The promises and challenges of patient-derived tumor organoids in drug development and precision oncology

In the era of precision medicine,cancer researchers and oncologists are eagerly searching for more realistic,cost effective,and timely tumor models to aid drug development and precision oncology.Tumor models that can faithfully recapitulate the histological and molecular characteristics of various human tumors will be extremely valuable in increasing the successful rate of oncology drug development and discovering the most efficacious treatment regimen for cancer patients.Two‐dimensional(2D)cultured cancer cell lines,genetically engineered mouse tumor(GEMT)models,and patient‐derived tumor xenograft(PDTX)models have been widely used to investigate the biology of various types of cancers and test the efficacy of oncology drug candidates.However,due to either the failure to faithfully recapitulate the complexity of patient tumors in the case of 2D cultured cancer cells,or high cost and untimely for drug screening and testing in the case of GEMT and PDTX,new tumor models are urgently needed.The recently developed patient‐derived tumor organoids(PDTO)offer great potentials in uncovering novel biology of cancer development,accelerating the discovery of oncology drugs,and individualizing the treatment of cancers.In this review,we will summarize the recent progress in utilizing PDTO for oncology drug discovery.In addition,we will discuss the potentials and limitations of the current PDTO tumor models.

Evaluation of the Effect of Chemotherapeutic Drug Training on Mobile Terminal for Neuro-Oncology Nurses Based on Kirkpatrick’s Model

Background: Since there has been training, there has been discussion about the effect of training. But training evaluation is not systematic until Kirkpatrick came up with the training evaluation model in 1959. At present, the prevailing model in the systematic summary of training evaluation is still The Kirkpatrick’s model. This model was further improved in 1994, more responsive to contemporary needs, and thus widely used all over the world. At the beginning, it was widely used in human resource management of enterprises. In recent years, this model has been gradually used in the medical field to evaluate the effect of medical training. The Kirkpatrick’s model has a systematic, integrated and persuasive evaluation system for trainees. It has good effects in the pre-service nurse training, the professional image and code of conduct nurses training, and the geriatric nurse training. At present, there are few studies on the chemotherapeutic drug training of neurologist nurses in China. In clinical work, nurses’ cognitive and practical behaviors of chemotherapeutic drug protection and drug extravasation prevention and treatment are insufficient. It directly harms the health of nursing staff and increases the complications of chemotherapy, increases pain of tumor patients, delays or interrupts chemotherapy, and aggravates the economic burden of patients. Especially, Chemotherapeutic drugs for neuro-oncology have particularity and necessity of urgent training. Objective: To investigate the effect of chemotherapeutic drug training through mobile terminal for neuro-oncology nurses based on the Kirkpatrick’s model. Methods: The training content and evaluation questionnaire for chemotherapeutic drugs were designed by nursing management personnel and senior nurses in our department according to the guidelines and common diseases requiring chemotherapy in the department. The content includes the basic knowledge of neuro-oncology chemotherapy, pharmacological knowledge, toxic and side effect of chemotherapy, etc., which are regularly pushed through the mobile terminal-WeChat. Forty nurses participated in the training and the effect is evaluated by Kirkpatrick’s model. Result: After the training, 100% of nurses were satisfied with the training content and 97.5% with the training form. The scores of nurses in learning level such as basic pharmacological knowledge, drug configuration and exposure, drug treatment and infusion, observation of toxic and side effects, and treatment of drug extravasation were significantly higher than those before the training (P < 0.01). The scores of nurses in the behavior level such as drug allocation, health education, toxic and side effect observation and prediction, treatment of exosmosis, occupational protection were significantly higher than those before the training. After the training, the satisfaction of managers, chemotherapy physicians and chemotherapy patients on the behavior of nurses was significantly higher than that before the training (P < 0.01). Conclusion: The chemotherapeutic drug training through mobile terminal based on Kirkpatrick’s model can improve the ability of neuro-oncology nurses, so as to improve the satisfaction of physicians and patients.

