大脑胶质瘤病的临床病理学特征:病例报告及文献综述

目的探讨大脑胶质瘤病的临床病理学特征。方法对1例大脑胶质瘤病患者的临床表现、影像学、组织病理学和免疫组织化学特征进行回顾性分析,并且复习相关文献。结果男性患者,24岁。临床表现为发作性黑蒙和发作时意识丧失性癫癎症状,以及随后出现的不能缓解的剧烈头痛。MRI显示左侧颞顶叶-基底节区弥散性不规则稍高信号,局灶信号不均匀,无明显占位效应;MRS显示病灶区Cho/NAA比值明显升高。手术切除部分左侧颞叶及海马组织,光学显微镜下观察肿瘤细胞呈轻至中等密度增生,弥漫性浸润;呈星形胶质细胞样形态,胞核为长梭形或纺锤形,染色质轻度深染;核分裂象罕见;未见微血管增生和坏死;肿瘤细胞排列形成明显的继发性结构,包括软脑膜下和室管膜下肿瘤细胞密集生长、血管周围肿瘤细胞聚集及神经元卫星现象等;灰质与白质分界不清,但神经元分布结构基本保留。免疫组织化学染色肿瘤细胞胶质纤维酸性蛋白和S-100蛋白表达阳性,少突胶质细胞系转录因子-2、突触素和神经元核抗原表达阴性;TP53过表达,约8%;Ki-67抗原标记指数约为10%。结论大脑胶质瘤病为临床少见、可累及多个脑叶的弥漫浸润性肿瘤,影像学上无明显占位效应,MRI和MRS检查可提示诊断。肿瘤细胞弥漫性浸润并形成明显的继发性结构,需与多中心/多灶性胶质瘤和脱髓鞘病变等相鉴别。TP53和Ki-67抗原标记指数可资与非肿瘤性病变相鉴别。     

Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy

Concurrent and post-radiotherapy temozolomide (T) significantly improves survival in patient with newly diagnosed glioblastoma multiforme. We aimed to assess the activity of the combination of T and pegylated liposomal doxorubicin (PLD) in this population. A combination of T (days 1–5, 200 mg/m² orally) and PLD (day 1, 40 mg/m² intravenous) was given every 4 weeks for six cycles following chemo-radiotherapy as a post-operative treatment. The primary endpoint was 6-month progression free survival (6PFS). Of the 40 patients who enrolled (53 years median age, 73% male), the 6PFS was 58% (95% confidence interval [CI], 41–72%). The median time to progression was 6.2 months (95% CI, 5.6–8.0 months) and overall survival (OS) was 13.4 months (95% CI, 12.7–15.8 months). Thirty-four patients had measurable disease: one had a complete response (3%), 28 had stable disease (82%), and five had progressive disease (15%). Treatment was well tolerated: hematological toxicity included grade 3 neutropenia (8%). Grade 3 non-hematologic toxicity included nausea and vomiting (8%) and palmar–plantar toxicity (5%). We concluded that combination T and PLD is well tolerated but does not add significant clinical benefit regarding 6PFS and OS.     

侧脑室内胶质瘤与脑膜瘤的碰撞瘤一例并文献复习

目的 报告1例罕见的侧脑室内胶质瘤与脑膜瘤的碰撞瘤,并探讨其发生原因.方法 39岁男性,6年前曾行侧脑室内胶质瘤切除术;此次以头痛及头晕发病,MRI示胶质瘤原位复发,且同时合并另一占位性病变,予以手术切除.术后病理证实为胶质瘤与脑膜瘤的碰撞瘤;本文同时也对这种碰撞瘤进行文献复习.结果 术后患者恢复满意,并行伽玛刀放射治疗,随访1年时患者状态良好.本文在复习侧脑室内胶质瘤与脑膜瘤的碰撞瘤发生原因后,总结了几种假设.结论 复发的胶质瘤诱发脉络丛内的蛛网膜细胞恶性转化可能是导致脑膜瘤的原因,同时胶质瘤的刺激也可能诱导了脑膜瘤的生长.     

