Role of bevacizumab in colorectal cancer growth and its adverse effects:A review

Angiogenesis affects both wound healing and malignant cell growth through nutrients and oxygen.Vascular endothelial growth factor(VEGF) is the most important element involved in this complex process.Inhibition of VEGF influences angiogenesis and may restrict tumor growth and metastatic ability.Modern antiangiogenic therapy is based on this theory.Bevacizumab is a recombinant humanized monoclonal antibody(immunoglobulin G1) which binds with VEGF-A forming a large molecule.It can not be bound with VEGF tyrosine kinase receptors preventing VEGF-A incorporation;thus its activity is inhibited inducing blockage of VEGFmediated angiogenesis.Bevacizumab,in combination with chemotherapy or other novel targeted therapeutic agents,is currently used more frequently in clinical practice,mainly for managing advanced colorectal cancer.It is also used for managing other malignancies,such as breast cancer,pancreatic cancer,prostate cancer,non small-cell lung cancer,metastatic renal carcinoma and ovarian tumors.Although it is generally considered a safe treatment,there are reports of some rare side effects which should be taken into account.Recent experiments in rats and mice show promising results with a wider therapeutic range.     

Intracranial hemorrhage in children with immune thrombocytopenic purpura

 We sent questionnaires to hospitals in Japan in order to study the incidence and conditions of intracranial hemorrhage (ICH) in children with immune thrombocytopenic purpura (ITP). From 1980 to 1995, 11 cases of ICH were reported in eight patients with ITP at 35 institutions. One patient had ICH four times, but only one patient died of the condition. From 1990 through 1995, ICH occurred in four (0.52%) of 772 patients with ITP. None of the patients died. The platelet count when ICH occurred was 5.2±3.7×10⁹/l (mean±SD) (n=11). Four of the eight patients (1980–1995) had received active treatment [e.g. intravenous immunoglobulin G (i.v. IgG)] immediately before ICH occurred. In seven cases (1980–1995), possible causes of ICH, including menstruation (n=2) and viral infections (n=3), were identified. Systemic lupus erythematosus (SLE) later developed in three patients. Although the incidence of ICH in children with ITP has not decreased compared with the rates in earlier studies, the mortality rate has decreased markedly. Our results suggest that menstruation, infection, and risk factors for progression to SLE may help to predict ICH in children with ITP. Large-scale prospective trials are needed to identify risk factors for ICH. Received: 24 June 1999 / Accepted: 26 May 2000     

脑动静脉畸形破裂出血37例显微手术治疗分析

目的探讨脑动静脉畸形(arteriovenous malformation,AVM)破裂出血的显微手术治疗方法及效果。方法采用回顾性分析的方法对37例脑AVM破裂出血病人的临床资料进行收集、整理和分析。结果全组37例均行显微手术治疗,术后随访3个月～2年,其中恢复工作21例,生活自理10例,需要他人照顾2例,死亡4例(死者均为术前脑疝时间较长患者)。结论选择适当的显微手术治疗能够改善脑AVM破裂出血的预后,血肿清除加AVM切除是该病首选的治疗方法。     

结直肠癌患者血清中血管内皮生长因子和一氧化氮表达水平及其临床意义

目的:探讨结直肠癌患者血清中血管内皮生长因子(VEGF)和一氧化氮(NO)表达水平及其临床意义.方法:分别采用酶联免疫吸附测定(ELISA)法和分光光度法检测74例结直肠癌患者术前和45例结直肠腺瘤患者以及40例健康人血清中VEGF和NO的含量.结果:结直肠腺瘤患者血清VEGF和NO含量与健康人无明显差异(P＞0.05);结直肠癌患者血清VEGF和NO表达水平分别较结直肠腺瘤组以及健康人明显增高(P＜0.01),且结直肠癌浸润深度、有无淋巴结转移以及Dukes分期与血清VEGF和NO含量呈明显正相关(r=0.834,P＜0.01).结论:VEGF和NO与结直肠癌的发生发展密切相关,术前检测血清VEGF和NO含量可作为判断结直肠癌浸润转移以及Dukes分期的有效生物学指标.     