Immuno-oncology combinations： raising the tail of the survival curve

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Pharmacogenomics in oncology

Precision therapy in the field of oncology is rapidly developing. Numerous somatic genetic markers in eg tyrosine kinase receptors or transcription factors have been identified to be indicative for the treatment with anti-cancer drugs. In contrast, only some recommendations have been developed considering hereditary variants in drug metabolizing enzymes such as TPMT, DYPD or UGT1A1. Although a huge knowledge has been gained on the association of drug transporters variants such as ABCB1 or ABCG2 and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. However, there is increasing evidence that individual phenotypic differences may result not only from genetics, but also from epigenetic alterations such as histone-acetylation or DNA-methylation. Moreover,interactions with non-coding RNAs contribute to protein expression and may modulate drug action. Currently intriguing developments of novel therapeutic approaches through epigenetic drugs are emerging. The overall complexity of epigenetics in drug action is so far only little understood. Of significant importance are the consequences of mi RNA interaction for drug resistance in cancer by regulating target genes and efflux transporters. Further intriguing findings address DNAmethylation as modifier of transporter function and its consequences in cancer development and treatment. The progress of science may lead to the discovery of rare, but functionally relevant SNPs and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.

Use of antiepileptic drugs in children with brain tumors: A review for acute management

Patients with primary or secondary tumors in the central nervous system may have seizures resulting from direct tissue damage,metabolic abnormalities,infection,or toxic side effects of medications.In pediatric patients,it is more frequent to use drugs to control secondary epilepsy.In this article,we discuss the main nuances of antiepileptic drugs for the proper management of children with central nervous system tumors.

Establishment of organoid models based on a nested array chip for fast and reproducible drug testing in colorectal cancer therapy

The conventional microwell-based platform for construction of organoid models exhibits limitations in precision oncology applications because of low-speed growth and high variability. Here, we established organoid models on a nested array chip for fast and reproducible drug testing using 50% matrigel. First, we constructed mouse small intestinal and colonic organoid models. Compared with the conventional microwell-based platform, the mouse organoids on the chip showed accelerated growth and improved reproducibility due to the nested design of the chip. The design of the chip provides miniaturized and uniform shaping of the matrigel that allows the organoid to grow in a concentrated and controlled manner. Next, a patient-derived organoid(PDO) model from colorectal cancer tissues was successfully generated and characterized on the chip. Finally, the PDO models on the chip, from three patients, were implemented for high-throughput drug screening using nine treatment regimens. The drug sensitivity testing on the PDO models showed good quality control with a coefficient of variation under 10% and a Z’ factor of more than 0.7. More importantly, the drug responses on the chip recapitulate the heterogeneous response of individual patients, as well as showing a potential correlation with clinical outcomes. Therefore,the organoid model coupled with the nested array chip platform provides a fast and reproducible means for predicting drug responses to accelerate precise oncology.

细胞微环境介导肿瘤耐药性的动力学建模研究进展

肿瘤耐药性是限制癌症疗效的最大障碍之一,肿瘤微环境在耐药性的发生发展过程中发挥着重要的作用.为了深入探究微环境介导肿瘤耐药性的作用和机制,需要全面系统地研究药物治疗过程中肿瘤生态系统的动态演化.数学模型可用于描述肿瘤微环境中的各种组分的相互作用和变化,进而揭示微环境介导肿瘤耐药性的机理和演化规律,并为设计更有效的治疗策略提供参考和依据.本文首先介绍了微环境介导肿瘤耐药性的生物学知识和相关概念;随后分类介绍了几类典型数学模型的最新研究进展;之后以脑胶质瘤微环境为例,介绍了使用不同方法建立耐药性的演化动力学模型的流程;最后展望了进一步的研究方向.

我院妇科抗肿瘤药物超说明书用药分析及循证评价

目的调查分析本院妇科抗肿瘤药物超说明书用药情况,并进行循证评价,为临床合理用药提供参考依据。方法提取我院2022年7月—2023年6月妇科住院患者使用抗肿瘤药物的医嘱,整理所有超说明书用药信息并记录,包括适应证、用法用量等。根据我院循证评价标准对相关循证证据进行评价。结果共纳入患者218人次,涉及抗肿瘤药物21种,相关医嘱1417条。超说明书用药169人次(占77.53%),符合超说明书用药的抗肿瘤药物19种,相关医嘱658条(占46.43%),超说明书用药类型以超适应证用药为主(占94.98%)。循证评价分析显示证据强度多为中等强度及以上(占88.15%)。结论妇科抗肿瘤药物超说明书用药情况普遍,均有循证医学证据支持,但个别用法证据等级较低,需加强管理,保障用药安全。

骨髓增生异常综合征在斑马鱼中的研究进展

骨髓增生异常综合征(myelodysplastic syndrome,MDS)是一种常见的血液疾病,其发病率呈现逐年上升的趋势。斑马鱼作为一种生物医学研究的模式生物,广泛应用于各类疾病的研究中。本文关注了近年来血液疾病在斑马鱼中的研究,MDS在小鼠、大鼠和斑马鱼中的研究及动物模型的应用,揭示了斑马鱼模型在其中发挥的重要作用。