预防性协同给药抑制裸鼠脑胶质瘤的生长

目的观察预防性单独及协同给药对脑胶质瘤生长的影响。方法将浓度为107/ml、细胞成活率95%以上的U251MG脑胶质瘤细胞悬液,接种至6w龄雄性裸鼠脑白质内。接种次日给药,2次/w,分4大组,即消炎痛口服给药组(两个剂量组);榄香烯腹腔注射给药组(两个剂量组);消炎痛和榄香烯低剂量协同用药组;对照组(肿瘤对照和空白对照)。给药20和30d时,断颈处死裸鼠,脑标本做石蜡切片,3μm厚,行HE、胶质纤维酸性蛋白(GFAP)等染色。结果肿瘤对照组:裸鼠脑内肿瘤增生明显,瘤内幼稚血管形成,瘤细胞向白质内浸润,GFAP染色强阳性。单独给药组:瘤细胞较肿瘤对照组少,GFAP染色阳性。协同给药组:给药30d时大量瘤细胞发生凋亡,GFAP呈阴性表达。结论预防性的两药协同作用可更好地诱导裸鼠脑内人脑胶质瘤细胞发生凋亡。     

胶质母细胞瘤组织RBM8A表达与病人预后及替莫唑胺化疗敏感性的关系

目的 探讨胶质母细胞瘤（GBM）组织RNA结合基序8A（RBM8A）蛋白表达与病人预后及替莫唑胺（TMZ）化疗敏感性的关系。方法 选取2015年6月至2020年6月手术切除的GBM组织130例及颅脑损伤减压术中切取的非肿瘤脑组织20例（对照）,用免疫组化法检测组织RBM8A表达。术随访时间3~50个月,中位随访时间为12个月。结果 GBM组织RBM8A高表达率[86.15%（112/130）]明显高于对照组[20%（4/20）;P<0.05]。随访期间死亡98例,失访2例;多因素Cox回归分析显示,RBM8A高表达是GBM病人生存预后不良的独立危险因素（P<0.05）。生存曲线分析显示,RBM8A高表达GBM病人中位无复发生存时间和总生存时间均明显低于低表达病人（P<0.05）;RBM8A低表达GBM病人中,TMZ化疗病人无复发生存时间和总生存时间均明显高于未化疗病人（P<0.05）;TMZ化疗与RBM8A高表达GBM病人无复发生存时间和总生存时间无明显关系（P>0.05）。结论 GBM组织RBM8A呈高表达,与病人不良生存预后有关。检测RBM8A有助于评估GBM病人对TMZ化疗敏感性。     

帕金森病患者血清EGF和BDNF水平变化与认知障碍的关系

目的探讨帕金森病(PD)患者血清表皮生长因子(EGF)和脑源性神经营养因子(BDNF)的变化及其与认知功能的关系。方法入选PD患者76例和年龄、性别相匹配的40例健康对照组,记录PD患者的性别、年龄、病程、受教育年限、HoehnYahr(H-Y)分级,采用蒙特利尔认知评估量表(Mo CA)对所有研究对象认知功能进行评估,采用酶联免疫吸附法(ELISA)检测血清EGF和BDNF水平,并对结果进行分析。结果 PD组血清EGF、BDNF水平明显低于健康对照组[(745±148)ng·L~(-1)比(952±157)ng·L~(-1),P0.05;(5.1±3.1)μg·L~(-1)比(6.8±3.9)μg·L~(-1),P0.05];早期PD组与中晚期PD组血清EGF和BDNF水平无差异(P0.05);但合并轻度认知功能障碍(MCI)的PD组血清EGF水平低于无MCI的PD组[(713±146)ng·L~(-1)比(865±189)ng·L~(-1),P0.01];PD患者Mo CA评分与受教育年限(β=0.611,P0.01)、血清EGF水平(β=0.513,P0.01)呈正相关,与病程(β=-0.373,P0.05)、H-Y分级(β=-0.264,P0.05)呈负相关。结论 EGF和BDNF水平的改变可能参与了PD患者的发病机制;血清EGF水平的下降可能与PD患者的MCI具有相关性,其可能为PD患者合并认知功能障碍的潜在早期预测指标。     

Primary osteosarcoma of the cerebrum with immunohistochemical and ultrastructural studies: report of a case

A 57-year-old woman with primary intracerebral osteosarcoma is reported. The tumor was identified by computed tomography as a mass with hemorrhage in the right parietal lobe. The surgical and pathological examinations confirmed an osteosarcoma of intracerebral origin. She suffered from repeated local recurrence of the tumor and died about 1 year after the onset. The pathological findings showed features of osteoblastic osteosarcoma with numerous osteoclastlike multinucleated giant cells. Immunohistochemically, tumor cells were positive for vimentin, and partially for actin. Multinucleated giant cells were reactive with vimentin and CD68 antibodies. Ultrastructurally, tumor cells were rich with rough endoplasmic reticulum. These findings are consistent with the histological features of skeletal or extraskeletal osteosarcoma. This is the third case of primary intracerebral osteosarcoma reported in the literature and the first one analyzed ultrastructurally.     

