Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Contribution of different somatosensory afferent input to subcortical somatosensory evoked potentials in humans

ObjectivesTo investigate the subcortical somatosensory evoked potentials (SEPs) to electrical stimulation of either muscle or cutaneous afferents.MethodsSEPs were recorded in 6 patients suffering from Parkinson’s disease (PD) who underwent electrode implantation in the pedunculopontine (PPTg) nucleus area. We compared SEPs recorded from the scalp and from the intracranial electrode contacts to electrical stimuli applied to: 1) median nerve at the wrist, 2) abductor pollicis brevis motor point, and 3) distal phalanx of the thumb. Also the high-frequency oscillations (HFOs) were analysed.ResultsAfter median nerve and pure cutaneous (distant phalanx of the thumb) stimulation, a P1-N1 complex was recorded by the intracranial lead, while the scalp electrodes recorded the short-latency far-field responses (P14 and N18). On the contrary, motor point stimulation did not evoke any low-frequency component in the PPTg traces, nor the N18 potential on the scalp. HFOs were recorded to stimulation of all modalities by the PPTg electrode contacts.ConclusionsStimulus processing within the cuneate nucleus depends on modality, since only the cutaneous input activates the complex intranuclear network possibly generating the scalp N18 potential.SignificanceOur results shed light on the subcortical processing of the somatosensory input of different modalities.     

Immune microenvironment of hepatocellular carcinoma,intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications

Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non-immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non-immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor-targeting immunotherapy.     

Glycaemic control for patients with severe acute brain injury: Protocol for a systematic review

Background

Hyperglycaemia is common in patients with acute brain injury admitted to an intensive care unit (ICU). Many studies have found associations between development of hyperglycaemia and increased mortality in hospitalised patients. However, the optimal target for blood glucose control is unknown. We want to conduct a systematic review with meta-analysis and trial sequential analysis to explore the beneficial and harmful effects of restrictive versus liberal glucose control on patient outcomes in adults with severe acute brain injury.

Methods

We will systematically search medical databases including CENTRAL, Embase, MEDLINE and trial registries. We will search the following websites for ongoing or unpublished trials: http://www.controlled-trials.com/ , http://www.clinicaltrials.gov/ , www.eudraCT.com , http://centerwatch.com/ , The Cochrane Library's CENTRAL, PubMed, EMBASE, Science Citation Index Expanded and CINAHL. Two authors will independently review and select trials and extract data. We will include randomised trials comparing levels of glucose control in our analyses and observational studies will be included to address potential harms. The primary outcomes are defined as all-cause mortality, functional outcome and health-related quality of life. Secondary outcomes include serious adverse events including hypoglycaemia, length of ICU stay and duration of mechanical ventilation, and explorative outcomes including intracranial pressure and infection. Trial Sequential Analysis will be used to investigate the risk of type I error due to repetitive testing and to further explore imprecision. Quality of trials will be evaluated using the Cochrane Risk of Bias tool, and quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.

Discussion

The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice.     

姑息性胃切除联合术后化疗评分在腹膜转移的胃癌患者预后评估中的临床意义

目的:探讨姑息性胃切除联合术后化疗评分在腹膜转移的胃癌患者预后评估中的临床意义。方法:回顾性分析2010年1月至2016年12月7年间收治的287例发生腹膜转移的胃癌患者的临床病理资料。通过χ2检验分析评分与患者临床病理因素间的关系。通过Kaplan-Meier法绘制生存曲线，Log-rank检验比较患者生存率的差异；采用Cox比例风险回归模型对患者进行预后分析。结果:与评分中得分为2分和1分的患者相比，得分为0分的患者肿瘤侵润至T4b 期的患者较少［31%(18/58)比50.8%(63/124)、56.2%(59/105)，P=0.039］。全组患者的中位生存时间仅为8.7月。对患者进行单因素预后分析结果显示，血清白蛋白浓度（≤40 g/L），腹水，腹膜转移范围较大，肿瘤T分期较晚，评分得分较高的患者预后较差（均P＜0.05）。将上述因素纳入Cox多因素分析结果显示:评分［HR（95%CI）:1.384（1.165~1.644），P=0.000］，血清白蛋白浓度［HR（95%CI）:0.759（0.593~0.971），P=0.028］，肿瘤T分期［HR（95%CI）:1.493（1.216~1.832），P=0.000］是患者预后的独立危险因素。结论:评分对于胃癌伴腹膜转移患者的预后生存评估具有重要的临床意义。     

甲状腺乳头状癌前上纵隔淋巴结转移临床病理特征初步分析

目的 探讨肿瘤位置、最大直径及甲状腺外浸等临床病理特征与甲状腺癌前上纵隔淋巴结转移的关系。 方法 研究分析初次手术治疗的60例甲状腺乳头状癌患者临床及病理资料,运用检验临床病理特征与前上纵隔淋巴结阳性率的相关性。 结果 肿块位置、最大直径、数量、腺体外侵、受累腺叶数及Ⅵ区淋巴结转移等特征,以及患者年龄等相关因素中,只有VI区淋巴结对前上纵隔淋巴结状态有影响;60例患者前上纵隔淋巴结转移率为10/60(16.67%)。相关因素的前上纵隔淋巴结转移率对比:≥55岁vs <55岁(20% vs 16.36%, P<0.05);肿块位于下极 vs 上极 vs 中极(P>0.05);最大直径≥1.5 cm vs 最大直径<1.5 cm(18.18% vs 15.79, P>0.05);单灶 vs 多灶(21.88% vs 10.71%, P>0.05);单叶 vs 多叶(17.5% vs 15%, P>0.05);男性vs女性(20% vs 15.55%, P>0.05); Ⅵ区淋巴结阳性vs 阴性(24.43% vs 3.57%, P<0.05); 结论 总体来说,甲状腺乳头状癌前上纵隔淋巴结转移率较低。本研究发现VI区淋巴结状态可能与前上纵隔淋巴结转移相关,未来仍需大样本前瞻性的研究验证。