干扰素刺激基因在肿瘤免疫中作用机制的研究进展

干扰素刺激基因(ISGs)是一种经干扰素诱导、刺激后显著表达的基因。可通过免疫抑制分子的浸润,免疫检查点抑制,免疫编辑等方式抑制或者促进肿瘤细胞的生长浸润。本文对ISGs在肿瘤免疫中的具体作用机制及其在肿瘤药物治疗中发挥的作用作一综述,有望为开发更为精准的治疗策略提供理论基础。

R语言实例解析肿瘤治疗药物经济学评价的分区生存模型

分区生存模型(partitioned survival model,PSM)作为药物经济学(pharmacoeconomics,PE)评价的一种决策模型,因其简单直观的特点,以及其分析数据直接源于临床文献且避免了复杂的状态间转移概率计算,在国外肿瘤治疗PE评价中得到广泛应用。R语言在进行肿瘤治疗药物PE评价的PSM分析中,以其快捷、直观且易于复现结果的特点,已在欧美研究者的多年应用经验中形成了多种功能专用程序包,极大地提高了研究效率。然而,我国采用R语言进行肿瘤治疗药物的PSM分析相关研究较少。本研究结合实际案例详细展示基于R语言进行肿瘤治疗药物PSM分析的完整操作流程,以期为该领域的研究者提供参考。

肿瘤内科发热性中性粒细胞减少患者药物治疗临床路径的应用探索

目的在肿瘤内科建立发热性中性粒细胞减少(FN)患者药物治疗临床路径(临床药径),以促进临床合理用药,降低药品费用支出。方法基于93例肿瘤内科FN患者的用药合理性分析,建立以循证药学为基础的FN临床药径,并采用计划-实施-检查-处理循环法对其进行完善。比较FN临床药径实施前后FN患者抗菌药物应用情况、抗菌药物联合应用情况、血培养送检率和“升白”药物不合理应用情况。结果FN临床路径实施后,抗菌药物总不合理占比、疗程过长占比、疗程和人均用药金额均低/短于实施前;抗菌药物单用占比和血培养送检率均较实施前明显上升,抗菌药物二联占比较实施前降低;应用“升白”药物总不合理率较实施前低(均P<0.05)。结论在肿瘤内科建立基于循证药学的FN患者临床药径新模式,可促进临床合理用药,减少药品费用支出,降低患者经济压力。

肿瘤科安全用药管理方法及价值探讨

目的探讨肿瘤科安全用药管理方法的有效性和价值。方法选取2023年1—12月麻城市人民医院肿瘤科58名医务人员为研究对象。2023年1—6月为对照组,实施传统的用药管理方式。2023年7—12月为研究组,实施改进的安全用药管理措施。分别从两组抽取361份处方进行研究。比较两组医务人员工作质量及处方审核合格率。结果研究组药物选择合理性、用药执行准确性评分高于对照组,差异有统计学意义(P均<0.05)。研究组处方审核合格率为98.6%(356/361),高于对照组的91.7%(331/361),差异有统计学意义(χ^(2)=18.767,P<0.05)。结论改进的安全用药管理措施能够有效提高医务人员工作质量,提高处方审核合格率。

肿瘤患者药物临床试验参与动机及影响因素的质性研究

探讨肿瘤患者参加药物临床试验的动机以及影响因素。采用描述性质性研究方法,对16名参加药物临床试验的肿瘤患者进行深入访谈,运用内容分析法对访谈资料进行整理分析。共归纳出2个主题:参与动机(包括对新药治疗的希望、医生建议参与药物临床试验、减轻经济负担、为社会作贡献)、影响因素(包括家人及亲朋好友的反对、对治疗效果的担忧、对药物不良反应的恐惧、药物临床试验相关知识缺乏、时间及交通不便)。因此,研究人员应从患者的角度出发,加强沟通交流,避免治疗性误解,帮助患者理性参与决策,减少患者的参与阻碍因素,以促进受试者招募。