Preoperative administration of bevacizumab is safe for patients with colorectal liver metastases

AIM:To assess the impact of preoperative neoadjuvant bevacizumab(Bev)on the outcome of patients undergoing resection for colorectal liver metastases(CLM). METHODS:Eligible trials were identified from Medline, Embase,Ovid,and the Cochrane database.The data were analyzed with fixed-effects or random-effects models using Review Manager version 5.0. RESULTS:Thirteen nonrandomized studies with a total of 1431 participants were suitable for meta-analysis. There was no difference in overall morbidity and severe complications between the Bev+group and Bev-group (43.3%vs 36.8%,P=0.06;17.1%vs 11.4%,P=0.07,respectively).Bev-related complications including wound and thromboembolic/bleeding events were also similar in the Bev+and Bev-groups(14.4%vs 8.1%, P=0.21;4.1%vs 3.8%,P=0.98,respectively).The incidence and severity of sinusoidal dilation were lower in patients treated with Bev than in patients treated without Bev(43.3%vs 63.7%,P<0.001;16.8%vs 46.5%,P<0.00,respectively). CONCLUSION:Bev can be safely administered before hepatic resection in patients with CLM,and has a protective effect against hepatic injury in patients treated with oxaliplatin chemotherapy.     

Notch1和血管内皮生长因子在出血性颅内动静脉畸形患者中的表达

目的研究Notch1和血管内皮生长因子（VEGF）在出血性颅内动静脉畸形（AVM）中的作用。方法回顾分析温州医学院神经外科手术治疗的AVM患者,共35例,根据病史和影像学特点,将AVM患者分为出血性AVM组（简称出血组）27例、非出血性AVM组（简称非出血组）8例,应用免疫组化、荧光实时定量PCR分别检测两组畸形血管团内Notch1和VEGF的表达差异及相关性。结果①在出血组和非出血组中,Notch1和VEGF在畸形血管团内皮细胞均表达明显,但两组Notch1、VEGF表达阳性率比较,差异均无统计学意义。②出血组的Notch1 mRNA水平为1.9±1.7,高于非出血组的1.5±0.6;出血组的VEGF mRNA水平为4.2±3.0,高于非出血组的2.9＋2.7,但两组比较差异均无统计学意义。③经Spearman相关分析,颅内AVM的Notch1与VEGF的阳性细胞率（r=0.638,P〈0.05）及其mRNA水平（r==0.611,P〈0.05）均呈正相关。结论 Notch1、VEGF在出血性AVM和非出血性AVM中均表达升高;但在出血性AVM中无特异性,Notch1与VEGF可能协同参与颅内AVM的形成。     

Progressive multifocal leukoencephalopathy: report of three cases in HIV-negative hematological patients and review of literature

Progressive multifocal leukoencephalopathy (PML) is a central nervous system (CNS) disease usually observed in immunodeficient patients, especially human immunodeficiency virus (HIV)-positive, caused by John Cunningham virus. This infectious complication has been described in many HIV-negative hematological patients, especially affected by lymphoproliferative diseases. PML has been observed after both chemotherapy and bone marrow transplantation and, recently, in association with rituximab. Diagnosis can be complicated, and often a CNS biopsy is required. Current treatment approaches are not effective in both HIV-positive and HIV-negative patients, and the outcome remain very poor in the majority of cases, even after combination therapies. We report three cases of PML in hematological patients, treated respectively with conventional chemotherapy and autologous and haploidentical transplantation, and review the literature on PML. All of them received rituximab, which has recently been in the focus of a Food and Drug Administration warning.     

手术切除婴幼儿颅内A2段巨大动脉瘤合并血管畸形一例

颅内动脉瘤合并血管畸形临床上较为罕见,开颅手术切除血管畸形及动脉瘤是有效的治疗手段之一。已有颅内出血的此类疾病患者,通过手术治疗防止其再次出血尤为重要。当患儿为婴幼儿时,手术难度及诊治难度均大大增加。作者总结了1例婴幼儿颅内大脑前动脉A2段巨大动脉瘤合并血管畸形患儿的病史、影像学表现及详细手术切除病灶的经过等临床资料,并结合文献复习分析了该疾病的诊治体会。     

自发性脑干出血患者自主神经系统功能变化的研究

目的　探讨自发性脑干出血后自主神经系统 (ANS)功能变化及出血部位对 ANS的影响。方法　对 2 1例急性自发性脑干出血患者 (观察组 )于发病后前 6周的血浆儿茶酚胺浓度进行测定 ,并对其心电图的低频带 (L FB)和高频带 (HFB)进行分析 ,然后与正常对照组比较。结果　观察组延髓出血患者与对照组比较 ,其超急性期、急性期心电图 L FB和超急性期 HFB明显降低 (P<0 .0 5 ,0 .0 1) ;非延髓出血患者心电图的 L FB、HFB无明显差异 ,但其超急性期、急性期血浆肾上腺素浓度明显高于对照组 (P <0 .0 1)。结论　观察组延髓出血患者存在短暂的 ANS功能障碍 ,非延髓出血患者 ANS功能未受明显影响     

