Molecular genetic alterations in glioblastomas with oligodendroglial component

Glioblastoma multiforme is the most malignant astrocytic glioma and usually resistant to chemotherapy. A small fraction of glioblastomas may contain areas with histological features of oligodendroglial differentiation. To determine the molecular genetic alterations in such "glioblastomas with oligodendroglial component", we investigated 13 of these tumors for genetic alterations and/or expression of the TP53, CDKN2A, PTEN, and EGFR genes. In addition, we performed microsatellite analyses for loss of heterozygosity (LOH) on chromosome arms 1p, 19q and 10q. None of tumors showed evidence for LOH on 10q. LOH on 1p was detected in 3 tumors, 1 of which additionally showed LOH on 19q. The 3 tumors with LOH on 1p showed neither TP53 mutations nor nuclear p53 accumulation. In contrast, 9 of 10 tumors without demonstrated losses on 1p showed nuclear p53 accumulation. TP53 mutations were identified in 3 of these cases. Further aberrations detected were epidermal growth factor receptor (EGFR) overexpression (3 of 13 tumors), homozygous CDKN2A deletion (2 of 11 tumors), and PTEN mutation (1 of 13 tumors). Taken together, our results indicate that "glioblastomas with oligodendroglial component" carry heterogeneous genetic alterations. LOH on 10q, PTEN mutation, and homozygous CDKN2A deletion appear to be less common in these tumors as compared to ordinary glioblastomas. Furthermore, a subset of these tumors demonstrates LOH on 1p, i.e., an alteration that has recently been linked to chemosensitivity and good prognosis in anaplastic oligodendrogliomas.     

Synucleinopathies: a pathological and molecular review

Synucleins are a family of small, presynaptic neuronal proteins comprised of α-, β-, γ-synucleins and synoretin, of which only α-synuclein aggregates have been associated with several neurological diseases. The normal neuronal function of synucleins are presently unknown, but several activities such as lipid vesicle binding, inhibition of phospholipase D2 and protein kinase C, dopamine uptake and as a chaperone have been ascribed to α-synuclein. The role of synuclein in the etiology of neuropathology has developed from several observations. Pathologically, synuclein was identified as the major component of Lewy bodies (LBs), the hallmark inclusions of Parkinson's disease (PD), and a fragment thereof was isolated from amyloid plaques of a different neurological disease, Alzheimer's disease (AD). Biochemically, recombinant α-synuclein was shown to be able to form fibrils which recapitulated the ultrastructural features of α-synuclein isolated from patients with dementia with LBs (DLB), PD and multiple system atrophy (MSA). Additionally, the identification of mutations within the synuclein gene, albeit in rare cases of familial PD, demonstrated an unequivocal link between synuclein pathology and neurodegenerative disease. The common involvement of α-synuclein in a spectrum of diseases such as PD, DLB, MSA and the LB variant of AD has led to the classification of these diseases under the umbrella term of synucleinopathies.     

Pleomorphic xanthoastrocytoma with a gangliomatous component: an immunohistochemical and ultrastructural study

We report a case of 24-year-old woman with left temporal pleomorphic xanthoastrocytoma (PXA) with atypical neuronal cells. Many neoplastic cells, otherwise typical of PXA, expressed glial fibrillary acidic protein, while neuronal cells with marked atypia were immunopositive for synaptophysin and neurofilament protein. This report supports a notion that PXA, like other astrocytic tumors, may have its gangliogliomatous counterpart.     

Correlations between molecular profile and tumor location in Chinese patients with oligodendroglial tumors

