乳腺癌新辅助化疗的研究进展

乳腺癌是一种女性最常见的恶性肿瘤,近年来我国乳腺癌的发病率呈逐年上升趋势。研究证实,新辅助化疗不仅可使不能手术的晚期乳腺癌患者获得手术机会,而且也增加了部分患者的保乳概率,但是约20%的乳腺癌患者不能从新辅助化疗中获益,并影响后续治疗效果。因此,制定合理的、个体化的新辅助化疗方案对于提高乳腺癌患者的生存质量和改善其预后尤为重要。目前,研究已发现的NCT相关的预测因子主要包块肿瘤类型、分子分型、ER、PR、Ki67等,而HER2、TOP2A、P53、PRAP单独作为预测因子的还存在争议。本文主要对乳腺癌新辅助化疗的现状、各种预测因子的作用及其不足之处进行了综述。     

Anaplastic thyroid cancer: outcomes of trimodal therapy

BackroundThe purpose of this study is to assess the impact of trimodal therapy [surgery, chemotherapy and external beam radiotherapy (EBRT)] in patients with anaplastic thyroid cancer (ATC) treated with curative intent.Materials and methodsRetrospective review of patients with ATC treated at a tertiary referral centre between January 2009 and June 2020. Data were collected regarding demographics, histology, staging, treatment and outcomes.ResultsSeven patients (4 female) were identified. Median age was 58 years (range 52–83 years). All patients received EBRT with concurrent doxorubicin. Six patients received surgery followed by chemoradiotherapy (CRT), and one underwent neoadjuvant CRT followed by surgery. Median radiological tumour size was 50mm (range 40–90 mm). Six patients had gross extrathyroidal extension and three had N1b disease. Prescribed radiotherapy schedules were 46.4 Gy in 29 bidaily fractions (n = 2, treated 2010), 60 Gy in 30 daily fractions (n = 2), 66 Gy in 30 fractions (n = 2) and 70 Gy in 35 fractions (n = 1; patient received neoadjuvant CRT). CRT was discontinued early for two patients due to toxicities. At median follow up of 5.8 months, 42.9% (3/7) patients were alive and disease-free. Only one patient developed a local failure. Three patients died from distant metastases without locoregional recurrence.ConclusionsDespite poor prognosis of ATC, selected patients with operable tumours may achieve high locoregional control rates with trimodal therapy, with possibility of long-term survival in select cases.     

sFas levels increase in response to cisplatin-based chemotherapy in lung cancer patients

The Fas/Fas Ligand (FasL) system and survivin have counteracting roles in cell survival. Therefore, we explored the role of circulating soluble Fas (sFas) and the tissue levels of Fas and survivin with regard to response to chemotherapy in lung cancer patients. Serum samples from 52 lung cancer patients and 54 control subjects (19 benign lung disease and 35 healthy control subjects) were collected prior to and 24 and 48 h after chemotherapy. sFas was statistically significantly higher in the cancer group than that in the control groups (p < 0.001). Baseline (before chemotherapy) sFas values showed a statistically significant inverse correlation with overall survival (r = ?0.599, p < 0.001). There was a significant increase in serum sFas levels 24 h after treatment (p < 0.05). Contrarily, tissue levels of Fas and survivin were not changed following the chemotherapy (p > 0,05). In conclusion, increased sFas may be an indicator of poor outcome in lung cancer patients. However, cisplatin‐based chemotherapy may not be effective via neither the Fas/FasL system nor survivin pathway. Indeed, larger sample size is required for further evaluation. Copyright © 2010 John Wiley & Sons, Ltd.     

Cancer chemotherapy induces cardiotoxicity by targeting cardiac stem cells

Overwhelming data indicate that cancer survivors are at higher risk of cardiovascular diseases because chemotherapy induces cardiotoxicity. Mechanistic explanation of this phenomenon is necessary to advise the clinical practice on the prevention of cardiotoxicity in cancer patients. Here we propose that chemotherapy induces cardiotoxicity by inadvertently interrupting the homeostasis of cardiac stem cells and depleting the resident cardiac stem cells pool. As a result, the heart loses the capability of regeneration and repair and demonstrates the cardiotoxicity symptoms. Our hypothesis is supported by several lines of emerging evidence: the high incidence of cardiotoxicity in paediatric cancer patients who still have more cardiac stem cells in the myocardium; the rescue of anthracycline cardiomyopathy by injection of cardiac stem cells; and the adverse cardiotoxicity induced by inhibitors of oncogenic kinases or pathways which target cardiac stem cells besides cancer cells. This may promote our growing appreciation that cardiac stem cells represent new targets of chemotherapy that contribute to cardiotoxicity and open up novel strategies for the preservation or expansion of the cardiac stem cells pool to overcome cardiotoxicity associated with chemotherapy.     