腹腔内注射贝伐珠单抗治疗结直肠癌患者恶性腹腔积液的疗效和安全性评价

目的探讨腹腔内注射贝伐珠单抗治疗恶性腹腔积液的近期疗效及安全性; 方法收集46例桂林医学院附属医院胃肠外科2010年3月至2014年5月伴有难以控制的恶性腹腔积液的晚期结直肠癌患者。检测其腹腔积液中VEGF含量;并利用单因素生存分析对比两组患者的预后。 结果对照组的血清VEGF平均值为（671.8±499.15）pg/mL,与治疗组［平均值为（665.19.19±499.15）pg/mL］相比差异无统计学意义。治疗组中,治疗前腹腔积液VEGF量的平均值为（1 225.11±609.71）pg/mL,无穿刺中位生存时间为6个月（1~21个月）。与对照组相比,治疗组的穿刺引流时间明显延长（t值=6.328,P<0.05）。治疗后,腹腔积液的VEGF量（317.69±172.14）pg/mL,与治疗前相比差异存在统计学意义。治疗后的血清VEGF平均值为（170.61±115.92）pg/mL,与治疗前差异具有统计学意义。在生存分析中,治疗组的预后明显好于对照组（P<0.05）。 结论对于一部分合适的患者,腹腔内注射贝伐珠单抗对于恶性腹腔积液的治疗可能是一种有效地、安全的治疗手段。     

Value of bevacizumab in treatment of colorectal cancer: A meta-analysis

AIM:To assess the efficacy and safety of bevacizumab in the treatment of colorectal cancer.METHODS:All randomized controlled trials of bevacizumab for the treatment of colorectal cancer from January 2003 to June 2013 were collected by searching the Cochrane Library, Pub Med, Chinese National Knowledge Infrastructure and Wanfang databases.The primary endpoint was overall survival(OS), and the secondary endpoints were progression-free survival, overall response rate and adverse events.Two reviewers extracted data independently.Statistical analyses were performed with Stata 12.0.The degree of bias was assessed using funnel plots for the effect size of OS at the primary endpoint.RESULTS:Following the inclusion criteria and exclusion criteria, ten studies comprising 6977 cases were finally included, of which nine were considered to be of high quality(4-7 points) and one of low quality(1-3 points).Our meta-analysis revealed the efficacy of bevacizumab in patients with colorectal cancer in terms of OS(HR = 0.848, 95%CI:0.747-0.963), progressionfree survival(HR = 0.617, 95%CI:0.530-0.719), and overall response rate(OR = 1.627, 95%CI:1.199-2.207).Regarding safety, higher rates of grade ≥ 3 hypertension, proteinuria, bleeding, thrombosis, and gastrointestinal perforation were observed in the bevacizumab treatment group(P 0.05); however, the incidence of serious toxicity was very low.There was no publication bias in the 10 reports included in this meta-analysis.CONCLUSION:The clinical application of bevacizumab in colorectal cancer is effective with good safety.     

Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study

AIM: To confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer(CRC)in Italy.METHODS: This multicentric, prospective, open-label study included patients with CRC previously untreated with chemotherapy. Patients were administered bevacizumab in combination with XELOX. The primary efficacy end-point was progression-free survival(PFS). Secondary end-points included time to overall response(TOR), duration of response(DOR), time to treatment failure(TTF) and overall survival(OS).The incidence and type of adverse events AEs and severe AEs were evaluated. Also, the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing, and quality of life(QoL)was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit.RESULTS: The intention-to-treat population included197 patients(mean age: 62.3 ± 9.9 years, 56.4%males). At baseline, 16/34 evaluable subjects(47.1%)harbored a KRAS and/or a BRAF mutation; the mean QoL index was 80.2 ± 14.3. First-line therapy was given for 223.7 ± 175.9 d, and after a mean followup of 387.7 ± 238.8 d all patients discontinued from the study mainly for disease progression(PD, 45.4%)and AEs(25.4%). Median PFS was 9.7 mo(95%CI:8.4-10.5) and the median values for secondary endpoints were: TOR = 3.9 mo(95%CI: 2.6-4.7), DOR= 8.5 mo(95%CI: 7.3-10.3), TTF = 6.7 mo(95%CI:6.0-7.7) and OS = 23.2 mo(95%CI: 20.1-27.2).Patients carrying at least one lesion had a lower overall response rate(66.7% vs 88.9%) and a lower probability of achieving complete or partial response than those without mutations, but the difference in relative risk was not statistically significant(P =0.2). Mean EQ-5D-3L raw index score significantly decreased to 74.9 ± 19.1 at the last visit(signed-rank test, P = 0.0076), but in general the evaluation on QoL perceived by patients was good.CONCLUSION: The efficacy of bevacizumab in combination with XELOX in terms of PFS in patients with aCRC or mCRC in Italy was confirmed, with acceptable toxicity.     

