兔眼球后Tenon囊下灌注Bevacizumab的眼内通透性研究

目的：比较兔眼球后Tenon囊下灌注和玻璃体腔注射bevacizumab后玻璃体和血清中的浓度,并观察bevacizumab视网膜荧光显影,探讨bevacizumab球后Tenon囊下灌注的眼内通透性和眼外给药途径的可行性。

方法：实验用健康成年新西兰兔20只,随机分为A组和B组,A组均单眼接受单次玻璃体腔注射1.25mg bevacizumab(1.25mg/0.05mL),B组均单眼单次Tenon囊下灌注5mg bevacizumab(5mg/0.2mL)。1、3d后抽取玻璃体和血液,使用双抗体夹心Elisa检测玻璃体和血清中bevacizumab药物浓度,比较两组中玻璃体和血清内bevacizumab浓度差异,并通过激光共聚焦观察视网膜免疫荧光。

结果：给药1d后,A组和B组玻璃体腔内bevacizumab药物浓度分别为254.40±13.65、1.60±0.32μg/mL。A组和B组血清内bevacizumab药物浓度分别为0.55±0.15、0.63±0.05μg/mL,两组血清bevacizumab浓度比较差异无统计学意义(t=1.168,P=0.277)。给药3d后,A组和B组玻璃体腔内bevacizumab药物浓度分别为236.80±8.70、1.40±0.23μg/mL,A组和B组血清内bevacizumab药物浓度分别为0.66±0.17、0.64±0.14μg/mL,两组血清内bevacizumab浓度比较差异无统计学意义(t=0.207,P=0.841),两种给药方式视网膜各层荧光分布均能明显显现。

结论：给药1、3d后玻璃体腔注药组在玻璃体腔内bevacizumab药物浓度要明显高于Tenon囊下灌注组,玻璃体腔内注射是较为有效的给药途径,而球后Tenon囊下灌注也能使bevacizumab进入玻璃体腔而且达到完全抑制VEGF活动所需的浓度(>500ng/mL),并能至少持续3d以上,两种给药方法在血清中均能检测到较高浓度的bevacizumab,且两者浓度差异无统计学意义(P>0.05),两种给药方式视网膜各层荧光分布均能明显显现,提示两种给药方式药物均能作用于视网膜各层。     

The effect of intravitreal bevacizumab and transpupillary thermotherapy on choroidal metastases and literature review

Aims:

To represent the effects of transpupillary thermotherapy (TTT) and intravitreal bevacizumab on choroidal metastases and review the literature.

Settings and Design:

A retrospective, interventional, noncomparative case series.

Materials and Methods:

A retrospective, interventional, noncomparative case series of five eyes in three patients with choroidal metastases was conducted. Fundus findings of choroidal metastases were divided into two types: Solitary or diffuse type. The size of the tumor was termed small (<10 mm diameter), medium (10–15 mm diameter) or large (>15 mm diameter). All eyes received one session of TTT followed by 3 weekly intravitreal bevacizumab injections as an adjuvant therapy. The parameters of treatment for TTT were 1.2–3 mm spot size, 150–300 mW, 60 s with the whole lesion covered confluently. The changes in preoperative and postoperative best-corrected visual acuity (BCVA) were recorded. Serial color fundus photography and optical coherent tomography were performed to measure the treatment efficacy.

Results:

All eight choroidal metastases were solitary type. The size of six tumors was small, the size of one tumor was medium, and the size of one tumor was large. All five eyes of the three patients had improvement of BCVA after treatment. Fundus photos revealed tumor shrinkage and the mean shrinkage percentage was 61.27 ± 21.71%. Optical coherence tomography revealed complete resolution of serous retinal detachment. There was no recurrence after 6 months follow-up.

Conclusions:

TTT combined with intravitreal bevacizumab injections brought about beneficial effects in reducing tumor size and improving vision in all five eyes of the three patients. Despite the retrospective nature of our study, the absence of control group and the size limitation that, of course, limit the statistical power, TTT combined with intravitreal bevacizumab seems to be efficient in providing another cost-reducing and time-saving treatment option for patients with choroidal metastases. The antineoplastic properties of bevacizumab make it a viable adjunctive therapy. Studies with more cases and a longer follow-up period are warranted.     