A biphasic tumor consisting of pilocytic astrocytoma with an anaplastic solitary fibrous tumor component in the pineal region: A case report and literature review

Here we report a case of a biphasic tumor consisting of pilocytic astrocytoma with anaplastic solitary fibrous tumor component in the pineal region. The majority of the tumor showed typical histologic features of pilocytic astrocytoma. A minor part of the tumor showed marked proliferation of short spindle cells around vessels. These spindle cells showed CD34 and CD99 immunoreactivity. From a review of the literature, we found that only one similar case has been reported. Contrary to the reported case, our case showed anaplastic features of solitary fibrous tumor histology.     

基质金属蛋白酶-12血清水平及启动子区-82A/G多态性与急性动脉粥样硬化性脑梗死的关系

目的 探讨基质金属蛋白酶-12(MMP-12)血清水平及启动子基因- 82A/G多态性与动脉粥样硬化性脑梗死的关系.方法 对608例动脉粥样硬化脑梗死和374名健康体检者进行研究,采用ELISA法测定血清MMP-12蛋白水平,同时采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法分析MMP-12基因启动子区- 82A/G多态性.结果 脑梗死组患者48 h内血清MMP-12为(17.36±9.12) ng/ml,对照组为(17.42±7.70) ng/ml,两组比较差异无统计学意义(t=0.047,P=0.962).脑梗死组AG+ GG基因型频率为7.6％,与对照组的5.9％基因型频率比较差异无统计学意义(x2 =0.281,P=0.584),G等位基因频率在两组间分别为3.8％和2.9％,两组比较差异同样无统计学意义(x2=0.746,P=0.374).结论 MMP-12血清水平及基因启动子- 82位点的多态与MMP-12基因表达和脑梗死没有相关性.     

A case of high‐grade astrocytoma with BRAF and ATRX mutations following a long‐standing course over two decades

Pediatric high‐grade gliomas are rare and occasionally hard to classify. These tumors often feature a well‐demarcated histology and are expected to have a better outcome than ordinary diffuse high‐grade gliomas in adults. We herein report a case of circumscribed high‐grade glioma that showed a distinct molecular profile and followed an excellent course for 26 years. The patient, a 3‐year‐old boy at onset, presented with a contrast‐enhancing mass in the right temporal lobe and underwent resection. Histologically, the tumor mainly consisted of compact bundles of GFAP‐positive spindle cells. With its malignant features including brisk mitotic activity and pseudopallisading necrosis, a diagnosis of high‐grade astrocytoma was made and adjuvant chemoradiotherapy was administered. After a disease‐free period of two decades, the tumor recurred locally. The resected tumor was histologically identical to the primary tumor and additionally contained pleomorphic cells, but lacked eosinophilic granular bodies and reticulin networks. The primary and recurrent tumors both harbored the BRAF V600E mutation, and the recurrent tumor was immunonegative for ATRX. Combined BRAF and ATRX mutations are rare in gliomas, with only a pediatric case of glioblastoma being reported in the literature. However, our case cannot be regarded as glioblastoma because of its well‐demarcated histology and excellent course. The distinction of either a diffuse or localized nature in gliomas is important, particularly in children, for predicting prognoses and selecting adjuvant therapies that consequently affect life‐long health care. The present case provides novel insights into pediatric high‐grade astrocytomas.     

A case of recurrent epilepsy‐associated rosette‐forming glioneuronal tumor with anaplastic transformation in the absence of therapy

Rosette‐forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy‐associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5‐year‐old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET‐like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high‐grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild‐type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high‐grade regions. By immunohistochemistry there was loss of nuclear alpha‐thalassemia mental retardation syndrome, X‐linked (ATRX) expression only in the high‐grade region. Next‐generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high‐grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q‐codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole‐arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy.     

新生儿窒息血清酶变化与脑损伤相关性及预后评估

目的 观察血清酶活性在新生儿窒息的变化,探讨其与脑损伤程度的相关性及预后.方法 103例窒息新生儿(轻度69例,重度34例)和40例正常新生儿作对照,均在生后24～48h测定磷酸肌酸激酶(CK)、磷酸肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)、α-羟丁酸酶(α-HBDH)、谷草转氨酶(AST);并于生后第2d做神经行为测定(NBNA),分析其与各个血清酶之间的相关性;100例窒息组患儿(3例因合并多脏器功能衰竭死亡)均于生后4～7d做头颅CT检查;并于生后第3个月及第6个月随访神经发育情况.结果 轻度窒息组及重度窒息组患儿血清酶活性均高于对照组(P<0.01),与临床分度呈正相关(窒息程度越重,血清酶活性越高,NBNA评分越低);α-HBDH、LDH、CK、CK-MB、AST与NBNA评分有一定的相关性(相关系数r分别为-0.797、-0.853、-0.826、-0511、-0.585);临床分度与头颅CT密切相关;血清酶α-HBDH、LDH、CK对预后判断具有一定的敏感性和特异性.结论 r羟丁酸酶、乳酸脱氢酶、磷酸肌酸激酶对早期评价脑损伤程度及判断预后具有重要价值,而磷酸肌酸激酶同工酶(心肌型)、谷草转氨酶活性升高仅提示可能存在脑损伤,不能判断其损伤程度及预后.     