Intraperitoneal hemorrhage associated with transhepatic cardiac catheterization: A report of two cases

Transhepatic cardiac catheterization has gained increased interest as a novel technique for venous vascular access with few complications. We report important intra-abdominal bleeding encountered in two patients during transhepatic cardiac catheterization. We describe their management and suggest possible nonoperative strategies. Cathet. Cardiovasc. Diagn. 43:177–178, 1998. © 1998 Wiley-Liss, Inc.     

Sequencing of treatment in metastatic colorectal cancer: Where to fit the target

Colorectal cancer is a lethal disease if not discovered early.Even though appropriate screening and preventive strategies are in place in many countries,a significant number of patients are still diagnosed at late stages of the disease.The management of metastatic colorectal cancer remains a significant clinical challenge to oncologists worldwide.While cytotoxic regimens constitute the main treatment of choice in this patient population,addition of the five biologics(bevacizumab,cetuximab,aflibercept,panitumumab and regorafenib)to these regimens has improved clinical outcomes.The most commonly used cytotoxic regimens include doublet combinations(FOLFOX/XELOX or FOLFIRI).Many clinical trials have been published and others are underway to compare the biologic agents with one another in order to prove the superiority of one regimen over another.Metastatic colorectal cancer patients have many treatment options;however,the optimal use and sequence of targeted agents remain to be determined.This review entails concise and updated clinical data on the management of metastatic colorectal cancer.The aim of the review is to determine where to fit the five biologic targets into the treatment algorithm of metastatic colorectal cancer patients and to derive treatment sequences that would achieve best clinical outcome based on the current available data.     

Gastrointestinal perforation in metastatic colorectal cancer patients with peritoneal metastases receiving bevacizumab

AIM:To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease.METHODS:We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts:(1) the AGITG MAX trial(Phase Ⅲ randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine,bevacizumab and mitomycin C);(2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer(TRACC) registry(any first-line regimen ± bevacizumab);and(3) two cancer centres in New South Wales,Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre(NSWCC) from January 2005 to Decenber 2012,(any first-line regimen ± bevacizumab).For the AGITG MAX trial capecitabine was compared to the other two arms(capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycin C).In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases.Secondary endpoints included progression-free survival,chemotherapy duration,and overall survival.Time-toevent outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test.RESULTS:Eighty-four MAX,179 TRACC and 69 NSWCC patients had peritoneal disease.There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts.Of the patients without peritoneal disease in the MAX trial,4/300(1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123(0.8%) in the capecitabine alone arm.In the TRACC registry 3/126(2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53(1.9%) in the chemotherapy alone arm.In a further analysis of patients without peritoneal metastases in the TRACC registry,the rate of gastrointestinal perforations was 9/369(2.4%) in the chemotherapy/bevacizumab group and 5/177(2.8%) in the chemotherapy alone group.The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts:MAX 6.9 m vs 4.9 m,HR = 0.64(95%CI:0.42-1.02);P = 0.063;TRACC 9.1 m vs 5.5 m,HR = 0.61(95%CI:0.37-0.86);P = 0.009;NSWCC 8.7 m vs 6.8 m,HR = 0.75(95%CI:0.43-1.32);P = 0.32.Chemotherapy duration was similar across the groups.CONCLUSION:Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone.     

