represent severe arthropathy. In the mild arthropathy group, bevacizumab was injected into the right knee once every 2 weeks. Bevacizumab was injected into the right knee of rabbits in one of the severe arthropathy groups once every 2 weeks for 16 weeks, and intra-articular bevacizumab injections were administered to the right knees of rabbits in the other severe arthropathy group once every 2 weeks after the eighth week. An equal volume of 0.9% saline was injected into the left knee of rabbits in all arthropathy groups. To explore the efficacy of bevacizumab, joint diameters were quantitatively measured, and cartilage and synovial changes were examined. Degeneration of articular cartilage was evaluated with the semiquantitative Osteoarthritis Research Society International grading system. Synovial damage was analyzed with a semiquantitative microscopic scoring system. In addition, we evaluated perfusion and angiogenesis using DCE-MRI (quantitative signal intensity changes). Immunohistochemical testing was used to measure VEGF levels (analyzed by Western blotting). Intra-articular bevacizumab treatment inhibited VEGF in our rabbit model of hemophilic arthropathy. VEGF protein expression levels were lower in the mild arthropathy group that received intra-articular bevacizumab (0.89 ± 0.45) than the mild arthropathy control group (1.41 ± 0.61) (mean difference -0.52 [95% CI -0.898 to -0.143]; p = 0.02). VEGF levels were lower in the severe arthropathy group that received treatment for 16 weeks (0.94 ± 0.27) than in the control knees (1.49 ± 0.36) (mean difference -0.55 [95% CI -0.935 to -0.161]; p = 0.01). In the severe arthropathy group, the Osteoarthritis Research Society International score indicating cartilage damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than in the control group (median 17 [range 13 to 18] versus 18 [range 17 to 20]; difference of medians 1; p = 0.02). Additionally, the scores indicated synovial damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than the control group (median 5 [range 4 to 9] versus 9 [range 8 to 12]; difference of medians 4; p = 0.02). The mean of mean values for signal intensity changes was higher in the nontreated severe groups than in the group of healthy knees. The signal intensity changes were higher in the severe arthropathy control groups (Groups BC and CC) (median 311.6 [range 301.4 to 361.2] and 315.1 [range 269.7 to 460.4]) than in the mild arthropathy control group (Group AC) (median 234.1 [range 212.5 to 304.2]; difference of medians 77.5 and 81, respectively; p = 0.02 and p = 0.04, respectively). In the severe arthropathy group, discoloration caused by hemosiderin deposition in the cartilage and synovium was more pronounced than in the mild arthropathy group. In the severe arthropathy group treated with intra-articular bevacizumab, joint diameters were smaller than in the control group (Group BT median 12.7 mm [range 12.3 to 14.0] versus Group BC median 14.0 mm [range 13.1 to 14.5]; difference of medians 1.3 mm; p = 0.02). Hemarthrosis damages the synovial tissues and cartilage in the knees of rabbits, regardless of whether they are treated with intra-articular bevacizumab. However, intra-articular injection of bevacizumab may reduce cartilage and synovial damage in rabbits when treatment is initiated early during the development of hemophilic arthropathy. If the findings in this study are replicated in larger-animal models that consider the limitations of our work, then a trial in humans might be appropriate to ascertain whether intra-articular injection of bevacizumab could reduce cartilage damage and synovial changes in patients with hemophilia whose hemarthroses cannot otherwise be controlled.

Targeting HIF-2α for the Treatment of CML By Affecting LSCs Metabolism and the Vascular Microenvironment

