MRI-guided lung SBRT: Present and future developments

Stereotactic body radiotherapy (SBRT) is rapidly becoming an alternative to surgery for the treatment of early-stage non-small cell lung cancer patients. Lung SBRT is administered in a hypo-fractionated, conformal manner, delivering high doses to the target. To avoid normal-tissue toxicity, it is crucial to limit the exposure of nearby healthy organs-at-risk (OAR).Current image-guided radiotherapy strategies for lung SBRT are mostly based on X-ray imaging modalities. Although still in its infancy, magnetic resonance imaging (MRI) guidance for lung SBRT is not exposure-limited and MRI promises to improve crucial soft-tissue contrast. Looking beyond anatomical imaging, functional MRI is expected to inform treatment decisions and adaptations in the future.This review summarises and discusses how MRI could be advantageous to the different links of the radiotherapy treatment chain for lung SBRT: diagnosis and staging, tumour and OAR delineation, treatment planning, and inter- or intrafractional motion management. Special emphasis is placed on a new generation of hybrid MRI treatment devices and their potential for real-time adaptive radiotherapy.     

Physics‐based enzyme design: Predicting binding affinity and catalytic activity

Computational enzyme design is an emerging field that has yielded promising success stories, but where numerous challenges remain. Accurate methods to rapidly evaluate possible enzyme design variants could provide significant value when combined with experimental efforts by reducing the number of variants needed to be synthesized and speeding the time to reach the desired endpoint of the design. To that end, extending our computational methods to model the fundamental physical–chemical principles that regulate activity in a protocol that is automated and accessible to a broad population of enzyme design researchers is essential. Here, we apply a physics‐based implicit solvent MM‐GBSA scoring approach to enzyme design and benchmark the computational predictions against experimentally determined activities. Specifically, we evaluate the ability of MM‐GBSA to predict changes in affinity for a steroid binder protein, catalytic turnover for a Kemp eliminase, and catalytic activity for α‐Gliadin peptidase variants. Using the enzyme design framework developed here, we accurately rank the most experimentally active enzyme variants, suggesting that this approach could provide enrichment of active variants in real‐world enzyme design applications. Proteins 2014; 82:3397–3409. © 2014 Wiley Periodicals, Inc.     

奈达铂联合调强放疗对局部晚期鼻咽癌的疗效的作用分析 *

摘要 目的： 分析奈达铂联合强调放疗在局部晚期鼻咽癌患者中的疗效。方法： 选择我院局部晚期鼻咽癌患者 87 例, 随机分为两 个组, 分别是奈达铂组 （ A 组） 和顺铂组 （B 组 ） ,对两组患者接受治疗后的近期疗效、 远期疗效以及毒性反应进行比较分析。结果： A、 B 两组患者鼻咽原发灶完全缓解 （CR ） 率分别为 91.8%、 86.8% （ P=0.632>0.05 ）, 颈部淋巴结转移灶的完全缓解 （CR ） 率分别为 87.8%、 84.2% （ P=0.864>0.05 ）, 均不存在统计学显著性差异。A、 B 两组患者 3 年的总生存率 （ OS ） 分别为： 81.6%、 78.9%, P=0.762; 局部控制率 （ LC ） 分别为： 93.9%、 94.7%, P=0.890; 两组患者 3 年的区域控制率 （RC ） 分别为： 98.0%、 97.3%, P=0.849; 两组患者 3 年 的无远处转移生存率 （DMFS ） 分别为： 79.6%、 76.3%, P= 0.724。A 组患者 Plt 下降发生率为 46.9%显著高于 B 组发生率 34.2% （ P<0.05 ）, 具有统计学显著性差异; A 组患者恶心呕吐的发生率 36.7%显著低于 B 组患者的发生率 76.3% （ P<0.05 ）, 具有统计学显 著性差异; 其余毒性反应的发生率均不存在统计学显著性差异 （P>0.05 ）。结论： 奈达铂联合强调放疗治疗局部晚期鼻咽癌的近期 疗效与远期疗效与顺铂相当, 但是奈达铂胃肠道不良反应发生率较顺铂低, 血小板的降低程度比顺铂更加严重。     

Institutional experience with a rotational total skin electron irradiation (RTSEI) technique—A three decade review (1981–2012)

Total skin electron irradiation (TSEI) for patients with cutaneous lymphomas is technically challenging, and numerous approaches have been developed to overcome the many field matching problems associated with such a large and complex treatment volume. Since 1981 we have delivered TSEI using a rotational total skin electron irradiation (RTSEI) technique in conjunction with patch, treat and boost fields in order to provide complete skin and dose coverage. Initially we used a 6 MeV electron beam at an extended source-skin distance (SSD) on a modified linear accelerator. More recently we began using a high dose rate electron mode on a commercially available linear accelerator. The RTSEI technique allows the delivery of a seamless surface dose to the majority of the patient''s skin surface in a single treatment. In this review paper we present our three-decade experience with the technical development, dosimetry, treatment delivery and clinical outcomes of our RTSEI technique.     