Cyclin A2 confers cisplatin resistance to endometrial carcinoma cells via up‐regulation of an Akt‐binding protein,periplakin

Although overexpression of cyclin A2 is reportedly an indicator of a poor prognosis of various malignancies including endometrial carcinoma, its molecular mechanism remains undetermined. To address this issue, we examined the effect of cyclin A2 on the development of resistance to chemotherapeutic drugs. The expression of cyclin A2 protein was increased in advanced‐stage and chemotherapy‐refractory stage endometrial carcinomas compared with that in early‐stage tumours. The expression levels of cyclin A2 in endometrial carcinoma cell lines correlated positively with the IC₅₀ for cisplatin. Endometrial carcinoma HHUA cells that overexpressed cyclin A2 showed increased resistance to cisplatin in vitro and in vivo, via the activation of a survival pathway, the inositol‐3 phosphate kinase (PI3K) cascade. The use of a cDNA microarray identified an Akt‐binding protein, periplakin, as a novel target of cyclin A2. The cyclin A2‐induced up‐regulation of periplakin was mediated via direct binding of Sp1 to the promoter that was activated by cyclin A2 along with chromatin remodelling involving CBP/p300, and the siRNA‐mediated silencing of periplakin suppressed the PI3K pathway. These results indicate cyclin A2 to be involved in the acquisition of aggressive behaviour of tumour cells through the activation of PI3K by cyclin A2‐induced periplakin, and to be a promising therapeutic target.     

Model‐free feedback design for a mixed cancer therapy

In this article, a model‐free feedback control design is proposed for the drug administration in mixed cancer therapy. This strategy is very attractive because of the important issue of parameter uncertainties unavoidable when dealing with biological models. The proposed feedback scheme use past measurements to update an on‐line simplified model. The control design is then based on model predictive control in which a suitable switching is performed between two different cost functions. The effectiveness of the proposed model‐free control strategy is validated using a recently developed model (unknown to the controller) governing the cancer growth on a cells population level under combined immune and chemotherapy and using real human data. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009     

化疗性静脉炎小鼠模型的建立

目的通过静脉注射盖诺(vinorelbine,VNB)为化疗性静脉炎(chemotherapy induced phlebitis,CIP)研究,提供效果稳定的CIP模型。方法49只成年小鼠随机分为6个实验组和1个对照组。实验组小鼠分别从右侧鼠尾静脉注射不同浓度的等体积VNB溶液,对照组则注射等体积生理盐水。注射后第5天对CIP临床表现进行分级评价后处死。制作石蜡切片并进行镜下分级。结果随注射VNB浓度及剂量的增加,小鼠静脉炎发生率也逐渐增高,但浓度剂量过高动物出现中毒死亡。用3.2mg/ml的VNB按38mg/kg注射组CIP发生率达100%,无动物死亡,出现红斑、水肿、条索状改变等典型CIP临床症状和内皮脱落、炎细胞浸润、组织水肿等CIP镜下改变,对照组未出现类似变化。结论本实验通过鼠尾静脉注射VNB成功建立了小鼠CIP模型。     

Species differences in tumour responses to cancer chemotherapy

Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies.     

An Integrated Approach for Analysis of the DNA Damage Response in Mammalian Cells: NUCLEOTIDE EXCISION REPAIR,DNA DAMAGE CHECKPOINT,AND APOPTOSIS*

DNA damage by UV and UV-mimetic agents elicits a set of inter-related responses in mammalian cells, including DNA repair, DNA damage checkpoints, and apoptosis. Conventionally, these responses are analyzed separately using different methodologies. Here we describe a unified approach that is capable of quantifying all three responses in parallel using lysates from the same population of cells. We show that a highly sensitive in vivo excision repair assay is capable of detecting nucleotide excision repair of a wide spectrum of DNA lesions (UV damage, chemical carcinogens, and chemotherapeutic drugs) within minutes of damage induction. This method therefore allows for a real-time measure of nucleotide excision repair activity that can be monitored in conjunction with other components of the DNA damage response, including DNA damage checkpoint and apoptotic signaling. This approach therefore provides a convenient and reliable platform for simultaneously examining multiple aspects of the DNA damage response in a single population of cells that can be applied for a diverse array of carcinogenic and chemotherapeutic agents.