Receptor tyrosine kinase signaling in cancer radiotherapy and its targeting for tumor radiosensitization

Purpose: One of the most important implications of ‘Radiation Biology’ research is to improve cancer radiotherapy with minimum side effects. In this regard, combination of chemotherapy with radiation has significantly improved tumor control as well as overall survival in a variety of cancers. However, this has been achieved at the cost of significant normal tissue toxicity, due to the lack of specificity of chemotherapy. Membrane-localized receptor tyrosine kinases (RTKs) have been found to play a driving role in various hallmarks of cancer. Moreover, an early successful clinical trial using RTK-antagonist (cetuximab) to improve tumor radiosensitivity has led to an advancement in this field of research. However, a comprehensive review integrating these findings of various oncogenic RTKs, from basic radiobiology-to-radiotherapy clinical trials, is lacking in literature. Therefore, the present review analyses relevant in-vitro, in-vivo, preclinical/clinical studies and postulates the concept of ‘Radiation Biology of RTKs in Cancer’.

Conclusions: The present review elucidates the effect of IR on various oncogenic RTKs and their mechanisms, downstream signaling, intracellular translocations, their role in the repair of radiation-induced DNA damage and post-irradiation survival. Based on the knowledge derived from RTK biology and the analysis of relevant clinical trials, this review attempts to identify radiobiological considerations, which could be implemented in future trials, combining radiotherapy with RTK-antagonist. Additionally, we identify the radiosensitizing potential of recently developed RTK-targeted nanoformulations. This review would probably change the Radiation Oncologist’s view for translation of tumor-specific radiosensitization in clinic.     

抗登革病毒单抗的独特型抗体的制备与鉴定

从19种抗登革病毒单克隆抗体(简称单抗)中筛选出4种具有中和活性的单抗。经过纯化免疫新西兰大白兔制备多克隆抗独特型抗体(Ab2)。制备的4种抗独特型抗体血清有很高的特异性,其中具有全交叉反应的3种单抗的抗血青中Ab2的水平较高。采用简便的去除抗血清中的同种型和同种异型抗体的方法,用夹心ELISA法检测Ab2的水平取得了满意的结果。     

放疗联合动脉化疗栓塞及酪氨酸激酶抑制剂治疗肝癌合并瘤栓的长期结果

目的 探讨调强放疗联合动脉化疗栓塞及酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）治疗肝细胞性肝癌合并静脉瘤栓患者的长期随访结果。方法 回顾性分析2015年10月至2018年10月北京大学肿瘤医院收治的63例肝细胞性肝癌合并静脉瘤栓且无远处转移患者,其中28例接受调强放疗联合动脉化疗栓塞及索拉非尼（A组）,35例接受调强放疗联合动脉化疗栓塞（B组）。采用倾向评分配比法,分析联合与不联合索拉非尼组的治疗疗效。结果 中位随访时间62个月。A组和B组的中位生存时间分别为19.0和15.2个月（χ²=3.15,P=0.076）,A组的中位无进展生存时间为10.7个月,高于B组的8.6个月（χ²=3.99,P=0.046）。经过倾向评分配比平衡组间差异后,A组的中位生存时间为30.6个月,明显高于B组的15.2个月（χ²=5.34,P=0.023）;A组的中位无进展生存时间12.5个月,仍然高于B组的8.3个月（χ²=4.79,P=0.026）。全组10例（15.9%）患者治疗中出现3级血液学毒性,7例（11.1%）患者出现3级肝功能异常。A组较B组的皮肤反应、手足综合征和腹泻发生率高,但均为1~2级不良反应。全组无4级不良反应,无放射诱发肝病及治疗相关死亡发生。结论 长期随访结果显示,肝细胞性肝癌合并静脉瘤栓患者在调强放疗加动脉化疗栓塞的基础上联合TKI提高了疗效。     

支气管动脉化疗栓塞结合同步放疗、静脉化疗治疗中心型肺癌

目的探讨支气管动脉化疗栓塞结合同步放疗、静脉化疗治疗中心型肺癌的疗效。方法178例中晚期中心型肺癌患者采用支气管动脉化疗栓塞,第2天行放疗。放疗总剂量60～70 Gy,6～7周完成。3～4周后采用长春瑞滨、顺铂或伊托铂苷、顺铂方案,共化疗2个周期。结果患者临床症状均有明显好转。CR 39.89%,PR 46.06%,有效率(CR+PR)85.95%,中位生存期为23.4个月,1、2、3年生存率分别为79.7%、45.3%、24.5%。无严重并发症发生。结论经支气管动脉化疗栓塞结合放疗、静脉化疗治疗中心型肺癌能延长患者的中位生存期,提高患者的生存率,具有较好的临床疗效。     