OBJECTIVE: To investigate possible correlations between molecular alterations and tumor location in Chinese patients with oligodendroglial tumors. METHODS: A series of 105 gliomas, including 42 oligoastrocytomas, and two control groups of 28 oligodendrogliomas and 35 astrocytomas, were retrospectively reviewed. In each case, the radiologic picture and loss of heterozygosity (LOH) on chromosome 1p and 19q detected by denaturing high-performance liquid chromatography (DHPLC) were analyzed. Correlations between molecular profile and tumor location were made by chi-square and Fisher's exact tests. RESULTS: Oligodendroglial tumors located in the nontemporal lobes were significantly more likely to have combination of LOH 1p and LOH 19q than tumors arising in the insula, temporal lobe, and temporal with another lobe (p=0.001). Subgroup analysis confirmed this finding in oligodendrogliomas (p=0.006), but the difference did not reach significance in the oligoastrocytoma group, although the trend was similar (p=0.067). In contrast to the oligodendroglial tumors, we detected no association between molecular alterations and location for diffuse astrocytomas. CONCLUSION: We conclude that molecular subsets of oligodendroglial tumors may arise preferentially in certain lobes of the brain, with tumors having LOH 1p and LOH 19q occurring most frequently in the nontemporal lobes. These findings suggest that molecular subsets of oligodendroglial tumors may arise from site-specific precursor cells, which has provided some information for the current management of these neoplasms in China.     

眼咽型远端型肌病二家系的临床、病理及分子学特点

目的 探讨2个眼咽型远端型肌病(OPDM)家系的临床、病理及分子生物学特点.方法 对2个家系的先证者行血清肌酶、肌电图、肌肉活体组织检查、肌肉酶组织染色及电镜分析,并于复诊时提取其静脉血DNA样本,进一步行编码多聚腺苷酸结合蛋白核1(PABPN1)、GNE基因突变分析.结果 家系1为同代3兄弟发病,家系2为2代4人发病.起病以发音困难伴双下肢无力居多;以发音及吞咽困难为表现的咽部肌群受累较突出.肌肉超微结构电镜分析未见到眼咽型肌营养不良样核内包涵体,2家系先证者PABPN1基因GCN重复拷贝数均为正常(10次,GCG6GCA3GCG1),且GNE基因2～12号外显子均未发现突变.结论 2个OPDM家系起病年龄、形式与日本患者类似,但肌肉受累方式有所不同.家系1为中国首个常染色体隐性遗传OPDM家系.本研究结果证实OPDM是一个表型、病理、遗传学独立的肌病实体.     

少突胶质细胞肿瘤的分子遗传学改变与其部位的相关性研究

目的 研究少突胶质细胞肿瘤分子遗传学改变和肿瘤部位的相关性.方法 回顾性地研究了105例胶质瘤.根据影像学资料记录每例肿瘤的部位,运用PCR-变性高效液相色谱技术检测肿瘤染色体1p和19q杂合性缺失的情况,用χ2检验和Fisher确切概率法评估肿瘤部位和分子遗传学特征之间的相关性.结果 位于非颞叶的少突胶质细胞肿瘤与位于颞叶的肿瘤相比,更倾向于具有1p和19q联合杂合性缺失,而星形细胞瘤的分子遗传学特征与其部位之间没有相关性.结论 不同分子亚型的少突胶质细胞肿瘤可能发生于不同的脑叶,即具有1p和19q联合杂合性缺失的肿瘤通常发生于非颞叶.     

Holoprosencephaly with cyclopia--report of a pathological study

A rare case of a lobar holoprosencephaly with cyclopia, associated with non-nervous system anomalies is being reported.     

Sialidosis type I: pathological study in an adult

Histological and ultrastructural findings observed throughout the nervous system and the extranervous organs in a case of sialidosis type I, also known as normosomatic group, are reported. The patient was a 22-year-old male with non-familial progressive myoclonus, macular cherry-red spot, moderate cerebellar syndrome and normal intelligence. Biochemical study showed an alpha-N-acetylneuraminidase deficiency in cultured fibroblasts. A complete and early autopsy was performed. Neuropathological study showed two prominent lesions: the first one was a fine cytoplasmatic vacuolation in several neurons of the cortex, basal ganglia and thalamus and the second one was a diffuse neuronal intracytoplasmic storage of lipofuscin-like pigment (LLP). As for the extranervous organs the main light and electron microscope findings were observed in the hepatocytes and in the Kupffer's cells, which showed an enlarged cytoplasm and lipopigment granules in different amount. Vacuoles containing dense lamellar bodies were found in tubular epithelial cells of the kidney. To our knowledge this is the first complete autoptic study of a case of sialidosis type I.     

