Failed B cell survival factor trials support the importance of memory B cells in multiple sclerosis

Clinical trials are probably the most informative experiments to help an understanding of multiple sclerosis (MS) biology. Recent successes with CD20‐depleting antibodies have focused attention towards B cell subsets as important mediators in MS. The trial of tabalumab (NTC00882999), which inhibits B cell activation factor (BAFF), is reported and reviewed and this trial is contrasted with the trial on the inhibition of a proliferation‐inducing ligand (APRIL) and BAFF using atacicept (NCT00642902). Both tabalumab and atacicept induce depletion of mature B cells and inhibit antibody formation, but they fail to deplete memory B cells and do not inhibit relapsing MS. Atacicept is reported to augment memory B cell responses and may precipitate relapse, suggesting the importance of APRIL. However, BAFF inhibition can enhance peripheral blood memory B cell responses, which was not associated with augmented relapse. Although other interpretations are possible, these data further support the hypothesis that memory B cells may be of central importance in relapsing MS, as they are the major CD20+ B cell subset expressing APRIL receptors. They also suggest that quantitative and/or qualitative differences in B cell responses or other factors, such as an immune‐regulatory effect associated with APRIL, may be important in determining whether MS reactivates following neutralization of peripheral B cell maturation and survival factors.     

听神经瘤术后面神经功能损伤危险因素分析

目的分析影响听神经瘤患者术后短期及长期面神经功能的危险因素。 方法回顾性分析厦门大学附属第一医院神经外科自2015年1月至2018年6月收治的62例听神经瘤患者的临床资料。于术后7 d及术后6个月对所有患者的面神经功能进行评估。收集可能与患者术后早期及长期面神经功能障碍存在相关性的因素，采用Logistic单因素与多因素回归对相关因素与患者术后短期及长期面神经功能的关系进行分析。 结果术后7 d，21例（33.9%）患者面神经功能正常，41例（66.1%）患者出现面神经功能损伤；术后6个月，49例（79.0%）患者面神经功能为正常，13例（21.0%）患者面神经功能损伤。Logistic单因素回归分析结果显示：肿瘤最大直径越大、肿瘤与面神经黏连越紧密，患者术后7 d发生面神经功能损伤的可能性越大（P=0.002、0.002）；术前临床症状持续时间为患者术后6个月面神经功能障碍的危险因素（P=0.035）。Logistic多因素回归分析结果显示：肿瘤与面神经的黏连程度、肿瘤最大直径为患者术后7 d面神经功能障碍的独立危险因素（P=0.003、0.014）；术前临床症状持续时间、肿瘤最大直径为患者术后6个月面神经功能障碍的独立危险因素（P=0.010、0.030）。 结论肿瘤与面神经的黏连越紧密、肿瘤最大直径越大，患者术后7 d发生面神经功能损伤的可能性越大。患者术前临床症状持续时间越长、肿瘤最大直径越大，术后6个月发生面神经功能损伤的可能性越大。     

靶向测序诊断黑棘皮病1家系

【摘要】 报道临床症状不典型的家族性黑棘皮病1家系。先证者女，4岁，自1周岁时，颈部、腹部出现黑色斑片，近年来逐渐扩大至唇周、躯干前部。腹部皮肤全反式共聚焦显微镜检查可见乳头环下延扭曲及沟壑结构，乳头环内可见中高折光颗粒结构。先证者父亲及祖母既往有类似病史，但随着年龄增长色素沉着自发性消退，仅有局部皮纹增粗。采集先证者及父母、祖母外周血，对先证者外周血DNA行Panel靶向测序，结果显示，先证者存在FGFR3基因14号外显子c.1949A>C（p.Lys650Thr）错义突变，Sanger测序验证证实先证者及其父亲和祖母均存在此突变。诊断：家族性黑棘皮病。     

Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice

In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes.     

Can EGFR mutation status be reliably determined in pre‐operative needle biopsies from adenocarcinomas of the lung?

The identification of EGFR mutations in non‐small‐cell lung cancer is important for selecting patients, who may benefit from treatment with EGFR tyrosine kinase inhibitors. The analysis is usually performed on cytological aspirates and/or histological needle biopsies, representing a small fraction of the tumour volume. The aim of the present investigation was to evaluate the diagnostic performance of this molecular test. We retrospectively included 201 patients with primary adenocarcinoma of the lung. EGFR mutation status (exon 19 deletions and exon 21 L858R point mutation) was evaluated on both pre‐operative biopsies (131 histological and 70 cytological) and on the surgical specimens, using PCR. Samples with low tumour cell fraction were assigned to laser micro‐dissection (LMD). We found nine (4.5%) patients with EGFR mutation in the lung tumour resections, but failed to identify mutation in one of the corresponding pre‐operative, cytological specimens. Several (18.4%) analyses of the pre‐operative biopsies were inconclusive, especially in case of biopsies undergoing LMD and regarding exon 21 analysis. Discrepancy of mutation status in one patient may reflect intra‐tumoural heterogeneity or technical issues. Moreover, several inconclusive results in the diagnostic biopsies reveal that attention must be paid on the suitability of pre‐operative biopsies for EGFR mutation analysis.     