调强放疗联合时辰化疗治疗局部进展期鼻咽癌的近期疗效及不良反应

目的 比较时辰化疗与常规化疗联合调强放疗在局部进展期鼻咽癌患者治疗过程中的不良反应、免疫功能、近期疗效。方法 选取2015年7月至2017年4月在贵州医科大学附属肿瘤医院初治局部进展期鼻咽癌患者159例,采用简单随机分组法,前瞻性将159例初治局部进展期鼻咽癌患者随机分为时辰化疗组与常规化疗组,前者采用时辰化疗模式给药,后者采用常规模式给药,两组均采用调强放射治疗,评价近期疗效及观察不良反应。结果 时辰化疗组与常规化疗组近期疗效完全缓解（CR）、部分缓解（PR）、稳定（SD）、进展（PD）差异无统计学意义（P>0.05）,两组有效率（CR+PR）差异无统计学意义（P>0.05）;时辰化疗组的白细胞减少（Z=-2.222,P<0.05）、中性粒细胞减少（Z=-1.999,P<0.05）、呕吐（Z=-2.298,P<0.05）、口腔黏膜炎（Z=-3.571,P<0.05）发生率低于常规化疗组,差异有统计学意义;时辰化疗组CD16+56+淋巴细胞计数高于常规化疗组（Z=-2.332,P<0.05）。结论 时辰化疗作为一种新的治疗模式,与调强放疗联合可在不降低临床疗效的同时减轻治疗相关不良反应的发生率及严重程度,减轻免疫抑制,值得临床推广及应用。     

MRI methods for evaluating the effects of tyrosine kinase inhibitor administration used to enhance chemotherapy efficiency in a breast tumor xenograft model

Purpose

To evaluate whether quantitative MRI parameters are sensitive to the effects of the tyrosine kinase inhibitor gefitinib and can discriminate between two different treatment protocols.

Materials and Methods

Untreated mice with BT474 breast tumor xenografts were characterized in a preliminary study. Subsequently, tumor volume, apparent diffusion coefficient (ADC), transendothelial permeability (K^ps), and fractional plasma volume (fPV) were measured in three groups of mice receiving: 1) control vehicle for 10 days, or gefitinib as 2) a single daily dose for 10 days or 3) a 2‐day pulsed dose.

Results

Gefitinib treatment resulted in significant tumor growth inhibition (pulsed: 439 ± 93; daily: 404 ± 53; control: 891 ± 174 mm³, P < 0.050) and lower cell density (pulsed: 0.15 ± 0.01, daily: 0.17 ± 0.01, control: 0.24 ± 0.01, P < 0.050) after 9 days. Tumor ADC increased in treated groups but decreased in controls (P > 0.050). Tumor K^ps decreased with pulsed treatment but rebounded afterwards and increased with daily treatment (P > 0.050). Tumor fPV increased in both treated groups, decreasing afterwards with pulsed treatment (P > 0.050).

Conclusion

Quantitative MRI can provide a sensitive measure of gefitinib‐induced tumor changes, potentially distinguish between treatment regimens, and may be useful for determining optimal treatment scheduling for enhancing chemotherapy delivery. J. Magn. Reson. Imaging 2009;29:1071–1079. © 2009 Wiley‐Liss, Inc.     

Pharmacokinetic MRI for assessment of malignant glioma response to stereotactic radiotherapy: Initial results

The purpose of this study was to assess the value of dynamic, contrast-enhanced MRI in patients with malignant glioma (a) to predict before stereotactic radiotherapy local tumor control, (b) to investigate temporal changes in tumor microcirculation after stereotactic radiotherapy, and (c) to analyze whether malignant glioma response may be predicted earlier by alterations in the tissue pharmacokinetics rather than in terms of tumor volume. Ninety MRI studies were performed of 18 patients with malignant glioma before and 6, 18, 26, 52, and 72 weeks after the end of stereotactic radiotherapy. The signal time courses of the contrast-enhanced tumors were analyzed using a pharmacokinetic two-compartment model that calculates for the parameter A, reflecting the degree of MRI signal enhancement [no units] and the exchange rate constant k₂₁ [min^?1]. Before radiotherapy, the amplitude A was significantly (P < .05) lower in patients with subsequent local tumor control (n = 8; mean A = .34 ± .15) compared to patients without subsequent local tumor control (n = 10; mean A = .94 ± .71). In the local tumor control group, early after stereotactic radiotherapy (at 6–18 weeks), there was a significant (P < .05) time-dependent decrease in the parameter k₂₁, whereas there was still no alteration in the tumor volume. A low amplitude A before radiotherapy, combined with an early drop of k₂₁ after stereotactic radiotherapy, reliably characterized the group of patients with subsequent tumor volume decrease. Our preliminary results suggest that two contrast-enhanced dynamic MR studies, one before and one early after stereotactic radiotherapy, offer important information on local tumor control within the first 6 to 18 weeks after stereotactic radiotherapy. Moreover, this response may be evidenced before tumor volume changes and provides a therapeutic window to broaden treatment options and to improve treatment outcome.     