Although the advent of tyrosine kinase inhibitors (TKI) drugs significantly increased the long-term survival of chronic myeloid leukemia (CML), residual LSCs can still lead to drug resistance and disease recurrence. As LSCs in CML rely on hypoxia-inducible factors (HIF) to maintain their own energy metabolism in the hypoxic environment of bone marrow, HIF-2α has not been systematically explored in CML. Here, we explored how HIF-2α participated in drug resistance and provided a potential new clinical strategy for CML. We first investigated the expression of HIF in the database and found the overexpression of HIF-2α in the bone marrow of CML patients compared with normal subjects, while there was no difference in HIF-1α and HIF-3α (Fig. 1A-B). We then collected bone marrow samples from normal subjects and CML patients. We found that compared with normal hematopoietic stem cells (Lin-CD90+CD34+CD38-), CML LSCs (Lin-CD90+CD34+CD38-) had higher levels of HIF-related proteins than common leukemia cells (Fig. 1C). To further explore the role of HIF-2α in the pathogenesis of CML, we constructed HIF-2α conditional knockout mice through transfecting the plasmid of Cre-BCR-ABL-GFP with transposase and Ctrl-BCR-ABL-GFP without transposition to HSPCs (Fig. 2A). After the first round of leukemia transplantation, the onset of CML was delayed in the HIF-2α knockout mice and the median survival time was prolonged from 31d in the Ctrl group to 60d (Fig. 2B). Next, we harvested fully onset CML mice for the secondary transplantation and found the median survival time extended from 46d to 117d in the HIF-2α knockout group (Fig. 2C). Then we investigate the biological function of HIF-2α in CML LSCs. We performed the clone formation assay on bone marrow cells of the first round of onset CML mice and found that HIF-2α knockout reduced the colony-forming ability of CML cells (Fig. 3A). To explore the tumorigenic ability of HIF-2α knockout, limiting dilution assay (LDA) was performed and found that the LSCs ratio of CML decreased by 30 times after HIF-2α knockout, from 1/76960 to 1/2237970 (Figure. 3B). Meanwhile, we explored the effect of HIF-2α knockout on the chemosensitivity in CML. TKI treatment combined with HIF-2α knockout can significantly improve the efficacy of TKI and extend the mouse survival time (Figure. 3C). To explore the specific mechanism by which HIF2A affects LSCs, we firstly investigate the effect of HIF-2α on LSCs metabolism. We detected metabolism-related indexes of LSCs in the CML model and found that the glycolysis ability of LSCs was weakened after HIF-2α knockout (Fig. 4A). At the same time, its oxidative phosphorylation pathway and reactive oxygen species (ROS) were enhanced (Fig. 4B-C) which may be an important cause of LSCs apoptosis. As HIF-2α can directly promote the transcription of pro-angiogenic factors, we detected the content of vascular endothelial growth factor (VEGF) α in the supernatant of mice bone marrow and found that it was significantly increased after the onset of CML but decreased after HIF-2α knockout (Fig. 5A). Fluorescent staining of bone marrow sections revealed that the density of blood vessels in bone marrow increased, whether in the intima (Fig. 5B) after the onset of CML. Next, we treated CML mice with VEGF Monoclonal antibody and found that it alone could prolong the survival time. However, the VEGF Monoclonal antibody did not affect HIF-2α knockout CML mice (Fig. 5C). These results suggest that HIF-2α is involved in bone marrow vascular remodelling after the onset of CML. To investigate the functional effect of HIF-2α in human CML, the CDX CML mouse model was made with CML cell lines (K562 and MEG-01) to observe the tumorigenesis of CML in nude mice, and they were treated with TKI. We found that HIF-2α knockout could delay the onset of CML and improve the therapeutic effect of TKI (Fig. 6A). To better apply the effect of HIF-2α on CML chemosensitivity to the clinic, we explored the effect of inhibitors of HIF, PT2399, on CML chemosensitivity. PT2399 can significantly increase the chemosensitivity of CML cell lines to TKIs and prolong the survival curve of CML mice treated with TKIs (Fig. 6B). In conclusion, HIF-2α knockout could inhibit the function of LSCs by affecting their metabolic pattern and vascular microenvironment in CML. Therefore, targeting HIF-2α may become a new strategy, and its specific inhibitor PT2399 may be a candidate drug for clinical application in CML treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase II Study of Ramucirumab Plus Irinotecan Combination Therapy as Second-Line Treatment in Patients with Advanced Gastric Cancer: HGCSG1603

BackgroundRamucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer.Materials and MethodsPatients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m2 combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug.ResultsThirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%–41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed.ConclusionAlthough the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer.