Morphological imaging and CT histogram analysis to differentiate pancreatic neuroendocrine tumor grade 3 from neuroendocrine carcinoma

PurposeTo compare morphological imaging features and CT texture histogram parameters between grade 3 pancreatic neuroendocrine tumors (G3-NET) and neuroendocrine carcinomas (NEC).Materials and methodsPatients with pathologically proven G3-NET and NEC, according to the 2017 World Health Organization classification who had CT and MRI examinations between 2006-2017 were retrospectively included. CT and MRI examinations were reviewed by two radiologists in consensus and analyzed with respect to tumor size, enhancement patterns, hemorrhagic content, liver metastases and lymphadenopathies. Texture histogram analysis of tumors was performed on arterial and portal phase CT images. images. Morphological imaging features and CT texture histogram parameters of G3-NETs and NECs were compared.ResultsThirty-seven patients (21 men, 16 women; mean age, 56 ± 13 [SD] years [range: 28-82 years]) with 37 tumors (mean diameter, 60 ± 46 [SD] mm) were included (CT available for all, MRI for 16/37, 43%). Twenty-three patients (23/37; 62%) had NEC and 14 patients (14/37; 38%) had G3-NET. NECs were larger than G3-NETs (mean, 70 ± 51 [SD] mm [range: 18 - 196 mm] vs. 42 ± 24 [SD] mm [range: 8 - 94 mm], respectively; P = 0.039), with more tumor necrosis (75% vs. 33%, respectively; P = 0.030) and lower attenuation on precontrast (30 ± 4 [SD] HU [range: 25-39 HU] vs. 37 ± 6 [SD] [range: 25-45 HU], respectively; P = 0.002) and on portal venous phase CT images (75 ± 18 [SD] HU [range: 43 - 108 HU] vs. 92 ± 19 [SD] HU [range: 46 - 117 HU], respectively; P = 0.014). Hemorrhagic content on MRI was only observed in NEC (P = 0.007). The mean ADC value was lower in NEC ([1.1 ± 0.1 (SD)] × 10⁻³ mm²/s [range: (0.91 - 1.3) × 10⁻³ mm²/s] vs. [1.4 ± 0.2 (SD)] × 10⁻³ mm²/s [range: (1.1 - 1.6) × 10⁻³ mm²/s]; P = 0.005). CT histogram analysis showed that NEC were more heterogeneous on portal venous phase images (Entropy-0: 4.7 ± 0.2 [SD] [range: 4.2-5.1] vs. 4.5 ± 0.4 [SD] [range: 3.7-4.9]; P = 0.023).ConclusionPancreatic NECs are larger, more frequently hypoattenuating and more heterogeneous with hemorrhagic content than G3-NET on CT and MRI.     

基于"络病学说"分析虫类药在肿瘤患者治疗中的应用

“络病学说”作为重要的中医基础病机之一,近年来被广泛应用于肿瘤类疾病的临床诊疗中,其对于肿瘤的发生发展以及转移等机制研究与治疗均有理论指导意义。“络病”在形态与功能上与现代医学中的肿瘤微血管、微循环概念相似;瘀阻络脉与肿瘤患者血液高凝状态类似,故运用“通络法”抗肿瘤具有充足的理论依据。虫类药是动物药的别称,作为通络药的代表,善于搜刮剔络,在肿瘤的防治中起到了活血化瘀通络、攻毒散结通络、搜风解毒通络以及补益培本通络等作用。通过梳理“络病学说”的起源、发展与成熟阶段的主要思想内涵,整理并总结现代肿瘤治疗中“络病学说”的相关研究与应用,并分析虫类药在通络法中的具体应用,以期为开展中医络病防治肿瘤的临床应用提供理论依据。     

利咽散结方对自发性高血压大鼠血压及相关炎性因子的影响

目的研究利咽散结方对自发性高血压大鼠血压及相关炎性因子的影响。方法将36只自发性高血压大鼠随机分为利咽散结方组、氨氯地平组、模型组,每组12只。正常WKY大鼠12只作为正常组。利咽散结方组给予利咽散结方药液15.6 g/kg灌胃,氨氯地平组给予氨氯地平药液0.001 g/kg灌胃,模型组和正常组均给予等体积的蒸馏水灌胃,均1次/d,连续8周。测量各组大鼠灌胃前及灌胃2周、4周、6周、8周后血压,末次灌胃结束后用ELISA法测定血清炎性因子肿瘤坏死因子(TNF-α)、超敏C反应蛋白(hs-CRP)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)水平。结果利咽散结方组与氨氯地平组灌胃2周、4周、6周、8周后收缩压与舒张压均显著低于同期模型组(P均<0.05);利咽散结方组灌胃2周、4周、6周、8周后收缩压均显著高于同期氨氯地平组(P<0.05),而舒张压与同期氨氯地平组比较差异均无统计学意义(P均>0.05)。模型组血清TNF-α、hs-CRP、IL-6水平均明显高于正常组(P均<0.05),IL-10水平明显低于正常组(P<0.05);利咽散结方组与氨氯地平组血清TNF-α、hs-CRP、IL-6水平均明显低于模型组(P均<0.05),且利咽散结方组均明显低于氨氯地平组(P均<0.05);利咽散结方组与氨氯地平组血清IL-10水平均明显高于模型组(P均<0.05),且利咽散结方组明显高于氨氯地平组(P<0.05)。结论利咽散结方可显著降低自发性高血压大鼠血压,其降收缩压效果不如氨氯地平,降舒张压效果与氨氯地平相近,其作用机制可能与调节炎性因子水平有关。