黑色素瘤治疗药物的研究进展

黑色素瘤是临床上常见的皮肤恶性肿瘤,且发病率呈逐年增加的趋势。该病恶性程度高,易发生转移。全球新批准并上市的治疗黑色素瘤的治疗药物有威罗菲尼、达拉菲尼、曲美替尼、易普利姆玛、nivolumab以及pembrolizumab,处于研发后期的黑色素瘤治疗药物有cobimetinib、binimetinib、talimogene laherparepvec、贝伐单抗、seviprotimut-L、NGc GM3/VSSP以及c-Kit抑制剂甲磺酸伊马替尼等。对近年来上市和处于研发后期的黑色素瘤的治疗药物进行了详细介绍,同时对其未来发展方向进行了展望,以期为黑色素瘤治疗药物的研发指明方向,给黑色素瘤患者带来希望。     

Biological activity of bevacizumab,a humanized anti-VEGF antibody <Emphasis Type="Italic">in vitro</Emphasis>

Bevacizumab (Avastin, Genentech) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), a critical angiogenic factor involved in both physiological and pathological conditions. It has been recently approved by the US FDA as a first-line therapy for widespread metastatic colorectal cancer. This report is a detailed biological characterization of bevacizumab in a variety of in vitro models. It is shown that bevacizumab potently neutralizes VEGF and blocks its signal transduction through both the VEGFR-1 and VEGFR-2 receptors, as demonstrated by the inhibition of VEGF-induced cell proliferation, survival, permeability, nitric oxide production, as well as migration and tissue factor production. Although bevacizumab retains the ability to bind to human Fc receptors and complement protein C1q, it does not demonstrate cell or complement-mediated cytotoxicity in either VEGF producing or targeting cells. Thus the mechanism of anti-tumor activity of bevacizumab is most likely due to its anti-angiogenesis effect through binding and neutralization of secreted VEGF.     

Bevacizumab and glioblastoma: Scientific review,newly reported updates,and ongoing controversies

Anti‐angiogenic therapy for glioblastoma has been in the spotlight for several years, as researchers and clinicians strive to find agents with meaningful efficacy against glioblastoma. Bevacizumab in particular, in the second half of the last decade, became the most significant breakthrough in anti‐glioblastoma therapy since temozolomide. Optimism for bevacizumab has been somewhat challenged given recent clinical trials that have raised questions regarding its clinical effectiveness, the optimal timing of its use and the validity of endpoints, among other issues. In addition, uncertainty has recently arisen regarding the effects of bevacizumab on quality of life and neurocognitive function, two key clinical endpoints of unquestionable significance among glioblastoma patients. In this review, we highlight these controversies and other recent work related to bevacizumab for glioblastoma. Cancer 2015;121:997–1007. © 2014 American Cancer Society.     

Dynamic susceptibility contrast MRI measures of relative cerebral blood volume as a prognostic marker for overall survival in recurrent glioblastoma: results from the ACRIN 6677/RTOG 0625 multicenter trial

Background

The study goal was to determine whether changes in relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI are predictive of overall survival (OS) in patients with recurrent glioblastoma multiforme (GBM) when measured 2, 8, and 16 weeks after treatment initiation.

Methods

Patients with recurrent GBM (37/123) enrolled in ACRIN 6677/RTOG 0625, a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide, consented to DSC-MRI plus conventional MRI, 21 with DSC-MRI at baseline and at least 1 postbaseline scan. Contrast-enhancing regions of interest were determined semi-automatically using pre- and postcontrast T1-weighted images. Mean tumor rCBV normalized to white matter (nRCBV) and standardized rCBV (sRCBV) were determined for these regions of interest. The OS rates for patients with positive versus negative changes from baseline in nRCBV and sRCBV were compared using Wilcoxon rank-sum and Kaplan–Meier survival estimates with log-rank tests.