P-97 Updated results of HGCSG1603: A phase 2 trial of ramucirumab plus irinotecan combination therapy as second-line treatment for patients with advanced gastric cancer

Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. We previously reported the efficacy and safety of RAM plus irinotecan (IRI) combination therapy in the second-line treatment for advanced gastric cancer (AGC). This is an updated analysis of the HGCSG1603 trial.

Results of a phase II trial of ramucirumab plus irinotecan as second-line treatment for patients with advanced gastric cancer (HGCSG 1603).

217 Background: Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. The RAINBOW trial showed RAM plus paclitaxel (PTX) increased overall survival (OS) compared with PTX alone for advanced gastric cancer (AGC) in second-line treatment. WJOG 4007 trial demonstrated equivalent efficacy between irinotecan (IRI) and PTX. We conducted this trial to examine the efficacy and safety of RAM plus IRI combination therapy in the second-line treatment for AGC. Methods: This non-randomized, single arm, phase 2 trial was carried out at 22 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM 8 mg/kg and IRI 150 mg/m2 combination therapy administered every two weeks were continued until progression or emergence of adverse events requiring discontinuation. The primary endpoint was progression-free survival (PFS) rate at six-month, the target was set as 16% with an expected threshold of 39%. A total of 35 cases are planned for registration. The secondary endpoints were OS, PFS, response rate (RR) and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011180029. Results: Between Jan 2018 and Sept 2019, 35 patients were enrolled. Median age was 70 (range, 47-80); female/male were 10/25; ECOG PS 0/1, 22/13. PFS rate at six months was 26.5% (95%C.I., 13.2-41.8%, p = 0.1353). Median PFS and OS were 4.2 (95%C.I., 2.5-5.4 months) and 9.6 months (95%C.I., 6.5-16.6 months), respectively. RR was 26% and disease control rate was 85%. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (51%), leucopenia (43%), anemia (20%), anorexia (14%), febrile neutropenia (11%), diarrhea (9%), hypertension (9%), proteinuria (9%), hypokalemia (9%), hypoalbuminemia (9%), thrombocytopenia (6%), and hyponatremia (6%). No death and new safety signals with a causal relation to study treatment were observed. Conclusions: Although the primary endpoint was not achieved statistically, the results are clinically encouraging, especially take into account that more elderly patients enrolled in this trial. The combination of RAM plus IRI has anti-cancer activity and manageable safety profile in second-line treatment for patients with AGC. Clinical trial information: jRCTs011180029.

The exploration of new therapeutic targets for HPV-negative head and neck squamous cell cancer through the construction of a ceRNA network and immune microenvironment analysis.

Previous studies have shown that human papillomavirus (HPV)-negative patients with head and neck squamous cell cancer (HNSCC) suffer from an unsatisfactory prognosis. Long noncoding RNAs (lncRNAs) have been verified to participate in many biological processes, including regulating gene expression as competing endogenous RNAs (ceRNAs), while few studies focused the ceRNA network regulation mechanism in patients with HPV-negative HNSCC tumor. Meanwhile, the immune microenvironment may be critical in the development and prognosis of HPV-negative tumors. Our study aimed to further investigate the pathogenesis and potential biomarkers for the diagnosis, therapy and prognosis of HPV-negative HNSCC through a ceRNA network. Comprehensively analyzing the sequencing data of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in The Cancer Genome Atlas HNSCC dataset, we constructed a differentially expressed ceRNA network containing 131 lncRNAs, 35 miRNAs and 162 mRNAs. Then, survival analysis in the network was cited to explore the prognostic biomarkers. Eight mRNAs, nine lncRNAs, and one miRNA were identified to be associated with prognosis. Neuropilin (NRP) binding function, retinoid X receptor (RXR) binding, and the vascular endothelial growth factor (VEGF) signaling pathway were associated with the enrichment analysis, and they also related to the immune microenvironment. Combined with the analysis of the immune microenvironment differences, we obtained new targeted therapies using an RXR agonist, or a combination of the VEGF monoclonal antibody and an NRP antagonist, which may provide a promising future for HPV-negative HNSCC patients.

A multicenter, open label, randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer: TORG1833.