Micronuclei and other nuclear anomalies in normal human buccal mucosa cells of oral cancer patients undergoing radiotherapy: a field effect

We evaluated micronuclei and other nuclear anomalies in exfoliated epithelial cells of the oral cavity on the side opposite the lesion targeted by radiotherapy and correlated them with radiation doses. Buccal smears were obtained from oral cancer patients undergoing radiotherapy with a cumulative dose of at least 1000 rad for 3 weeks and from controls matched for age, gender and habits. The exfoliated cells from the mucosa were collected using a cytobrush; smears were prepared, fixed in 80% methanol and stained using the Feulgen plus fast green method. The mean number of micronuclei and other nuclear anomalies/1000 cells was significantly greater in patients undergoing radiotherapy treatment, but the differences were not significant compared to radiation doses. It appears that radiotherapy has a potent clastogenic effect on buccal mucosal cells of oral cancer patients.     

In silico simulation of the effect of hypoxia on MCF-7 cell cycle kinetics under fractionated radiotherapy

The treatment outcome of a given fractionated radiotherapy scheme is affected by oxygen tension and cell cycle kinetics of the tumor population. Numerous experimental studies have supported the variability of radiosensitivity with cell cycle phase. Oxygen modulates the radiosensitivity through hypoxia-inducible factor (HIF) stabilization and oxygen fixation hypothesis (OFH) mechanism. In this study, an existing mathematical model describing cell cycle kinetics was modified to include the oxygen-dependent G1/S transition rate and radiation inactivation rate. The radiation inactivation rate used was derived from the linear-quadratic (LQ) model with dependence on oxygen enhancement ratio (OER), while the oxygen-dependent correction for the G1/S phase transition was obtained from numerically solving the ODE system of cyclin D-HIF dynamics at different oxygen tensions. The corresponding cell cycle phase fractions of aerated MCF-7 tumor population, and the resulting growth curve obtained from numerically solving the developed mathematical model were found to be comparable to experimental data. Two breast radiotherapy fractionation schemes were investigated using the mathematical model. Results show that hypoxia causes the tumor to be more predominated by the tumor subpopulation in the G1 phase and decrease the fractional contribution of the more radioresistant tumor cells in the S phase. However, the advantage provided by hypoxia in terms of cell cycle phase distribution is largely offset by the radioresistance developed through OFH. The delayed proliferation caused by severe hypoxia slightly improves the radiotherapy efficacy compared to that with mild hypoxia for a high overall treatment duration as demonstrated in the 40-Gy fractionation scheme.     

In vitro radiosensitization of breast cancer with hypoxia‐activated prodrugs

KP167 is a novel hypoxia‐activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU‐55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER_0.01 of 1.60–3.42). KP167 induced greater radiosensitization in TNBC (SER_0.01 2.53 in MDAMB‐231, 2.28 in MDAMB‐468, 4.55 in MDAMB‐436) and luminal spheroids (SER_0.01 1.46 in MCF‐7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER_0.01 of 1.56–2.37 compared with AQ4N SER_0.01 of 1.13–1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs.     

面向生物信息学的工作流管理系统框架

生物信息学实验的实施通常需要整合多种类型的数据和工具,随着大量的web服务、算法程序和分析工具的出现,如何高效整合这些可用资源共同完成分析实验是当前生物信息学研究的重要内容之一,工作流技术已经成为解决这类问题的一种通用机制.然而,生物信息学工作流的实施涉及高通量数据的计算与存储,同时面临着资源异构性和分布性的挑战.本文首先介绍了生物信息学工作流的基本机制,然后阐述了面向生物信息学的工作流管理系统框架,最后讨论了框架应用中存在的问题和可能的解决途径.     