Pre-treatment 3H-TdR labelling of cervical biopsies: histology, staging and tumour response to radiotherapy

Pre-treatment data from tumour biopsies labelled in vitro with tritiated thymidine are reported for 54 patients undergoing radical radiotherapy by 137Cs or Cathetron 60Co intracavitary insertions plus external irradiation for carcinoma of the uterine cervix. Labelling indices were obtained ranging from 1.8 to 27.8%. No correlation was observed between mean labelling indices and the histological type of tumour or its degree of differentiation. Comparison of data obtained in this study with previously reported data for carcinoma in situ and invasive carcinoma indicate that with increasing clinical stage of the disease, a considerable lengthening of the potential doubling time of the tumour cells, from less than 1 to 8 days, occurs. The degree of vaginal spread of the tumour was directly related to the degree of parametrial involvement. The mean time taken for the vaginal component of the tumour to resolve following radiotherapy was related to its initial spread and the pre-treatment labelling index. The greater the spread of the tumour, the lower the labelling index and the longer the time taken for resolution. Up to 1 year following radiotherapy the incidence of locally recurrent, or metastatic disease was unrelated to the pre-treatment labelling index.     

EGFR-TKI在非小细胞肺癌二线治疗与一线治疗中的疗效比较

含铂两药联合化疗方案目前仍是晚期非小细胞肺癌(NSCLC)的标准一线治疗方案,分子靶向药物为晚期NSCLC患者提供了新的治疗选择.临床研究证实,在晚期NSCLC患者的二线治疗中,表皮生长因子酪氨酸激酶抑制剂(EGFR-TKI)与标准化疗相比具有明确的非劣效性.然而,肿瘤组织标本检测显示EGFR基因突变阳性的NSCLC患...     

Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1‐13C]pyruvate and 13C magnetic resonance spectroscopic imaging

We show here that hyperpolarized [1‐¹³C]pyruvate can be used to detect treatment response in a glioma tumor model; a tumor type where detection of response with ¹⁸fluoro‐2‐deoxyglucose, using positron emission tomography, is limited by the high background signals from normal brain tissue. ¹³C chemical shift images acquired following intravenous injection of hyperpolarized [1‐¹³C]pyruvate into rats with implanted C6 gliomas showed significant labeling of lactate within the tumors but comparatively low levels in surrounding brain.Labeled pyruvate was observed at high levels in blood vessels above the brain and from other major vessels elsewhere but was detected at only low levels in tumor and brain.The ratio of hyperpolarized ¹³C label in tumor lactate compared to the maximum pyruvate signal in the blood vessels was decreased from 0.38 ± 0.16 to 0.23 ± 0.13, (a reduction of 34%) by 72 h following whole brain irradiation with 15 Gy. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.     

Assessment of treatment response after lung stereotactic body radiotherapy using diffusion weighted magnetic resonance imaging and positron emission tomography: A pilot study

Background and purposeThere is no early predictor of treatment response after lung stereotactic body radiotherapy (SBRT). We conducted this pilot study to evaluate whether serial diffusion weighted magnetic resonance imaging (DW-MRI) or positron emission tomography (PET) could predict response after SBRT.Material and methodsEarly stage non-small cell lung cancer patients who received SBRT were eligible. DW-MRI and PET were undertaken pretreatment and every 3 months after SBRT in the first year. Patients with <1 year of follow-up were excluded from the analysis. The apparent diffusion coefficient (ADC) value and maximum standardized uptake value (SUV_max) of tumors were measured and compared between groups with or without local recurrence (LR).ResultsFifteen patients were enrolled and the data of 14 patients were analyzed. The median ADC value was significantly lower in patients with LR (n = 3) than in those without LR (n = 11) at 3 and 6 months (1.11 vs. 1.54 and 0.98 vs. 1.69 [×10⁻³ mm²/s]; p = 0.039 and 0.012, respectively) while there was no significant difference pretreatment and at 9 and 12 months after treatment. No significant difference was observed in the SUV_max at any time point.ConclusionsDW-MRI could be an early predictor of treatment response after lung SBRT.     