TPS9120 Background: Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways are shown to be interrelated in several preclinical studies. Furthermore, recent clinical studies have shown the adding effect of an anti VEGF monoclonal antibody with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Thus, osimertinib plus ramucirumab would be the promising candidate for the new standard treatment in EGFR mutation positive NSCLC. Methods: This study is an investigator initiated trial. Previously untreated EGFR mutation positive advanced non squamous NSCLC patients aged 20 years or older with a performance status of 0 or 1 are randomized at a 1:1 ratio to receive osimertinib (80mg) every day either without or with ramucirumab (10mg/kg) every 2 weeks until evidence of disease progression or development of unacceptable toxicity. The primary endpoint of the study is progression free survival (PFS) assessed by the central image reviewer. Secondly endpoints include PFS (assessed by an attending physician), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), safety and toxicity profile. Stratification factors are gender and the type of EGFR mutation (exon 19 deletion, Leu858Arg point mutation in exon 21). We determined that, with a sample size of 120 patients (60 in each arm), the trial will have 80% power to show a hazard ratio for disease progression or death of 0.667 at a one-sided alpha level of 0.2 (as calculated on the basis of 80 such events) for comparison between the two arms with 1.5-year accrual and 2-year follow-up periods. Study enrollment began in November 2018 and is continued for 3.5 years among 20 sites of Thoracic Oncology Research Group (TORG). Seven patients were enrolled at time of submission. Clinical trial information: 184146.

Progress of Bevacizumab in Malignant Pleural Effusion Caused by Non-small Cell Lung Cancer

肺癌是全球范围内发病率最高的恶性肿瘤，晚期肺癌所致的恶性胸腔积液（malignant pleural effusion, MPE）严重影响患者的生活质量和预后。MPE的治疗手段包括胸腔穿刺术、胸膜固定术、胸腔埋管引流、胸腔内灌注治疗等。血管内皮生长因子（vascular endothelial growth factor, VEGF）及其受体是一组影响血管生成的重要配体和受体，是控制血管生成的主要因素，在MPE的形成中发挥重要作用。贝伐珠单抗是一种重组的人源化VEGF单克隆抗体，可与内源性VEGF竞争性结合VEGF受体，抑制新血管生成以及降低血管通透性，阻碍胸腔积液形成，延缓肿瘤发展进程。本综述旨在讨论贝伐珠单抗治疗非小细胞肺癌所致恶性胸腔积液的研究进展，探讨贝伐珠单抗临床应用的方法、疗效、安全性以及未来的发展方向。

HGCSG 1603: Phase II study of ramucirumab and irinotecan combination therapy as second-line treatment in patients with metastatic or advanced gastric cancer.

TPS183 Background: As second-line chemotherapy for gastric cancer, a survival benefit has been shown in several clinical trials. Irinotecan and taxanes are recommended as second-line regimen. However, therapeutic outcomes have remained unsatisfactory and more effective treatment are expected. Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody that prevents ligand binding of VEGF-A, VEGF-C, and VEGF-D and the receptor-mediated pathway activation in endothelial cells, subsequently inhibiting neovascularization. In the REGARD study, RAM monotherapy for previously treated advanced gastric or gastro-esophageal junction adenocarcinoma improved median overall survival (mOS) compared with placebo. Moreover, in the RAINBOW study, RAM plus paclitaxel (PTX) versus placebo plus PTX, mOS showed significantly longer in RAM plus PTX group than in placebo plus PTX group. In contrast, there are no data on the efficacy of RAM and irinotecan in the second-line treatment for gastric cancer. The WJOG 4007 study demonstrated an equivalent efficacy between irinotecan and PTX. In this study, we propose to examine the efficacy of RAM plus irinotecan. Methods: This study is carried out as a multicenter, non-randomized, single arm, prospective, phase II study. The patients with metastatic or advanced gastric cancer that is refractory or intolerance to primary chemotherapy are eligible for this study. RAM and irinotecan combination therapy is administered every two weeks, which is continued until progression or emergence of adverse events requiring discontinuation. The primary endpoint is progression-free survival rate at six months, and the secondary endpoints are OS, progression-free survival, response rate, safety, and dose intensity for each drug. A total of 35 cases areplanned for registration. This study is registered with the University Hospital Medical Information Network. Clinical trial information: UMIN000030372.