血管内皮抑制素联合调强放疗对老年中晚期非小细胞肺癌的临床应用价值研究

目的探讨血管内皮抑制素联合调强放疗在老年中晚期非小细胞肺癌(NSCLC)中的放疗增敏作用及对T细胞、NK细胞的影响。方法选取2015年3月至2016年8月新疆维吾尔自治区人民医院NSCLC患者106例,依据简单随机数字表法分为对照组(采取调强放疗)与研究组(在对照组基础上使用血管内皮抑制素),每组53例。分析两组临床疗效、治疗前后NK细胞、T细胞水平、血清肿瘤标志物水平、EPO mRNA、EPO-R mRNA水平、毒副反应,随访3年后统计两组生存情况[中位总生存期(OS)、中位无进展生存期(PFS)]。两组比较采用独立样本t检验,组内治疗前后比较采用配对t检验,临床疗效、毒副反应发生率等采用c2检验。结果对照组肿瘤控制率低于研究组(69.81%比86.79%)(P<0.05);与治疗前比较,两组治疗后NK细胞、CD3±、CD4^+、CD4^+/CD8^+水平,血清CA199、CA125、CEA、CY211水平,EPO mRNA,EPO-R mRNA水平均降低,CD8^+水平增高,差异有统计学意义(P均<0.05);与对照组治疗后比较,研究组治疗后NK细胞[(8.01±1.64)%比(10.44±2.13)%]、CD3±[(53.51±6.02)%比(59.33±5.15)%],CD4^+[(32.31±4.01)%比(36.40±3.86)%]、CD4^+/CD8^+[(0.94±0.28)%比(1.23±0.30)%],中位PFS(5个月比8个月)、中位OS(18个月比23个月)升高,CD8^+[(34.22±3.08)%比(29.56±2.50)%],CA199[(35.20±4.46)kU/L比(30.15±4.14)kU/L]、CA125[(34.91±6.03)kU/L比(29.77±5.30)kU/L]、CEA[(22.50±3.97)μg/L比(17.97±4.10)μg/L]、CY211[(7.19±2.01)μg/L比(4.56±1.34)μg/L],EPO mRNA水平(0.85±0.08比0.80±0.06)、EPO-RmRNA水平(0.88±0.09比0.81±0.08)降低,差异具有统计学意义(P均<0.05);与对照组比较,研究组血红蛋白减少、肝肾功能损伤、恶心呕吐、中性粒细胞减少发生率之间比较差异无统计学意义(P>0.05)。结论联合采取调强放疗及血管内皮抑制素治疗老年中晚期NSCLC,可有效提高肿瘤控制率,改善患者生存状况,可能是因其能降低血清肿瘤标志物水平,减轻对免疫功能的影响,调节EPO mRNA、EPO-R mRNA,且具有安全性。     

三维适形放疗治疗食管鳞癌的近期疗效、生存率及预后的影响因素分析

目的:观察三维适形放疗治疗食管鳞癌的近期疗效、生存率并分析其预后的影响因素。方法:纳入我院从2010年11月～2016年10月收治的食管鳞癌患者150例进行研究,按治疗方式的不同分成研究组(n=84,三维适形放疗治疗)和常规组(n=66,常规放疗治疗)。随访3年,比较两组近期疗效、毒副反应发生情况以及3年生存情况。单因素分析研究组患者3年生存情况与性别、年龄、病变长度、病变部位、大体肿瘤体积(GTV)的关系,多因素Logistic回归分析三维适形放疗食管鳞癌患者预后的影响因素。结果:研究组治疗总有效率显著优于常规组(P0.05)。研究组放射性食管损伤、血液毒性反应发生率均显著低于常规组(均P0.05)。研究组1、2、3年存活率均显著高于常规组(均P0.05)。单因素Logistic分析结果显示:不同年龄、病变长度、病变部位以及GTV的食管鳞癌患者三年生存率比较差异有统计学意义(均P0.05)。多因素Logistic回归分析发现年龄≥70岁、病变长度≥50 mm、病变部位为胸下段、GTV≥40 cm3均是三维适形放疗食管鳞癌患者3年内死亡的危险因素。结论:三维适形放疗治疗食管鳞癌患者的近期疗效优于常规放疗,可降低毒副反应发生率,提高生存率。年龄≥70岁、病变长度≥50 mm、病变部位为胸下段、GTV≥40 cm~3均是三维适形放疗食管鳞癌患者3年内死亡的危险因素,值得临床重点关注。