Biphasic changes in the levels of poly(ADP-ribose) polymerase-1 and caspase 3 in the immature brain following hypoxia–ischemia

Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA repair-associated enzyme that has multiple roles in cell death. This study examined the involvement of PARP-1 in ischemic brain injury in the 7-day old rat, 0.5–48 h after unilateral carotid artery ligation and 2 h of 7.8% oxygen. This experimental paradigm produced a mild to moderate injury; 40–67% of animals in the ligated groups had histological evidence of neuronal death. Ipsilateral cortical injury was seen at all survival times, while mild contralateral cortical injury was seen only at the 1 h survival time. Hippocampal injury was delayed relative to the cortex and did not show a biphasic pattern. Immunohistochemical staining for PARP showed bilateral increased staining as early as 1 h post-hypoxia. PARP staining at early time periods was most intense in layer V of cortex, but did not demonstrate a pattern of cell clusters or columns. Ipsilateral PARP-1 levels quantified by western blotting showed a biphasic pattern of elevation with peaks at 0.5 and 12 h post-hypoxia. Contralateral PARP-1 levels were also elevated at 0.5 and 24 h. PARP activity as determined by immunoreactivity for poly(ADP-ribose) (PAR) was increased ipsilaterally at 0.5, 2 and 12 h survival times. Cortical caspase 3-activity was increased ipsilaterally at 6, 12, and 24 h and contralaterally at 0.5, 1, 2 and 6 h post-hypoxia.

There are three main findings in this study. First, changes in the distribution and amount of cell death correlate well with measured PARP-1 levels after hypoxia–ischemia, and both display biphasic characteristics. Second, there are significant early, transient morphological and biochemical changes in the contralateral cortex after neonatal hypoxia–ischemia due to unilateral permanent occlusion of a carotid artery followed by 2 h of systemic hypoxia. Third, variability in the responses of individual pups to hypoxia–ischemia suggests the presence of unidentified confounding factors.     

Midwinter insomnia in the subarctic region: evening levels of serum melatonin and cortisol before and after treatment with bright artificial light

"Midwinter insomnia" (MI), mainly characterized by difficulties in falling asleep at night, is a common complaint during the period of obscuration or "dark period" north of the arctic circle. We hypothesize that MI is a result of a phase delay of the sleep-wake cycle due to insufficient exposure to daylight. In the present study based on this hypothesis, we wanted to find out whether otherwise healthy subjects with MI show abnormalities in the endocrine markers melatonin and cortisol late in the evening, and whether exposure to intensive light for one half hour in the morning for 5 days has any effect on the insomnia and on the endocrine variables. Nine subjects with typical MI were compared to eight controls. Before light exposure, the MI group had a significantly lower level of plasma melatonin in the evening than the controls, and a nonsignificant increase of plasma cortisol. After light exposure, the following results were seen in the MI group: sleep latency was moderately but significantly shortened, plasma melatonin increased to the same level as in the controls, and there was a nonsignificant increase of plasma cortisol. These results are largely in accordance with the predictions made from the phase delay hypothesis. However, other explanations cannot be ruled out.     

Distribution and levels of insulin-like growth factor I mRNA across the life span in the Brown Norway×Fischer 344 rat brain

Previous studies have reported changes in insulin-like growth factor I (IGF-I) mRNA expression during early postnatal development of the rat brain. Although changes in IGF-I gene expression have been documented in a wide range of central nervous system structures during early development and investigated in the hippocampus during aging, no study has compared changes in IGF-I gene expression in different brain regions across the life span. The present study assessed the distribution of IGF-I gene expression using in situ hybridization in rats aged 2–30 months. Dot blots were used as a quantitative assessment of cortical IGF-I mRNA. Results indicate that both the distribution and levels of brain IGF-I mRNA do not change significantly between 2 and 30 months of age in the rat. However, in spite of relatively constant levels of mRNA, other studies from our laboratory have demonstrated that cortical IGF-I protein levels decrease 36.6% between 11 and 32 months of age, suggesting that IGF-I function is decreased with increasing age.     