Modulation of vascular endothelial growth factor and mitogen-activated protein kinase-related pathway involved in extracorporeal shockwave therapy accelerate diabetic wound healing.

Extracorporeal shockwave therapy (ESWT) has a significant positive effect to accelerate chronic wound healing. This study investigated whether the vascular endothelial growth factor (VEGF)-related pathway has involved in ESWT enhancement of diabetic wound healing. A dorsal skin defect (area, 6 × 5 cm) in a streptozotocin-induced diabetes rodent model was used. Thirty-two male Wistar rats were divided into four groups. Group I consisted of nondiabetic control; group II, diabetic control without treatment; group III, diabetic rats received ESWT; and group IV, rats received Avastin (a VEGF monoclonal antibody) on day 0 (post-wounding immediately) to day 7 and ESWT on day 3 and day 7. The wound healing was assessed clinically. The VEGF, endothelial nitric oxide synthase (eNOS), and Ki-67 were analyzed with immunohistochemical staining. The mRNA expression of mitogen-activated protein kinase-related genes was measured by real-time quantitative real-time polymerase chain reaction. The results revealed wound size was significantly reduced in the ESWT-treated rats as compared to the diabetic control (p < 0.01). The positive effect of ESWT-increasing wound healing was significantly suppressed in pretreatment of the Avastin group. Histological findings revealed significant increase in neo-vessels in the ESWT group as compared to the control. In immunohistochemical stain, significant increases in VEGF, eNOS, and Ki-67 expressions were noted in the ESWT group as compared to that in controls. However, Avastin suppressed the shockwave effect and down-regulation of VEGF, eNOS, and Ki-67 expressions in the Avastin-ESWT group as compared to that in the ESWT alone group. We found that highly mRNA expression of Kras, Raf1, Mek1, Jnkk, Jnk, and Jun at early stage in the ESWT group, as compared to the diabetic control. These evidences indicated treatment with multiple sessions of ESWT significantly enhanced diabetic wound healing associated with increased neovascularization and tissue regeneration. The bio-mechanism of ESWT-enhanced wound healing is correlated with VEGF and mitogen-activated protein kinase-mediated pathway.

Beyond Bevacizumab: An Outlook to New Anti-Angiogenics for the Treatment of Ovarian Cancer.

In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. Nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease, two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication. Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated.

Currently Used Biologic Agents in the Management of Behcet's Syndrome.

Behcet's s yndrome (BS) is a multisystem vasculitis with frequent mucocutaneous, joint, eye and visceral organ involvement. From early 2000s, biologic drugs have been increasingly used in the management of BS, enabling rapid and complete remission in most cases with critical organ involvement. Despite the current experience with steroids and traditional immunosuppressives, biologics are exceptionally promising for treatment of resistant cases. Among the biologics used in BS, TNF-alpha antagonists are the oldest and their efficacy has been proven in recalcitrant ocular, vascular, gastrointestinal and neurologic involvements. These drugs have significantly reduced morbidity and mortality in BS and they have an acceptable safety profile. Tocilizumab, an IL6 receptor antibody, has been shown to be effective in BS patients with neurologic involvement and amyloidosis, and IL1β antagonists such as anakinra, canakinumab, gevokizumab were effective in the management of ocular involvement. Studies investigating the efficacy of daclizumab, IL2 receptor antibody, and secukinumab, IL17 monoclonal antibody, in the management of BS with eye involvement failed to demonstrate significant clinical improvement and both studies were halted. A monoclonal vascular endothelial growth factor antagonist, bevacizumab, was shown to be effective in BS-related macular edema. Alemtuzumab and ustekinumab are among other biologics which were effective in controlling disease symptoms. In this review, we discuss the efficacy and safety of various recently developed biologic agents targeting different pathways involved in the pathogenesis of BS.

The future of antiangiogenic treatment in glioblastoma.

