The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

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Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

欧洲药物战略（2020）及其对中国医药领域的启示

在当前国际制药技术出现重大创新和变革、药品研发技术信息化和数字化程度不断发展，以及新型冠状病毒肺炎（COVID-19）疫情大流行的背景下，欧盟委员会为满足未竟临床需求、激励行业创新、增强监管系统应变能力、巩固欧盟药品监管体系国际地位，于2020年底发布了《欧洲药物战略》（Pharmaceutical Strategy for Europe，PSE）。PSE被视为欧洲未来5年卫生政策的“基石”，对欧洲制药领域发展和管理具有重要指导意义。通过对PSE制定背景及发展战略目标、具体举措等内容进行梳理分析，并结合中国COVID-19疫情防控与行业发展、药品科学监管与鼓励创新等实际工作提出政策建议。     

Repurposing of parenterally administered active substances used to treat pain both systemically and locally

Pain is a constant in our lives. The efficacy of drug therapy administered by the parenteral route is often limited either by the physicochemical characteristics of the drug itself or its adsorption–distribution–metabolism–excretion (ADME) mechanisms. One promising alternative is the design of innovative drug delivery systems that can improve the pharmacokinetics |(PK) and/or reduce the toxicity of traditionally used drugs. In this review, we discuss several products that have been approved by the main regulatory agencies (i.e., nano- and microsystems, implants, and oil-based solutions), highlighting the newest technologies that govern both locally and systemically the delivery of drugs. Finally, we also discuss the risk assessment of the scale-up process required, given the impact that this approach could have on drug manufacturing.Teaser: The management of pain by way of the parenteral route can be improved using complex drug delivery systems (e.g., micro- and nanosystems) which require high-level assessment and shorten the regulatory pathway.     

淄博市放射工作人员外周血淋巴细胞微核率分析

[摘要]?目的?探讨GeneXpert MTB/RIF检测技术在肺结核诊断中的应用价值。方法?以2020年7月—2021年6月在天门市第一人民医院治疗的疑似肺结核患者107例作为研究对象，所有患者均留取痰标本，进行痰涂片、痰培养、GeneXpert MTB/RIF检测、比例法药敏试验。以培养法和比例法药敏结果为金标准，计算GeneXpert MTB/RIF检测结核分枝杆菌（Mycobacterium tuberculosis，MTB）及其对于利福平耐药性检测的灵敏度、特异度、与金标准的的一致率。结果?107例疑似肺结核患者中，痰涂片阳性39例（36.45%），涂片阴性68例（63.55%）。以痰培养结果为金标准，GeneXpert MTB/RIF检测TBM的灵敏度为85.42%（41/48），特异度为88.14%（52/59）。GeneXpert MTB/RIF与痰培养诊断一致率为86.92%（93/107）；进一步分析，GeneXpert MTB/RIF检测痰涂片阳性患者MTB的灵敏度为97.22%（35/36），特异度为33.33%（1/3），检测涂片阴性患者MTB的灵敏度为50.00%（6/12），特异度为91.07%（51/56）。以比例法药敏结果为金标准，确认痰培养阳性36例患者中利福平耐药有4例（11.11%），敏感的有32例（88.89%）；GeneXpert MTB/RIF检测痰培养阳性患者利福平耐药的灵敏度为75.00%（3/4），特异度为93.75%（30/32）。GeneXpert MTB/RIF与比例法药敏试验一致率为91.67%。结论?GeneXpert MTB/RIF检测技术对于肺结核诊断以及利福平的耐药分析具有重要实用价值，可以作为金标准。     

Pan-cancer proteomic map of 949 human cell lines

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A systematic review of the methodological quality of economic evaluations in genetic screening and testing for monogenic disorders

PurposeUnderstanding the value of genetic screening and testing for monogenic disorders requires high-quality, methodologically robust economic evaluations. This systematic review sought to assess the methodological quality among such studies and examined opportunities for improvement.MethodsWe searched PubMed, Cochrane, Embase, and Web of Science for economic evaluations of genetic screening/testing (2013-2019). Methodological rigor and adherence to best practices were systematically assessed using the British Medical Journal checklist.ResultsAcross the 47 identified studies, there were substantial variations in modeling approaches, reporting detail, and sophistication. Models ranged from simple decision trees to individual-level microsimulations that compared between 2 and >20 alternative interventions. Many studies failed to report sufficient detail to enable replication or did not justify modeling assumptions, especially for costing methods and utility values. Meta-analyses, systematic reviews, or calibration were rarely used to derive parameter estimates. Nearly all studies conducted some sensitivity analysis, and more sophisticated studies implemented probabilistic sensitivity/uncertainty analysis, threshold analysis, and value of information analysis.ConclusionWe describe a heterogeneous body of work and present recommendations and exemplar studies across the methodological domains of (1) perspective, scope, and parameter selection; (2) use of uncertainty/sensitivity analyses; and (3) reporting transparency for improvement in the economic evaluation of genetic screening/testing.     

Care pathway of women with interval breast cancer in 2016, based on medico-administrative data

BackgroundSince 2004, an organised screening programme (OS) for breast cancer has been in place for 50-74 years women who are not at an increased risk. Despite this, 17% of cancers diagnosed within 24 months following an OS mammogram are interval cancers (IC), diagnosed even though the OS had not reported cancer. After identifying IC from the French administrative healthcare database (SNDS), our objective was to describe the care pathways of women with IC in 2016.Materials and MethodsThe IC identification algorithm is based on breast imaging tests conducted in the 24 months prior to diagnosis and on the compatibility of their timeline with ACR3 lesion follow-up (BIRADS guidelines). The care pathways of 3 groups were compared: women with IC, diagnosed through the OS, and diagnosed outside the OS programme (personalised screening or based on clinical signs, PSCS group).ResultsRespectively, 12,965 (46%), 3433 (12%), and 11,761 women (42%) were classified in the OS, IC and PSCS groups, i.e. 20.9% IC cases among the women taking part in the OS programme. The women from the IC group presented with more forms with lymph node or metastatic involvement than those of the OS group. Their pathways were more complex than in the OS group: at an equivalent stage, more total mastectomies and more adjuvant or neoadjuvant chemotherapy regimens.ConclusionThe care pathways of women with IC are intermediate with respect to those of the OS or PSCS group.Cases of IC probably include several cancer prognosis profiles.