经皮经肝胆管引流支架植入联合三维适形放射治疗恶性梗阻性黄疸48例分析

目的观察经皮肝胆管穿刺引流(PTCD)及胆管内支架置入术(PTBS)联合三维适形放疗(3D-CRT)治疗恶性梗阻性黄疸的疗效及应用价值。方法对48例恶性梗阻性黄疸患者行经皮肝胆管穿刺置管引流及胆管内支架植入,术后予3D-CRT,常规分割,总剂量DT 40～60 Gy/4～6周,观察近期疗效及生存率。结果 48例均引流成功,术前血清总胆红素(221.85±54.73)μmol/L,术后1、2及3周总胆红素分别下降为(129.68±23.58)、(88.29±15.70)和(48.58±11.61)μmol/L;经3D-CRT后肿瘤完全缓解3例,部分缓解36例,稳定9例,肿瘤总有效率81.3%;1、2年累积生存率分别是77.1%、37.5%;中位生存期18.5个月;无治疗相关的严重并发症。结论 PTBD+支架植入联合3D-CRT治疗恶性梗阻性黄疸是一种安全、有效的姑息性治疗方法,可以改善恶性肿瘤伴黄疸患者的临床症状,提高生存质量并延长生存时间。     

声学定量技术对ARB与ACEI在高血压病治疗中单用与联用优势的评价

目的 应用超声心动图声学定量技术评价血管紧张素Ⅱ受体拮抗剂（ARB）与血管紧张素Ⅱ转换酶抑制剂（ACEI）在原发性高血压病治疗中单独用药与联合用药的疗效.方法 随机选择150例1～3级原发性高血压病患者分为ARB组、ACEI组及ARB-ACEI联合用药组,每组50例,ARB组应用缬沙坦80 mg/d、ACEI组应用雅施达4 mg/d、ARB-ACEI联合用药组应用缬沙坦80 mg/d及雅施达4 mg/d口服治疗,3组疗程均为12个月.观察治疗前、治疗后患者血压及症状体征的变化情况、声学定量技术评价心脏形态学、室壁运动状态及心脏整体功能变化情况.结果 （1）3组用药方式均在治疗2 w后血压开始下降,5 w后趋于平稳.（2）3组受检者的心脏形态学参数在治疗12个月后均明显降低（P〈0.01）并趋于稳定,左室壁运动状态及心脏整体功能均随之明显改善（P〈0.01）.（3）3组用药方式降压作用均较为明显,但联合用药作用稍优于单独用药（P〈0.05）,ACEI组在逆转左室重构的疗效较ARB稍优（P〈0.05）.结论 （1）ARB及ACEI均能有效逆转原发性高血压病所导致的左室重构,明显改善心脏整体功能,1级及2级高血压可视情况选用单药治疗,而3级高血压可采用联合用药治疗.（2）声学定量技术能够全面、客观地评价心脏结构、室壁运动状态及心脏整体功能情况.     

3T diffusion-weighted MRI in the response assessment of colorectal liver metastases after chemotherapy: Correlation between ADC value and histological tumour regression grading