A major recent clinical research focus for glioblastoma has been the therapeutic evaluation of antiangiogenic agents. Several vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and a soluble decoy VEGF receptor have demonstrated nominal benefit among patients. In contrast, bevacizumab, a humanized VEGF monoclonal antibody, exhibits evidence of apparent antitumor benefit, although these data remain controversial. In this review, we summarize how results of clinical trials evaluating bevacizumab to date influence the future of this therapeutic for recurrent and newly diagnosed glioblastoma patients. Recently reported, placebo-controlled phase III studies demonstrate a meaningful progression-free survival increment, but no overall survival benefit among newly diagnosed patients treated with bevacizumab. For unclear reasons, quality-of-life surveys from these studies revealed divergent results. Among recurrent patients, uncontrolled trials demonstrate improved overall radiographic response and progression-free survival rates, although the impact of bevacizumab on overall survival remains to be defined by an ongoing randomized phase III trial. The role of bevacizumab for glioblastoma remains uncertain but will likely be strongly influenced by results of a randomized phase III study among recurrent patients as well as further investigation of gene expression biomarker profiles to identify newly diagnosed patients more likely to derive survival benefit.

Vascular Endothelial Growth Factor (VEGF) inhibitors as a novel strategy in the treatment of Arterio Venous Malformations (AVMs): time for a clinical study

The current standard treatment of AVMs is based around embolisation and surgery, used individually or in combination. The outcomes are often suboptimal with radical surgery resulting in significant morbidity and less radical surgery often leading to recurrence. Pathological processes associated with AVM include angiogenesis and neogenesis. At the molecular level, these processes are regulated by several growth factors of which VEGF and its tyrosine kinase receptors (VEGFR) play a dominant role. VEGFR expression and its intracellular signaling are increased in experimental and clinical AVM. VEGF inhibitors are increasingly used as anti-angiogenesis agents in the treatment of certain cancers. Numerous clinical studies have assessed therapeutic effects of bevacuzimab, a VEGF monoclonal antibody, in patients with Hereditary Hemorrhagic Telangiectasia. Results have been promising with most studies showing reduced bleeding and lesion regression with systemic and topical bevacuzimab. Oral presentations for BAOMS Annual Scientific Meeting 2-4 July 2014, Edinburgh International Conference Centre, ScotlandBritish Journal of Oral and Maxillofacial SurgeryVol. 52Issue 8Preview Full-Text PDF

Increased Expression of Vascular Endothelial Growth Factor Attenuates Contusion Necrosis without Influencing Contusion Edema after Traumatic Brain Injury in Rats

To clarify the role of vascular endothelial growth factor (VEGF) in the formation of contusion edema and necrosis after traumatic brain injury, we examined the time course of changes in the VEGF expression (enzyme-linked immunosorbent assay), cerebrovascular permeability (extravasation of Evans blue), and water content (dry-wet weight method) of the contused brain tissue in a cortical impact injury model using rats. In addition, we tested the effects of administration of bevacizumab (VEGF monoclonal antibody) on changes in the cerebrovascular permeability and water content of the contused brain tissue, as well as the neurological deficits (rota rod test) and volume of contusion necrosis. Increased VEGF expression was maximal at 72 h after injury (p<0.003). Increases in cerebrovascular permeability and water content, however, became maximal within 24 h (p<0.001) after injury (p<0.01), respectively. Administration of bevacizumab did not influence these changes in cerebrovascular permeability and water content, but led to a significant rise in the neurological deficits at 72 h-14 days (p<0.05 or 0.01) and the volume of contusion necrosis at 21 days (p<0.001) after injury. These findings suggest that increased expression of VEGF after injury does not contribute to the formation of contusion edema, but attenuates the formation of contusion necrosis. This is probably because of an increased angiogenesis and improved microcirculation in the areas surrounding the core of contusion.