Working with pathological and healthy forms of splitting: a case study

The author illustrates through a case discussion how he understands the concept of splitting and how he makes use of that understanding in tracking, and at times, interpreting movement of the unconscious transference and countertransference. He views splitting not simply as a primitive defense but also as essential to early emotional development and to healthy psychological maturation in the course of analytic work. In the analytic relationship discussed in this article, the author presents both aspects of splitting--as a primitive defense and as a healthy movement toward new and more complex object relatedness. Difficulties arise when one fails to distinguish pathological from healthy but immature forms of splitting. Healthy splitting in its beginnings represents an important developmental step that serves as a transition to ambivalence and mature integration. The author demonstrates the importance of the analyst's capacity to distinguish pathological splitting from healthy splitting during periods of analytic impasse.     

Human cerebral malaria: a pathological study

The following report using light and electron microscopic and immunological techniques is based on a series of 19 Burmese patients who died of cerebral malaria. The principal change was blockage of cerebral capillaries by Plasmodium falciparum-infected erythrocytes. Ring hemorrhages and segmental necrosis of cerebral capillaries were common. Cerebral edema was variable in these cases. Electron-dense knobs, 40 X 80 nm in size, which protruded from the membrane of infected erythrocytes, formed focal junctions between endothelial cells and erythrocytes. These junctions resulted in the entrapment of erythrocytes and caused blockage in the capillary lumen. Immunoperoxidase study revealed that P. falciparum antigens and IgG deposits in the capillary basement membrane. This implies that damage to the cerebral capillary could be related to immune mechanisms.     

加强胶质细胞瘤分子病理学机制研究

探索与揭示脑的奥秘是当代自然科学所面临的重大挑战。2000年以神经信息学为核心,由全球科学家共同参与的国际科研计划—人类脑计划正式启动,标志着脑科学研究进入了一个新的时代。以研究脑、认识脑、保护脑和开发脑为宗旨、对脑的发育、分化及相关疾病的研究已成为各国科学家竞相研究的热点[1]。胶质细胞瘤是中枢神经系统最常见的恶性肿瘤,是一类严重危害人类生命和健康的疾病。成人胶质细胞瘤发生率约占颅内肿瘤的45%,儿童胶质细胞瘤也是中枢神经系统内最常见的实体性肿瘤。目前,尽管包括手术、放疗及化疗措施对胶质细胞瘤综合治疗水平已…     

多发性硬化周围神经损害的肌电图及病理研究

目的：探讨多发性硬化（MS）产生周围神经损害的肌电图，病理特点和影响MS累及周围神经的相关因素。方法：33例MS患者，均满足Poser的确定诊断标准，排除其他神经系统疾病，30名正常自愿受试者作为对照，排除周围神经损害的相关因素，两组分别进行运动，感觉神经传导检测，F波潜伏期及出现率，H反射潜伏期检测，腓肠神经活检，光镜及电镜观察周围神经病理变化。结果：（1）33例MS患者中，9例有根性疼痛，3例有手袜套样感觉障碍，6例不对称性肌萎缩，2例有明显的自主神经症状；（2）肌电图显示复合肌肉动作电位波幅降低，正中神经，尺神经感觉运作电位波幅增高，F波及H反射的潜伏期延长，F波出现率降低。MS周围神经损害的程度与神经功能缺损、病程及病变部位有关，神经功能缺损越重，病程越长，胫神经和腓总神经运动传导波幅降低越明显，正中神经、尺神经感觉动作电位波幅增高越明显；脊髓型MS周围神经受损明显高于脑型；（3）6例患者腓肠神经活检，光镜下可见有髓纤维呈不同程度的髓鞘脱失。电镜下以轴索变性为主，髓鞘板层解离及髓球形成。结论：MS是一种以CNS受损为主的脱髓鞘疾病，在部分患者可对同时累及周围神经系统，脱髓鞘改变主要发生在脊神经根，远端轴突可继发轴索损害，肌电图是比较理想的可全面评价MS周围神经损害的临床检测手段，对判断预后有一定的实用价值。     

Familial centronuclear myopathy: a clinical and pathological study

A congenital myotubular myopathy in a family is presented. An elderly woman, her daughter and her granddaughter showed the characteristic clinical and histological pattern of the disease. It is still a matter of debate whether the disease is of myopathic or neuropathic origin. The similarity of the muscle fibre with a myotube of the fetus might point towards an arrest of the maturation after 20th week of gestation perhaps caused by a lack of a trophic factor from the motor nerve.     