Results

Patients surviving at least 1 year (OS-1) had significantly larger decreases in nRCBV at week 2 (P = .0451) and sRCBV at week 16 (P = .014). Receiver operating characteristic analysis found the percent changes of nRCBV and sRCBV at week 2 and sRCBV at week 16, but not rCBV data at week 8, to be good prognostic markers for OS-1. Patients with positive change from baseline rCBV had significantly shorter OS than those with negative change at both week 2 and week 16 (P = .0015 and P = .0067 for nRCBV and P = .0251 and P = .0004 for sRCBV, respectively).

Conclusions

Early decreases in rCBV are predictive of improved survival in patients with recurrent GBM treated with bevacizumab.     

Editor's choice: Medical management of brain tumors and the sequelae of treatment

Patients with malignant brain tumors are prone to complications that negatively impact their quality of life and sometimes their overall survival as well. Tumors may directly provoke seizures, hypercoagulable states with resultant venous thromboembolism, and mood and cognitive disorders. Antitumor treatments and supportive therapies also produce side effects. In this review, we discuss major aspects of supportive care for patients with malignant brain tumors, with particular attention to management of seizures, venous thromboembolism, corticosteroids and their complications, chemotherapy including bevacizumab, and fatigue, mood, and cognitive dysfunction.     

Palliative chemotherapy for patients 70 years of age and older with metastatic colorectal cancer: a single-centre experience

BackgroundMetastatic colorectal cancer (mcrc) commonly affects elderly people, an understudied subset of patients. We analyzed the survival impact of the first and subsequent lines of chemotherapy in eligible non-trial patients 70 years of age and older with mcrc treated between 2004 and 2012.MethodsThis single-centre retrospective analysis estimated overall survival (os) and progression-free survival (pfs) using the Kaplan–Meier method. Multivariate analysis was used to adjust for age, sex, Eastern Cooperative Oncology Group performance status, score on the Charlson comorbidity index, dependency in activities of daily living, and exposure to 1 or more chemotherapy doublets, capecitabine alone, or best supportive care (bsc).ResultsOf 109 patients identified, 29 elected bsc, and 80 received chemotherapy. In multivariate analysis, age was not associated with os [hazard ratio (hr): 0.99; 95% confidence interval (ci): 0.92 to 1.05], but a performance status of 2 or higher was associated with a decreased likelihood of survival (hr: 3.12; 95% ci: 1.87 to 5.76), and exposure to 1 or more doublets was associated with improved survival (hr: 0.33; 95% ci: 0.17 to 0.66). In univariate analysis, a trend toward improved os was observed for first-line doublet chemotherapy compared with capecitabine (hr: 0.66; 95% ci: 0.41 to 1.07), and pfs was superior (hr: 0.46; 95% ci: 0.26 to 0.84). Compared with exposure to 1 doublet, exposure to the 3 potential cytotoxic chemotherapies was not associated with improved os (hr: 0.77; 95% ci: 0.41 to 1.43). The incidence of neutropenia with first-line folfiri was 40%; the incidences of bevacizumab-related arterial and venous thrombosis were both 8%.ConclusionsExposure to 1 or more doublet chemotherapies for mcrc was associated with better outcomes in non-trial patients 70 years of age and older. Elderly patients treated with palliative chemotherapy and bevacizumab should be monitored carefully for arterial and venous thrombotic events.     

Poly‐S‐nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab,partly by inhibiting autophagy through the generation of nitric oxide

Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short‐term therapeutic effects, whereas long‐term therapeutic benefits are rarely observed, probably due to hypoxia‐induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S‐nitrosated human serum albumin (SNO‐HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO‐HSA significantly suppressed hypoxia‐induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO‐HSA was also confirmed in vivo by combining it with Bev. In C26‐bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO‐HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO‐HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO‐HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO‐HSA to suppress autophagy‐mediated drug resistance and enhance the efficacy of chemotherapy.     

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine,bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial

Background:

Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.

Methods:

In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.

Results:

The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log₁₀CEC hazard ratio (HR) 0.41, 95% CI 0.18–0.91) and 6 weeks (log₁₀CEC HR 0.16, 95% CI 0.05–0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS.

Conclusion:

CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.