Clinicopathological Investigation of Vascular Endothelial Growth Factor and von Hippel–Lindau Gene-Related Protein Expression in Immunohistochemically Negative Pituitary Adenoma – Possible Involvement in Tumor Aggressiveness

Objectives. Immunohistochemically negative pituitary adenoma is known to be relatively indolent, but a few aggressive and highly vascular cases have been reported, which sometimes show high expression of vascular endothelial growth factor (VEGF). Methods. The present study investigated the relationship between high expression of VEGF and the clinical character of pituitary adenomas in 30 cases of immunohistochemically negative pituitary adenomas using immunohistochemical staining with monoclonal VEGF antibody and related upstream factors, including von Hippel–Lindau gene-related protein (pVHL). Correlations between the histological findings and the clinical characteristics were investigated. Results. Immunohistochemical staining using VEGF antibody showed high expression in 7 (23.3%) and low expression in 23 (76.7%) cases, and pVHL staining showed high expression in 24 (80%) and low expression in 6 (20%) cases. The pVHL low expression group showed significantly higher expression of VEGF (p = 0.005019), and significantly higher recurrence or regrowth rate (p = 0.04535) than the pVHL high expression group, whereas Ki-67 labeling index of >3% also showed significant correlation with recurrence or regrowth rate (p = 0.01745). However, there was no significant correlation between pVHL staining and Ki-67 labeling index (p = 0.49978). Conclusion. Low expression of pVHL with high expression of VEGF may be involved in the unusual aggressive clinical course in some pituitary adenomas.

Role of Endogenous Vascular Endothelial Growth Factor in Endothelium-Dependent Vasodilation in Humans

Angiogenesis inhibitors have remarkably improved the outcome of patients with several types of cancer. Hypertension is the most reported side effect of angiogenesis inhibitors interfering with vascular endothelial growth factor signaling. In this study, we test the hypothesis that circulating vascular endothelial growth factor at physiological concentrations is essential to preserve normal endothelial control of vasomotor tone. In 7 healthy male volunteers, infusion of bevacizumab (monoclonal vascular endothelial growth factor antibody) into the brachial artery for 15 minutes (144 μg/dL forearm volume per minute) did not affect forearm vasodilator tone as measured with venous occlusion strain gauge plethysmography. In a separate group of 12 male volunteers, a similar bevacizumab infusion reduced the vasodilator response to 2 dosages of acetylcholine from (mean ± SE) 440 ± 157% and 926 ± 252% to 169 ± 40% and 612 ± 154% (P<0.05). Finally, in a third group of 12 volunteers, bevacizumab did not alter the percentage increase in forearm blood flow during infusion of sodium nitroprusside at dosages equipotent to acetylcholine. Bevacizumab acutely and specifically reduced endothelium-mediated vasodilation at local concentrations that resemble plasma concentrations after systemic exposure to bevacizumab. This observation suggests a physiological role for vascular endothelial growth factor in maintaining normal endothelial control of vasomotor tone. The role of the endothelium in the mechanism of bevacizumab-induced hypertension deserves further exploration.

Effective Control of Recalcitrant Pruritus by Bevacizumab: A Possible Role for Vascular Endothelial Growth Factor in Chronic Itch?

Prurigo is a difficult to treat condition characterized by severe pruritus presenting with chronic secondary scratch lesions. We report here a dramatic improvement in pruritus in a patient with prurigo simplex who was being treated with bevacizumab, a monoclonal vascular endothelial growth factor (VEGF) antibody. On the basis of the increased VEGF expression measured in the skin of this patient, serum levels of VEGF were subsequently analysed in 27 consecutive patients with prurigo and 19 healthy controls. VEGF levels were significantly increased in the serum of patients with prurigo. Moreover, VEGF concentrations correlated with physician-assessed disease activity. Based on these observations, we speculate that VEGF is involved in the pathophysiology of prurigo.

Bevacizumab combined with low-dose S-1 as maintenance therapy with a long progression-free survival in an elderly patient with heavily pre-treated advanced gastric cancer: A case report