ORIGINAL ARTICLE: Argyrophilic grain disease with delusions and hallucinations: a pathological study

No clear clinical syndrome for argyrophilic grain disease (AGD) has yet been identified. Previous studies have documented its clinical features, namely, personality changes characterized by emotional disorder involving aggression or ill temper and relatively well‐preserved cognitive function, but the clinical manifestations of delusions and hallucinations as they appear in AGD have not been thoroughly described. Here, we report on a 72‐year‐old Japanese AGD patient who showed psychiatric symptoms, memory impairment and emotional change. He perceived and described a person who was not present and tried to grasp things on the floor though nothing was there. He also insisted that somebody was watching him and consequently always kept his curtains closed. These psychiatric symptoms were observed at an early stage in the patient's disease course. Serial neuroradiological examination showed progressive atrophy of the bilateral temporal lobes. The patient died at 79 years‐of‐age. Microscopic neuropathological examination showed transactivation responsive region (TAR)‐DNA‐binding protein of 43 kDa (TDP‐43) positive structures in addition to widespread argyrophilic grains and coiled bodies. According to recent recommendations for pathological diagnosis, this case corresponds to AGD with limbic TDP‐43 pathology. This case shows that patients with AGD that is eventually confirmed through autopsy can present with delusions and hallucinations early in the course of their disease. The clinical significance of TDP‐43 pathology in the brains of patients with AGD remains uncertain.     

抗肌萎缩蛋白病一家系的临床、分子病理及遗传学特点

目的 分析并确定1个抗肌萎缩蛋白病(dystrophinopathy)家系的临床、分子病理及遗传学特征.方法 收集先证者及其家系成员的临床资料,对先证者行肌肉活体组织检查,采用抗层黏连蛋白α2(1aminin α2,又称merosin)、抗emerin蛋白、抗肌萎缩蛋白(dystrophin)中央棒状区(Dys1)、C′末端(Dys2)、N′末端(Dys3)单克隆抗体行免疫组织化学染色;提取外周血基因组DNA,采用多重连接探针扩增(MLPA)进行抗肌萎缩蛋白Duchenne型肌营养不良(DMD)基因检测.结果 该家系中包括先证者在内共有3例患者临床诊断为肌营养不良,均无腓肠肌肥大,但病情重、进展较快,同时先证者肌肉活体组织检查行免疫组织化学染色提示dystrephin蛋白部分缺失,merosin、emerin染色呈阳性表达.MLPA检测显示先证者DMD基因第45～54外显子缺失,其母在第45～54外显子区域为杂合性缺失.结论 该家系中的先证者DMD基因为第45～54外显子缺失,突变基因来自母亲,其母为表型正常的携带者.dystrophin蛋白表达异常是造成抗肌萎缩蛋白病表型的病理基础,其临床后果不仅取决于dystrophin蛋白表达缺失的程度,还取决于DMD基因缺失区域的功能.     

Anaplastic ganglioglioma with sarcomatous component: An immunohistochemical study and molecular analysis of p53 tumor suppressor gene

The present case report describes a case of ganglioglioma with a distinct sarcomatous component in the left temporal lobe of a 59‐year‐old Japanese man. Neoplastic neuroglial tissue contained both benign and anaplastic glial components with a MIB‐1 labeling index of 0.1% and 12.0%, respectively. Sarcomatous tissue adjacent to the anaplastic glial tissue was dominated by pleomorphic fibroblastic cells with a MIB‐1 labeling index of 10.8%. They were immunoreactive for smooth muscle actin, type IV collagen, and alpha 1 antitrypsin, but not for desmin and CD34. Interestingly, some of the sarcomatous cells were double‐positive for smooth muscle actin and GFAP. The p53 protein had accumulated in the anaplastic astrocytes and sarcomatous cells, but direct DNA sequencing of PCR products failed to detect any mutation in the p53 gene (from exon 4 to exon 10).