Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.     

US Food and Drug Administration Analysis of Patient-Reported Diarrhea and Its Impact on Function and Quality of Life in Patients Receiving Treatment for Breast Cancer

ObjectivesMany trials conclude “no clinically meaningful detriment” to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration.MethodsThis study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months.ResultsGenerally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms.ConclusionsIn trials with moderate to large differences in symptomatic toxicity by arm, reporting “no meaningful difference in functioning and HRQL between arms” based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent.     

基于住院病案首页数据的全国部分医院心血管临床专科评估探索

目的运用“基于住院病案首页数据的心血管临床专科评估框架”,对全国部分医院的心血管临床专科进行评估。方法梳理112所医院心血管专科重点疾病和重点手术操作的编码情况,计算评估框架中的各个指标,根据医院纳入标准,运用基于数据的多指标综合评价方法,对医院进行打分排序。结果112所医院2010—2012年心血管疾病患者出院人次、重点疾病和重点手术/操作缺失数量均呈偏态分布。按照综合评价医院的纳入标准共56所医院纳入排序,前十位是YN05、SD04、BJ14、SH02、ZJ01、HN01、SX09、YN08、SD01、SX08。重点疾病和重点手术操作均完整的医院共12所,其排序是:BJ14、SH02、HN02、BJ01、TJ01、SH05、SC01、NA03、GD02、SH08、YN03、HL01。本研究综合评价的56所医院中,有30所在国家公布的名单之内,26所不在国家公布的名单之内。结论运用“基于住院病案首页数据的心血管临床专科评估框架”进行心血管临床专科评估是科学、可行的,为专科评估方法提供了新的思路,为专科对口支援建设提供了数据支持。     

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer

BackgroundFamily history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.ObjectiveTo detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.Design, setting, and participantsA two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls.Outcome measurements and statistical analysisFrequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls.Results and limitationsEleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa.ConclusionsOur approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease.Patient summaryMultiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.     

Cost-effectiveness of postmastectomy hypofractionated radiation therapy vs conventional fractionated radiation therapy for high-risk breast cancer

BackgroundThe phase 3 NCT00793962 trial demonstrated that postmastectomy hypofractionated radiation therapy (HFRT) was noninferior to conventional fractionated radiation therapy (CFRT) in patients with high-risk breast cancer. This study assessed the cost-effectiveness of postmastectomy HFRT vs CFRT based on the NCT00793962 trial.MethodsA Markov model was adopted to synthesize the medical costs and health benefits of patients with high-risk breast cancer based on data from the NCT00793962 trial. Main outcomes were discounted lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). We employed a time-dependent horizon from Chinese, French and USA payer perspectives. Model robustness was evaluated with one-way and probabilistic sensitivity analyses.ResultsPatients receiving CFRT versus HFRT gained an incremental 0.0163 QALYs, 0.0118 QALYs and 0.0028 QALYs; meanwhile an incremental cost of $2351.92, $4978.34 and $8812.70 from Chinese, French and USA payer perspectives, respectively. Thus CFRT versus HFRT yielded an ICER of $144,281.47, $420,636.10 and $3,187,955.76 per QALY from Chinese, French and USA payer perspectives, respectively. HFRT could maintain a trend of >50% probabilities of cost-effectiveness below a willingness-to-pay (WTP) of $178,882.00 in China, while HFRT was dominant relative to CFRT, regardless of the WTP values in France and the USA. Sensitivity analyses indicated that the ICERs were most sensitive to the parameters of overall survival after radiotherapy.ConclusionsPostmastectomy HFRT could be used as a cost-effective substitute for CFRT in patients with high-risk breast cancer and should be considered in appropriately selected patients.     