Gastric cancer is known to have a high incidence in several countries around the world, while the treatment of advanced gastric cancer remains a challenge. Recent studies have shown that the antibody bevacizumab, a monoclonal vascular endothelial growth factor antibody, is effective in several solid tumors, while experience regarding its effect on gastric cancer remains limited. An 84-year-old patient with advanced gastric remnant cancer with liver and retroperitoneal lymph node metastasis treated in our hospital benefitted from the use of bevacizumab. Since previous treatment with multiple chemotherapeutic agents resulted in progressive disease (PD), a combined treatment with bevacizumab (intravenously) and low-dose S-1 (orally) was administered. With this individualized treatment, the patient exhibited stable disease (SD) and therapy was maintained for a long period of time as maintenance therapy, with a progression-free survival of ∼25 months prior to PD. The serum tumor marker cancer antigen (CA) 199 decreased from 508.7 to 188.1 ng/ml. No severe side-effects of bevacizumab were observed, with the exception of controlled grade I bleeding gums due to the long-term use of bevacizumab. Although no large-scale clinical trials have been conducted to evaluate the role of bevacizumab in maintenance therapy and second- or even third-line treatment of advanced gastric cancer, we showed that bevacizumab combined with S-1 was effective and well-tolerated by this patient, suggesting that it be considered a viable option for elderly patients with advanced gastric cancer as maintenance therapy and that it provide a novel treatment for advanced gastric cancer. However, additional clinical trials are required to evaluate the exact effects of long-term bevacizumab treatment on patients with advanced gastric cancer.

Abstract 4374: Combination of Bevacizumab and oncolytic virus hRr3 in an experimentalmodel of pancreatic carcinoma

Abstract Aim: Proangiogenic growth factors stimulate endothelial cells in nearby vessels to proliferate and migrate into the tumor. Vascular endothelial growth factor (VEGF) is an endothelial cell specific growth factor that is known to facilitate angiogenesis. Excess levels of VEGF are linked with poor prognosis. The effect oncolytic herpes viruses (OHSV) on VEGF A are not accurately determined. Nevertheless; limited number of studies on wild type herpes simplex type 1 (HSV1) have been shown to enhance VEGF A. The aim of the present study was to evaluate the effect of combination of OHSV hrR3 with a novel monoclonal VEGF A antibody Bevacizumab in a xenograft experimental model. Materials and Methods: Several cell were tested for expression of VEGFA. BxPC3 cell line had the highest and MIA PaCa-2 had the lowest expression of VEGFA among the other cell lines. 20 BALB-C nu/nu mice were divided into 4 experimental groups. All animals were implanted 5 mm diameter of BxPC-3 tumor xenograft on each side of their flank. After 2 week of observation; Control group (n=5) received no therapy; oncolytic viral therapy group (OVT) (n=5) received 5x106 pfu hrR3 injected intratumorally per week for two weeks; Bevacizumab treated group (BVT) (n=5) received 5mg/kg Bevacizumab intraperitoneally two times a week for 3 weeks; Combination therapy group (CT) (n=5) received both Bevacizumab and hRr3 virus injected intratumorally the same periods as other groups. The same was performed for MIA PaCa-2 cell lines as In order to confirm our results in a low expression cell line. Tumor diameters were evaluated every 3 days by caliper for 8 weeks. Tumor specimen was collected for conventional hematoxylin eosin stain, immunohistochemistochistry for VEGFA, Thrombospondin1, CD 31, HSV type 1 antigen and TUNEL. In MIA PaCa-2 cell line; VEGFA antigen distribution was especially evaluated on day 1, 3, 5, 7, 14 following hRr3 treatment. Results: The BxPC3 tumor volumes of the animals in the combination therapy were significantly lower than the other groups (p&amp;lt;0.05). Nevertheless; we were unable to show a statistically significant difference among OVT and BVT groups in terms of tumor volume. Histopathologically the CT and the OVT group had degenerated cells and low cellular density and expressed HSV antigen. Interestingly we found highest VEGFA expression in OVT group when compared to other groups (p&amp;lt;0.001). Tumor response was highest in combination group in the MIA PaCa-2 tumors as well (p&amp;lt;0.05). In Mia PACA2 tumors VEGFA expression was increasingly expressed starting from day 5 (p&amp;lt;0.05). Conclusion: Oncolytic virus seems to induce the VEGFA and this may be the proangiogenic stimulus in OHSV to induce angiogenesis. If a combination therapy towards blocking the VEGF A can be administered with OHSV; it may enhance the effect of the virus. Combination of OHSV with an antiangiogenic agent such as Bevacizumab seems to be a safe and effective treatment modality. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4374. doi:1538-7445.AM2012-4374