Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.     

Immunohistochemical and molecular analysis of PI3K/AKT/mTOR pathway in esophageal carcinoma

Among the numerous signaling pathways involved in tumorigenesis, PI3K‐AKT‐mTOR is a key one that regulates diverse cellular functions. However, its prognostic value in esophageal carcinoma remains unclear. In our study, we examined the immunohistochemical expression of phosphorylated (p‐) AKT, mTOR, p70S6K and 4E‐BP1 along with the mutational status of PIK3CA and AKT1 genes by High Resolution Melting Analysis and Pyrosequencing in 44 esophageal carcinomas. The results were correlated with the clinicopathological characteristics of the patients in an effort to define their possible prognostic significance. Total p‐mTOR cytoplasmic expression, assessed in 10 random areas, was positively correlated with tumor stage (Kruskal–Wallis ANOVA, I/II vs III/IV, p = 0.0500). Μoreover, maximum p‐mTOR cytoplasmic immunoexpression, estimated in hot spot areas, was positively associated with tumor grade (Mann–Whitney U test, I/II vs III, p = 0.0565). Interestingly, p‐4E‐BP1 immunoreactivity was negatively correlated with tumor histological grade (Mann–Whitney U test, I/II vs III, p = 0.0427). No mutation was observed in exons 9 and 20 of PIK3CA gene and in exon 4 of AKT1 gene. In conclusion, our findings depict the presence of activated PI3K/AKT/mTOR pathway in esophageal cancer bringing forward p‐mTOR and p‐4E‐BP1 for their potential role in esophageal carcinogenesis. Additional studies are warranted to validate our findings.     

Cost of postoperative complications: How to avoid calculation errors

Postoperative complications(PC) are a basic health outcome, but no surgery service in the world records and/or audits the PC associated with all the surgical procedures it performs. Most studies that have assessed the cost of PC suffer from poor quality and a lack of transparency and consistency. The payment system in place often rewards the volume of services provided rather than the quality of patients' clinical outcomes. Without a thorough registration of PC, the economic costs involved cannot be determined. An accurate, reliable appraisal would help identify areas for investment in order to reduce the incidence of PC,improve surgical results, and bring down the economic costs. This article describes how to quantify and classify PC using the Clavien-Dindo classification and the comprehensive complication index, discusses the perspectives from which economic evaluations are performed and the minimum postoperative follow-up established, and makes various recommendations. The availability of accurate and impartially audited data on PC will help reduce their incidence and bring down costs. Patients, the health authorities, and society as a whole are sure to benefit.     

Inactivated influenza vaccine formulated with single-stranded RNA-based adjuvant confers mucosal immunity and cross-protection against influenza virus infection

Influenza vaccination is considered the most valuable means to prevent and control seasonal influenza infections, which causes various clinical symptoms, ranging from mild cough and fever to even death. Among various influenza vaccine types, the inactivated subunit type is known to provide improved safety with reduced reactogenicity. However, there are some drawbacks associated with inactivated subunit type vaccines, with the main ones being its low immunogenicity and the induction of Th2-biased immune responses. In this study, we investigated the role of a single-stranded RNA (ssRNA) derived from the intergenic region in the internal ribosome entry site of the Cricket paralysis virus as an adjuvant rather than the universal vaccine for a seasonal inactivated subunit influenza vaccine. The ssRNA adjuvant stimulated not only well-balanced cellular (indicated by IgG2a, IFN-γ, IL-2, and TNF-α) and humoral (indicated by IgG1 and IL-4) immune responses but also a mucosal immune response (indicated by IgA), a key protector against respiratory virus infections. It also increases the HI titer, the surrogate marker of influenza vaccine efficacy. Furthermore, ssRNA adjuvant confers cross-protective immune responses against heterologous influenza virus infection while promoting enhanced viral clearance. Moreover, ssRNA adjuvant increases the number of memory CD4⁺ and CD8⁺ T cells, which can be expected to induce long-term immune responses. Therefore, this ssRNA-adjuvanted seasonal inactivated subunit influenza vaccine might be the best influenza vaccine generating robust humoral and cellular immune responses and conferring cross-protective and long-term immunity.     

Caution! Overestimation of treatment effects of corticosteroid therapy for community-acquired pneumonia in a meta-analysis of randomized controlled trials

It is well known that a meta-analysis of randomized controlled trials aims to increase the power and precision of the estimated intervention effects. However, when a meta-analysis includes a limited number of patients and a small number of events, overestimation of intervention effect estimates may occur and could cause spurious results. Although many biases can cause the overestimation, random error may be the most common cause. Trial sequential analysis (TSA) can explore the independent effect of random error on intervention effect estimates in meta-analyses and protect meta-analyses against overestimation due to random error.     

Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

脑卒中后偏瘫肩痛患者生活质量的影响因素研究

目的 探讨脑卒中后偏瘫肩痛患者生活质量的直接和间接影响因素，以期为临床症状管理提供参考信息。 方法 采用一般资料调查表、脑卒中后偏瘫肩痛症状评估表、简易疲乏量表、医院焦虑抑郁量表、Fugl-Meyer上肢功能评分量表和脑卒中生活质量专用量表对205例脑卒中后偏瘫肩痛患者进行调查。结果 偏瘫肩痛患者的生活质量总分为（144.48±27.69），整体处于中等水平。生活质量的主要影响因素是肩痛困扰、肩痛频度、肩外旋、疲乏程度和抑郁，可以解释总变异的63.3%。路径分析结果显示，疲乏程度、肩痛频度和肩痛困扰可直接影响患者的生活质量（β_(疲乏程度-生活质量)=-0.252，P<0.001；β_(肩痛频度-生活质量)=-0.147，P<0.001；β_(肩痛困扰-生活质量)=-0.317，P<0.001）；疲乏程度和肩痛频度亦可通过肩痛困扰来间接影响患者的生活质量（ β_(疲乏程度-肩痛困扰-生活质量)=-0.066，P<0.001；β_(肩痛频度-肩痛困扰-生活质量)=-0.064，P<0.001）。结论 临床上应同时关注脑卒中患者疲乏和偏瘫肩痛症状，关注抑郁和疲乏对症状体验的协同作用，提高医护人员症状管理的效率，从而提高脑卒中偏瘫肩痛患者的生活质量。