Incidence,risk factors and survival of patients with brain metastases at initial metastatic breast cancer diagnosis in China

PurposeTo characterize the incidence, risk factors and survival of patients with brain metastases at initial diagnosis of metastatic breast cancer (MBC) in China.MethodsThe China National Cancer Center database was used to identify 2087 MBC patients diagnosed between 2003 and 2015. Clinicopathological features, treatment and survival information were extracted. Multivariable logistic and Cox regression were performed to determine factors predictive of brain metastases at MBC diagnosis and survival, respectively.ResultsBrain metastases occurred in ninety patients (4.3%) at MBC diagnosis, and in 27 patients (2.5%), 42 patients (7.2%) and 21 patients (5.2%) with hormone receptor positive, human epidermal growth factor receptor 2 negative (HR + HER2-), HER2-positive and triple negative breast cancer (TNBC), respectively. HER2-positive subtype (OR = 2.38; 95% CI 1.40–4.04; p < 0.0001), TNBC subtype (OR = 1.89; 95% CI 1.02–3.51; p = 0.005), and metastases to all three sites of bone, liver and lungs (OR = 3.23; 95% CI 1.52–6.87; p = 0.002) were shown to increase the risk of BM at MBC diagnosis. Median survival after BM was 23.7 months. First-line tyrosine kinase inhibitors (TKI) improved survival compared to trastuzumab-based regimen (44.9 vs 35.4 months, p = 0.09). Factors that independently decreased BM death risk were ECOG<2, brain metastases only and multidisciplinary treatment.ConclusionHER2-positive and TNBC subtypes have a higher incidence of BM at initial MBC diagnosis. Brain screening might be considered in patients with HER2-positive disease at MBC diagnosis, and further prospective randomized study is warranted.     

68Ga-PSMA PET/CT在前列腺癌术前诊断及手术策略制订中的应用

目的评估⁶⁸Ga标记的前列腺特异性膜抗原(⁶⁸Ga-PSMA)PET/CT对前列腺癌的诊断效能,并探讨⁶⁸Ga-PSMA PET/CT对术前制订保留血管神经束(NVB)和淋巴结清扫策略的指导作用。方法回顾性分析2018年6月至2019年10月中国医学科学院肿瘤医院行⁶⁸Ga-PSMA PET/CT检查的46例初诊疑似前列腺癌患者的临床资料。中位年龄66.50(60.00,69.25)岁,中位前列腺特异性抗原(PSA)值15.97(8.58,33.10)ng/ml。46例中,41例⁶⁸Ga-PSMA PET/CT检查诊断为肿瘤,6例诊断有淋巴结转移;5例诊断为前列腺增生或前列腺炎。46例中40例同期行mpMRI检查,33例诊断为肿瘤,6例诊断有淋巴结转移;46例中17例同期行^11C-胆碱PET/CT检查,12例诊断为肿瘤,4例诊断有淋巴结转移。41例PSMA-PET/CT诊断为前列腺癌的患者中,高危22例,中危19例;其中37例行mpMRI检查,15例行^11C-胆碱PET/CT检查。41例均行根治性前列腺切除术。根据⁶⁸Ga-PSMA PET/CT显示的肿瘤位置,术前制订NVB处理策略:若肿瘤邻近前列腺单侧包膜,则保留健侧的NVB;若肿瘤局限于前列腺内,则保留双侧NVB。共16例保留了NVB(单侧6例,双侧10例)。对中高危组患者常规行淋巴结清扫。采用配对χ²检验或Fisher精确检验比较⁶⁸Ga-PSMA PET/CT、mpMRI、^11C-胆碱PET/CT对病灶检出的敏感性和特异性。采用Spearman相关分析检测⁶⁸Ga-PSMA PET/CT的SUV_max值与Gleason评分和治疗前PSA值的相关性。结果 41例行根治术患者术后病理确诊为前列腺癌,手术切缘均未见癌组织;中位Gleason评分8(7,9)分;病理分期20例≤pT_2c期,21例≥pT₃期;7例淋巴结阳性(11枚阳性淋巴结)。术后30 d内7例(17.1%)发生并发症,Clavien-Dindo分级均≤2级。41例术后随访中位时间16(12,20)个月,术后1、6、12个月分别有19例(46.3%)、39例(95.1%)、41例(100.0%)恢复控尿。5例未行手术的患者中,4例行抗生素治疗后PSA下降;1例PSA未下降者行穿刺活检,病理未见癌。⁶⁸Ga-PSMA PET/CT诊断前列腺癌的敏感性为100.0%(41/41),显著优于^11C-胆碱PET/CT[80.0%(12/15),P=0.016]和mpMRI[83.7%(31/37),P=0.009];特异性为100.0%(5/5),与^11C-胆碱PET/CT[100.0%(2/2),P=1.000]和mpMRI [33.3%(1/3),P=0.107]的差异均无统计学意义。41例中,⁶⁸Ga-PSMA PET/CT诊断淋巴结转移的敏感性[71.4%(5/7)]与^11C-胆碱PET/CT的差异无统计学意义[75.0%(3/4),P=1.000],与mpMRI的差异有统计学意义[16.7%(1/6),P=0.016]。Gleason评分≥8分与<8分患者⁶⁸Ga-PSMA PET/CT的原发灶SUV_max值分别为19.60(9.58,24.38)与8.55(5.18,12.88);治疗前PSA值≥20 ng/ml与<20 ng/ml患者的SUV_max值分别为19.40(13.00,23.5)与8.40(5.35,13.95),差异均有统计学意义(P<0.05)。结论 ⁶⁸Ga-PSMA PET/CT对前列腺癌原发病灶诊断的敏感性高、特异性高,术前可根据PSMA PET/CT显示的肿瘤位置,制订是否保留NVB的处理策略;但其对淋巴结转移灶诊断的敏感性还不足以指导术前制订淋巴结清扫策略。     