急性脑出血患者24小时心率变异性变化与动态心电图异常

目的：了解急性脑出血对心脏自主神经活性改变，心电图复极改变和心律失常的影响。方法：检测61例急性大脑半球壳核和额顶颞叶出血患者和39例对照的24h动态心电图，分析其心率变异性变化，心电图复极改变和心律失常。结果：右侧壳核和额顶颞叶出血患者急性期室上性快速心律失常和心房颤动发生率明显增高，左侧壳核和额顶颞叶出血患者急性期心电图ST段降低发生率明显增高，右侧壳核和额顶颞叶出血组心率变异性指标HF，RMSSD，PNN50明显下降和LF／HF明显增高，伴室上性快速心律失常者LF／HF高于无室上性快速心律失常者，HF明显低于无室上性快速心律失常者。结论：左侧和右侧大脑半球出血对心脏的影响不高，岛叶病变在其中起着主要作用。     

长春瑞滨联合贝伐单抗治疗非小细胞肺癌的临床分析

目的分析长春瑞滨联合贝伐单抗治疗非小细胞肺癌(NSCLC)的临床疗效及生存情况。 方法选择我院2017年4月至2020年3月接诊的42例NSCLC患者作为观察对象,依据临床治疗方案将患者分为观察组22例和对照组20例,给予对照组患者顺铂+长春瑞滨治疗,观察组患者在对照组基础上联合贝伐单抗治疗。评估两组患者治疗2周后的临床疗效、血清肿瘤因子[血清血管生成素样蛋白2(ANGPTL2)、抗菌肽人类阳离子抗菌蛋白18(hCAP18)及血清癌胚抗原(CEA)]水平、药物不良反应及12个月随访后的生存情况。 结果观察组疾病控制率(81.82%)高于对照组(60.00%),差异有统计学意义(P<0.05);治疗后,两组患者的血清hCAP18、CEA及ANGPTL2水平均低于治疗前,且观察组较对照组更低,差异有统计学意义(P<0.05);观察组1年生存率(77.27%)高于对照组(45.00%),差异具有统计学意义(P<0.05);两组患者的不良反应发生率比较差异无统计学意义(P>0.05)。 结论给予NSCLC患者长春瑞滨联合贝伐单抗治疗,有助于改善患者的临床疗效,提高患者的疾病控制率,降低患者的血清hCAP18、CEA及ANGPTL2水平,提高患者的1年生存率,且安全性较好。     

Treatment of diuretic refractory pleural effusions with bevacizumab in four patients with primary systemic amyloidosis

Refractory pleural effusions present a challenging management problem and are associated with a poor prognosis in patients with primary systemic amyloidosis (AL). We report a series of four patients with AL who presented with bilateral pleural effusions that were refractory to diuretic therapy. After treatment with bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, three of the four patients had improvement in their pleural effusions, peripheral edema, and functional status. Additional studies are needed to further define the role of bevacizumab in the management of this group of patients.     

Impact of biomarkers on disease survival and progression in patients treated with octreotide for advanced hepatocellular carcinoma

Background Current determination of prognosis for advanced hepatocellular carcinoma (HCC) is mainly based on clinical assessment. We aimed to determine the impact of biomarkers as predictive factors for HCC progression and survival during octreotide-based treatments.Patients and methods We included patients who had been prospectively randomised to receive either octreotide (30 mg) alone monthly (n = 39) or in combination with rofecoxib (up to 50 mg bid daily, n = 32) for a minimum of 6 months, or until death occurred.Results Overall median survival (154 days) and median time to progression (94 days) were not different for both treatments and the biomarkers investigated (VEGF-A, IGF-1, PGE-2, ET-A) were similarly distributed amongst treatment groups. Combined univariate group analysis revealed that survival was decreased for an uptake ratio of > 2 on initial octreoscan (P = 0.05); baseline serum VEGF-A and IGF-1 were further significantly associated with survival. On multivariate analysis, uncorrected serum VEGF-A appeared to be the most significant predictor for tumor progression and survival.Conclusions Biomarkers, in addition to established tumor markers, are independent predictors of tumor progression and survival in patients with advanced HCC treated with octreotide. Furthermore, the involvement of VEGF-A implies the inhibition of angiogenesis as a potential mechanism of action for this drug.     

原发性脑肿瘤并发非肿瘤性颅内出血的病因及临床特点

对７例经手术及病理证实的原发性脑肿瘤并发颅内出血者的临床资料进行了分析。结果：脑膜瘤４例,脉络丛乳头状瘤,实质性血管网织细胞瘤、多型性胶质母细胞瘤各１例;伴硬脑膜下血肿３例,蛛网膜下腔出血２例,脑室内及脑内出血各１例。