应用妥泰后大鼠癫痫模型血清NSE水平变化的研究

目的观察应用妥泰后发育期大鼠癫痫模型血清神经元特异性烯醇化酶(NSE)水平变化，探讨妥泰减少发育期大鼠癫痫发作引起的脑神经元损伤。方法戊四唑点燃发育期大鼠癫痫模型，随机分为正常对照组、点燃模型组、妥泰治疗组，观察大鼠血清NSE水平变化、惊厥发作频率和发作程度。结果正常对照组大鼠无惊厥发作．血清NSE水平在正常范围；癫痫模型组大鼠惊厥出现时间早，发作程度重，血清NSE水平明显高于其它两组；妥泰治疗组大鼠惊厥出现时间晚．发作程度轻，血清NSE水平略高于正常对照组而低于癫痫模型组。结论妥泰应用后血清NSE水平降低．考虑是由于其减少癫痫发作引起的神经元损伤。     

A study of the de- and regenerative changes in the sympathetic nervous system of the adult mouse after treatment with the antiserum to nerve growth factor.

In the adult mouse, the antiserum to nerve growth factor (NGF) induced marked atrophic changes of the ganglionic cell bodies in the superior cervical ganglion (SCG) and a disappearance of adrenergic nerve terminals in several peripheral tissues. By fluorescence histochemistry a lower-than-normal content of the noradrenaline (NA) transmitter was observed within the entire adrenergic neurone only 1 day after a single injection of NGF-antiserum (0.1 ml/g body weight). An atrophy of adrenergic nerve cell bodies and a disappearance of adrenergic nerve terminals were observed after 3 days, but the antiserum-induced effects did not appear maximally developed until 7 days after treatment. These fluorescence histochemical findings were paralleled by a gradual decrease of the endogenous NA levels in peripheral tissues and also of the weight of the SCG. A gradually proceeding restoration towards normal of the adrenergic innervation apparatus was observed fluorescence histochemically following a 5-day treatment with NGF-antiserum (0.1 ml/g body weight each dose), and after 6 weeks to 3 months a normal or close to normal fluorescence microscopical appearance was regained in the peripheral tissues and also in the SCG. These findings were parelleled by the results of the determinations of endogenous NA in peripheral tissues and by the results of weighing the SCG. We discuss some important differences between NGF-antiserum and 6-hydroxydopamine with respect to their mode of action on the mature sympathetic nervous system. Finally, we suggest that a decreased availability of NGF in a terminal area, due to an interference with endogenous NGF by NGF-antibodies, may temporarily result in an impaired function of the supplying adrenergic neurone, including a degeneration of nerve terminals.     

A puzzling case of seizures and visual hallucinations during clomipramine treatment with a high dose but causing a low serum concentration

We present a puzzling case of a 25-year-old depressive man suffering from seizures and visual hallucinations during clomipramine treatment with a high dose but causing a low serum concentration. We examined alleles of cytochrome P450 (CYP) isozymes. It was revealed that he was not an ultrarapid metabolizer for CYP2D6, and that the genotypes were homozygous for CYP2D6 J and heterozygous for CYP2C19_m1. Throughout the treatment period, his compliance was good. Since he was a smoker, it seems likely that his low clomipramine level was due to smoking-induced CYP1A2 activity. These findings suggest that smoking-induced CYP1A2 activity overcomes the possibly inhibiting effects of homozygosity for CYP2D6J and heterozygosity for CYP2C19_ml, and that high-dose clomipramine is not always a direct cause of seizures.     

Carbamazepine as a single drug in the treatment of epilepsy. A prospective study of serum levels and seizure control.

Serum levels and seizure control were investigated in a prospective study when carbamazepine was given as a single drug to 32 patients with a variety of seizures. The patients included 13 previously untreated patients (group 1), and 19 who were unresponsive to other anticonvulsant drugs used in different combinations or as a single treatment (group 2). Thirteen patients (10 from group 1, and three from group 2) became seizure-free, and a greater than 50% reduction in seizure frequency occurred in 10 patients (nine from group 2, and one from group 1). Less than 50% reduction in seizure frequency occurred in five patients from group 2. As a wide range of serum levels was associated with complete freedom from seizures, or a greater than 50% reduction in seizure frequency, it was not possible to define a therapeutic range for carbamazepine. Side effects occurred at the start of treatment or after a dose increase. A wide range of serum levels was associated with side effects, and some patients could not tolerate levels greater than 42 mumol/l.