药物递送微球的制备及其在肿瘤治疗领域的应用

微球是一种理想的药物递送系统,为肿瘤治疗提供了新的手段。负载在微球中的抗肿瘤药物能够以可控且持续的方式释放,从而增强疗效,降低药物的副作用和毒性。药物递送微球的制备方法包括乳化溶剂挥发法、相分离法、喷雾干燥法、微流控技术等。这些方法具有各自的优势及局限。根据制备材料的不同,药物递送微球可分为天然聚合物微球、合成聚合物微球和生物陶瓷微球。天然聚合物微球具有良好的生物相容性和可降解性,合成聚合物微球机械性能优异,生物陶瓷微球因其具有生物相容性和特定的生物功能而广泛应用于骨组织工程领域。药物递送微球治疗肿瘤的方式多种多样,除传统的化疗外,还包括光热疗法、光动力疗法、放射性栓塞治疗和免疫治疗等。本文综述了当前微球作为纳米药物递送系统在肿瘤治疗中的最新进展,以期为微球的临床转化和推广应用提供参考。

真实世界研究的临床应用进展

真实世界研究(RWS)起源于实用性临床试验(PCT),其采取广泛的纳入标准,按照受试者的意愿,不使用安慰剂,因此更符合真实的临床情况。近年来,RWS受到各个领域的重视和应用。本文就RWS的起源、定义、发展概况以及在医学各领域的应用的研究进展进行综述,以期更好地服务临床。

Patient-derived xenograft models for oncology drug discovery

The success of targeted therapies for cancer patients rests on three major components:the right target(s),the right drug and drug combination,and the right patient population.Although much progress has been made in understanding the mechanism of disease and in refi ning pharmaceutical properties of therapeutic agents,the attrition rates between target discovery and drug marketing approval have been high,especially in oncology.One of the main reasons underlying this undesirable statistics is believed to be the lack of predictive power of the model systems used in the preclinical setting.Several strategies have been employed with the aim of improving the predictive value of the preclinical studies,such as incorporating genomic profi ling and molecular segmentation into model selection,and enhancing the development and application of patient-derived xenograft models even during early stage of drug discovery.This brief review will summarize some of the recent concept and practice in incorporating patient-derived models into all stages of drug discovery process,from target to clinical development.

化疗药物对肿瘤科护士的职业暴露调查及防护策略

目的:提高肿瘤科护士对化疗药物职业暴露的认识,提高自我保护意识,防止职业损伤,保证护理人员的安全。方法:采用自行设计的调查问卷对45名接触化疗药物的护士进行问卷调查。结果:90%的人能说出化疗药物的危害性,80%的人能说出化疗药物的危害途径,51%的人采取了相应的防护措施。结论:肿瘤科护士对化疗药物的危害性认识不足,自我防护意识薄弱,无完善的化疗防护措施。加强职业安全教育和管理,严格各项操作规程,完善的防护措施和休息制度,能有效控制护理人员职业暴露可能带来的危害,保障了护理人员的安全和身体健康。

DRGs视角下医改对肿瘤专科医院的绩效影响分析

目的分析DRGs视角下医药分开综合改革政策对肿瘤专科医院的绩效影响,为改革的进一步推进提供支撑。方法回顾性检索2016年1月—2018年3月病历资料,采用χ~2或t检验来推断改革前后的绩效影响。结果改革后,外地医保患者比例同比上涨3.28%,外科出院病人比例下降5.23%,平均住院日下降了0.53天,次均药费下降2 652.36元,DRGs组数增加9.78%,CMI下降5.49%。结论医药分开综合改革,实现了患者就医获得感的提升,但给DRGs绩效考核手段带来不确定性,需要不断探索改革期间的绩效评价模型。

北京市医药分开综合改革对肿瘤专科医院的影响——基于北京某肿瘤医院医保数据的实证分析

目的:分析北京市医药分开综合改革对肿瘤专科医院医保人群收治产生的政策影响,为改革的进一步开展和调整提供依据。方法:运用间断时间序列数据的分段回归模型,分析某肿瘤医院医保的门诊、住院、特种病的服务利用情况,以及其中药占比和患者自付比等在改革后的即时变化和趋势变化。结果:肿瘤治疗存在相对特异性,肿瘤专科医院的既往住院药占比介于49.31%~49.96%之间、实际补偿比介于57.05%~63.57%之间。医药分开综合改革后,案例医院医保人群的费用负担水平出现即刻变动并且呈现趋势变化,门诊人群次均费用的改革变化为-4.33元/月、实际负担率的改革变化为-2.32%/月;药占比下降,改革后门诊与住院药占比分别出现4.63%、2.98%的下降;材料占比有所升高,改革后门诊与住院材料占比分别出现0.22%、1.17%的上涨。结论:改革减弱了医院对药品收入的依赖,减轻了患者负担,但肿瘤治疗存在刚性需求,对医院财务以及基金会带来相对大的冲击,并且需要考虑费用平移后费用去向的临床合理性。