完全腹腔镜根治性膀胱切除加体内改良回肠通道术的学习效果分析

目的分析术者对完全腹腔镜根治性膀胱切除(LRC)+改良回肠通道术(MIC)的学习效果。方法回顾性分析首都医科大学附属北京朝阳医院2014年4月至2019年10月42例接受完全LRC+MIC患者的临床资料。男34例,女8例;年龄(63.4±9.1)岁。其中术者1行34例手术,术者2行8例。将术者1的34例按时间顺序分为3组,第1~12例为A组,第13~23例为B组,第24~34例为C组;术者2实施的8例为D组。4组中有腹部手术史者分别为0、1、4、3例,差异有统计学意义(P<0.05);4组年龄、体质指数、美国麻醉医师协会评分等差异均无统计学意义(P>0.05)。改良术式的重要步骤包括光源透射下离断肠系膜、输出袢固定的条件下行输尿管-输出袢反流性对端吻合、缝合后腹膜缺口。比较各组患者手术时间、构建回肠通道时间、出血量、并发症发生比例、淋巴结清扫数量、切缘阳性比例等重要手术指标。结果各组手术均顺利完成,均无中转开放手术。A~C组手术时间分别为330.0(320.0,360.0)、300.0(250.0,308.0)、270.0(216.0,324.0)min,差异有统计学意义(P=0.010);3组构建回肠通道时间分别为136.5(131.3,147.5)、92.0(79.0,119.0)、79.0(72.0,115.0)min,差异有统计学意义(P<0.001)。手术时间和构建回肠通道时间组间两两比较,A、B组,A、C组差异均有统计学意义(P<0.05),B、C组差异无统计学意义(P>0.05)。3组出血量[200.0(125.0,300.0)、100.0(100.0,150.0)、200.0(100.0,400.0)ml]、并发症发生比例[4/12、4/11、3/11]、淋巴结清扫数量[(19.0±10.7)、(16.0±9.8)、(23.3±8.5)枚]、切缘阳性比例(1/12、1/11、2/11)的比较,差异均无统计学意义(P>0.05)。D组手术时间420.0(350.0,450.0)min,与A组比较差异有统计学意义(P<0.05)。D组出血量200.0(112.5,350.0)ml,并发症发生比例2/8,淋巴结清扫数量(13.8±7.1)个,切缘阳性比例1/8,与A组比较差异均无统计学意义(P>0.05)。结论完全LRC+MIC学习效果明显,随着手术例数的增加,手术时间及构建回肠通道时间显著下降;该术式具有较好的可重复性和安全性。