Endocrine therapy for hormone treatment-naïve advanced breast cancer

A proportion of patients with hormone receptor-positive locally advanced or metastatic breast cancer will not have received prior endocrine therapy. However, there are limited clinical data specifically in these patients. We conducted a review of randomized phase II and III clinical studies of anastrozole, letrozole, exemestane, palbociclib, and fulvestrant to determine the evidence base supporting use of specific endocrine therapies in this patient population. From our findings, there is a paucity of clinical studies in patients with endocrine therapy-naïve disease; however, it appears that first-line treatment effects are consistent between patients who have and have not received prior endocrine treatment.     

CBR1 rs9024 genotype status impacts the bioactivation of loxoprofen in human liver

Loxoprofen is an anti‐inflammatory drug that requires bioactivation into the trans‐OH metabolite to exert pharmacological activity. Evidence suggests that carbonyl reductase 1 (CBR1) is important during the bioactivation of loxoprofen. This study examined the impact of the functional single nucleotide polymorphism CBR1 rs9024 on the bioactivation of loxoprofen in a collection of human liver samples. The synthesis ratios of trans‐OH loxoprofen/cis‐OH loxoprofen were 33% higher in liver cytosols from donors homozygous for the CBR1 rs9024 G allele in comparison with the ratios in samples from donors with heterozygous GA genotypes. Complementary studies examined the impact of CBR1 rs9024 on the bioactivation of loxoprofen in lymphoblastoid cell lines. CBR1 rs9024 genotype status impacts the synthesis of the bioactive trans‐OH metabolite of loxoprofen in human liver.     

华蟾素注射液辅助治疗前列腺癌的临床研究

目的研究华蟾素注射液辅助治疗前列腺癌的临床疗效。方法收集2015年1月—2017年2月襄阳市中心医院(湖北文理学院附属医院)肿瘤科收治的前列腺癌患者110例,随机分为对照组和治疗组,每组各55例。对照组患者给予相应的放化疗治疗。治疗组在放化疗开始时即静脉滴注华蟾素注射液,10~20 m L稀释于5%葡萄糖注射液250 m L中,连续用药6 d,停药1 d。连续用药3周为1个疗程,共治疗4个疗程。观察两组的临床疗效,比较两组治疗前后血清前列腺特异抗原(PSA)水平和毒副反应。结果治疗后,对照组客观缓解率(ORR)是69.09%,临床获益率(CBR)是85.45%;治疗组ORR是89.09%,CBR是96.36%,两组ORR、CBR比较差异有统计学意义(P0.05)。治疗后,两组患者血清PSA水平均显著降低,同组治疗前后差异有统计学意义(P0.05);治疗后,治疗组血清PSA水平显著低于对照组,两组比较差异有统计学意义(P0.05)。治疗组患者白细胞减少、恶心呕吐的发生率明显低于对照组,两组比较差异有统计学意义(P0.05)。结论华蟾素注射液辅助治疗前列腺癌临床疗效确切,能显著降低血清PSA水平,减少患者白细胞降低和恶心呕吐的发生率,具有一定的临床推广应用价值。     

影响脑卒中患者日常生活活动能力社区康复效果的相关因素

目的探讨影响脑卒中患者日常生活活动能力（ADL）社区康复效果的相关因素。方法202例脑卒中患者随机分为社区康复组103例和对照组99例，社区康复组进行康复治疗和随访，包括对高危因素的药物控制、康复治疗、卫生宣教、心理疏导等，对照组只进行随访。于入组时和治疗5个月后，应用巴氏指数（BI）、神经功能缺损量表及综合功能评定（FCA）中的认知项，对两组患者进行评定。将所有患者最后一次ADL评分作为因变量，分组情况、病程、高血压、高血脂、糖尿病、吸烟、发病部位、文化程度、性别、年龄、饮酒、睡眠质量、FCA认知功能（入组时）、FCA运动功能（入组时）、BI（入组时）、神经功能缺损程度评分（入组时）做为自变量，进行多元回归分析。结果分组情况、发病前是否饮酒、病程（入组时间早晚）、神经功能缺损评分及综合功能评分（运动功能和认知功能）与患者日后的ADL恢复存在相关性。结论早期社区康复治疗对提高脑卒中患者的ADL作用显著；认知障碍对患者的ADL有显著影响。     

Identification of the Promoter of Human Carbonyl Reductase 3 (<Emphasis Type="BoldItalic">CBR3</Emphasis>) and Impact of Common Promoter Polymorphisms on Hepatic <Emphasis Type="BoldItalic">CBR3</Emphasis> mRNA Expression

Purpose  Recent studies suggest that polymorphisms in human carbonyl reductase 3 (CBR3) influence the pharmacodynamics of doxorubicin. First, we sought to identify the promoter of CBR3. Next, we examined whether two CBR3 promoter polymorphisms (CBR3 -725T>C and CBR3 -326T>A) dictate promoter activity and hepatic CBR3 mRNA levels. Methods  The promoter activities of CBR3 reporter constructs were investigated in HepG2 and MCF-7 cells. CBR3 mRNA levels were documented in 95 liver samples from white (n = 62) and black (n = 33) donors. Genotype-phenotype correlation analyses were used to determine the impact of the CBR3 -725T>C and CBR3 -326T>A polymorphisms on hepatic CBR3 mRNA levels. Results  We identified the promoter of human CBR3. Liver samples from black donors showed higher relative CBR3 mRNA levels than samples from whites (CBR3 mRNA_blacks = 3.0 ± 3.1 relative fold vs. CBR3 mRNA_whites = 1.6 ± 1.5 relative fold, p = 0.021). The variant -725C and -326A alleles did not modify the gene reporter activities of engineered CBR3 promoter constructs. In line, hepatic CBR3 mRNA levels were not associated with CBR3 -725T>C and CBR3 -326T>A genotype status. Conclusions  These studies provide the first insights into the regulation and variable hepatic expression of polymorphic CBR3.     

Indignity,exclusion, pain and hunger: the impact of musculoskeletal impairments in the lives of children in Malawi

Purpose: To develop a conceptual model representing the impact of musculoskeletal impairments (MSIs) in the lives of children in Malawi. Method: A total of 169 children with MSIs (CMSIs), family and other community members participated in 57 interviews, focus groups and observations. An inductive approach to data analysis was used to conceptualise the impact of MSIs in children’s day-to-day lives. Results: The main themes that emerged were Indignity, Exclusion, Pain and Hunger. Indignity represents various affronts to children’s sense of inherent equal worth as human beings, for example when bullied by peers. Exclusion refers to CMSIs being excluded from three core daily activities: school, play and household chores. Some CMSIs experienced Pain, for example as an outcome of striving to participate. Children with severe mobility impairments were at increased risk of Hunger, having less access to food outside the home and placing a burden of care on the family that could restrict household productivity. Household Poverty was therefore included in the model, as this household impact was inseparable from the impact on CMSIs. Conclusion: It is recommended that rehabilitation interventions are planned and evaluated with consideration to their impact on Exclusion, Indignity, Pain, Hunger and Household Poverty using multi-faceted partnerships.

Implications for Rehabilitation

• Rehabilitation interventions in Malawi and similar developing nations would benefit from being planned and evaluated with attention to their impact on Exclusion, Indignity, Pain, Hunger, and Household Poverty.

• To this end the development of new evaluative instruments for children with disabilities in these settings is needed and should be based on empirical evidence including the concepts presented in this paper.

     

A systematic review of dual targeting in HER2-positive breast cancer

Background

Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15–20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer.

Materials and methods

A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.

Results

This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.

Conclusion

Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.