PurposeThe purpose of the study was to correlate the apparent diffusion coefficient (ADC) values of diffusion-weighted MR imaging (DW-MRI) by 3T device with the histological tumour regression grading (TRG) analysis of colorectal liver metastases after preoperative chemotherapy.Materials and methodsOur study included thirty-five patients with colorectal liver metastases who had undergone MRI by 3T device (GE DISCOVERY MR750; GE Healthcare) after preoperative chemotherapy. DW-MRI was performed using a single-shot spin-echo echo-planar sequence with multiple b-values (0, 150, 500, 1000, 1500 s/mm²), thus obtaining an ADC map. For each liver lesion (more than 1 cm in diameter) the fitted ADC values were calculated by two radiologists in conference and three ROIs were drawn: around the entire tumour (ADC_e), at the tumour periphery (ADC_p) and at the tumour center (ADC_c). All ADC values were correlated with histopathological findings after surgery. Hepatic metastases were pathologically classified into five groups on the basis of TRG. Statistical analysis was performed on a per-lesion basis utilizing the one-way analysis of variance (ANOVA). This retrospective study was approved by our institutional review board; written informed consent was obtained from all patients.ResultsA total of 106 colorectal liver metastases were included for image analysis. TRG1, TRG2, TRG3, TRG4 and TRG5 were observed in 4, 14, 36, 35 and 17 lesions, respectively. ADC_e and ADC_p values were significantly higher in lesions classified as TRG1 (2.40 ± 0.12 × 10⁻⁹ m²/s and 2.28 ± 0.26 × 10⁻⁹ m²/s, respectively) and as TRG2 (1.40 ± 0.31 × 10⁻⁹ m²/s and 1.44 ± 0.35 × 10⁻⁹ m²/s), compared to TRG3 (1.16 ± 0.13 × 10⁻⁹ m²/s and 1.01 ± 0.18 × 10⁻⁹ m²/s), TRG4 (1.10 ± 0.26 × 10⁻⁹ m²/s and 0.97 ± 0.24 × 10⁻⁹ m²/s), and TRG5 (0.93 ± 0.17 × 10⁻⁹ m²/s and 0.82 ± 0.28 × 10⁻⁹ m²/s). ADC_e, ADC_p and ADC_c values were significantly different in TRG classes (p < 0.0001). Statistical correlations were found between the ADC_e, ADC_p, ADC_c values and the TRG classes (Spearman correlation coefficient were −0.568, −0.542 and −0.554, respectively).ConclusionOur study showed a significant correlation between ADC values of 3T DW-MRI and histological TRG of colorectal liver metastases after preoperative chemotherapy.     

Evaluation of tumor blood flow in musculoskeletal lesions: dynamic contrast-enhanced MR imaging and its possibility when monitoring the response to preoperative chemotherapy-work in progress

Purpose The objective of this study was to calculate tumor blood flow (TBF) in musculoskeletal lesions and to evaluate the usefulness of this parameter in differentiating malignant from benign lesions and monitoring the treatment response to preoperative chemotherapy. Materials and methods Altogether, 33 patients with musculoskeletal lesions underwent a total of 50 dynamic magnetic resonance imaging (MRI) examinations, including 28 on 9 patients undergoing preoperative chemotherapy. TBF was calculated using deconvolution analysis. Steepest slope (SS) was determined from the time–intensity curve during the first pass of contrast medium. Results TBF ranged from 2.7 to 178.6 mL/100 mL/min in benign lesions and from 15.4 to 296.3 mL/100 mL/min in malignant lesions. SS ranged from 0.5%/s to 31.8%/s for benign lesions and from 3.1%/s to 64.8%/sec for malignant lesions. TBF and SS did not differ significantly between benign and malignant lesions. Among the nine patients who underwent preoperative chemotherapy, TBF after chemotherapy was lower in good responders (11.7, 11.0, 7.9 mL/100 mL/min) (n = 3, tumor necrosis ≥90%) than in poor responders (23.4–141.5 mL/100 mL/min) (n = 6, tumor necrosis <90%). Conclusion TBF and SS cannot reliably differentiate malignant from benign lesions. However, they have potential utility in evaluating the preoperative treatment response in patients with malignant musculoskeletal tumors.     

Early response of tumour to radiotherapy should be assessed by both uptake and retention of single photon tracers: in vitro analysis with 201Tl-chloride, 99Tcm-sestamibi and 99Tcm-tetrofosmin in human bladder cancer cells and human leukocytes.

The uptake and retention of single photon tracers in irradiated tumour cells was observed in an attempt at the early evaluation of the effect of radiation. T24 human bladder cancer cells were exposed to a single dose of 10 Gy or 20 Gy or a fractionated dose of 10 Gy (2 Gy for 5 days). The uptake of 201Tl chloride, 99Tcm-sestamibi and 99Tcm-tetrofosmin was observed by incubating in vitro for 60 min. The retention of the tracers was observed at 60 min after changing the incubation medium for a tracer-free medium. Uptake per culture well of all tracers in the cells exposed to 20 Gy declined as viable cell number decreased, but uptake per cell increased progressively. Uptake per cell of all tracers in the cells exposed to either a single dose or a fractionated dose of 10 Gy also increased, while a delay in growth was observed. The retention of these tracers decreased during this period and recovered thereafter. A binding assay with purified human leukocytes indicated that assessment with 99Tcm-sestamibi and 99Tcm-tetrofosmin is influenced by inflammatory cells. In conclusion, the effect of radiation may be underestimated if assessed by tracer uptake alone because of the increase in tracer uptake in viable irradiated cells. Observation of the retention of tracers may provide additional information.