In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells

Background

Brain tumor-initiating cells (BTICs) are stem-like cells hypothesized to form a disease reservoir that mediates tumor recurrence in high-grade gliomas. Oncolytic virotherapy uses replication-competent viruses to target and kill malignant cells and has been evaluated in clinic for glioma therapy with limited results. Myxoma virus (MyxV) is a safe and highly effective oncolytic virus (OV) in conventional glioma models but, as seen with other OVs, is only modestly effective for patient-derived BTICs. The objective of this study was to determine whether MyxV treatment against human BTICs could be improved by combining chemotherapeutics and virotherapy.

Methods

A 73-compound library of drug candidates in clinical use or preclinical development was screened to identify compounds that sensitize human BTICs to MyxV treatment in vitro, and synergy was evaluated mathematically in lead compounds using Chou-Talalay analyses. The effects of combination therapy on viral gene expression and viral replication were also assessed.

Results

Eleven compounds that enhance MyxV efficacy were identified, and 6 were shown to synergize with the virus using Chou-Talalay analyses. Four of the synergistic compounds were shown to significantly increase viral gene expression, indicating a potential mechanism for synergy. Three highly synergistic compounds (axitinib, a VEGFR inhibitor; rofecoxib, a cyclooxygenase-2 inhibitor; and pemetrexed, a folate anti-metabolite) belong to classes of compounds that have not been previously shown to synergize with oncolytic viruses in vitro.

Conclusions

This study has identified multiple novel drug candidates that synergistically improve MyxV efficacy in a preclinical BTIC glioma model.     

左房粘液瘤手术的麻醉(附5例报告)

作者复习有关文献,结合5例左房粘液瘤手术的麻醉,进行了讨论。指出麻醉管理上的几个特点,选用吗啡、芬太尼或单用芬太尼静脉复合麻醉,在麻醉诱导和维持期血压与心率均较平稳。认为在麻醉前对此病的特点应有充分的了解和估计,选用吗啡或芬太尼静脉复合麻醉是可行的,不但有其优点,而且也是安全的。     

Gamna–Gandy nodules in a cardiac myxoma

A 33-year-old female was admitted for surgery for removal of a left atrial myxoma. Histological examination of the tumour showed features characteristic of myxoma. Additionally, Gamna-Gandy bodies were present in the tumour. This is a rare finding.     

Fibrous dysplasia associated with intramuscular myxoma (Mazabraud's syndrome): a long-term follow-up of three cases

The association between of fibrous dysplasia and intramuscular myxomas is extremely rare. The authors summarize the characteristics of Mazabraud's syndrome, as well as its clinical course on the basis of 24 cases reported in the literature and 3 cases of their own. The syndrome is quite uniform, and mostly occurs in women. Usually the presentation of poliostotic fibrous dysplasia bilaterally in the lower limbs and pelvic bones is followed by the appearance of multifocal intramuscular myxomas in the adjacent muscles, mostly decades later. These hamartomas tend to recur locally or symmetrically in the ipsilateral muscle groups and may reach enormous size without treatment. Malignant transformation (osteosarcoma, fibrosarcoma) on the basis of fibrous dysplasia in Mazabraud's syndrome has been reported in the literature. In our cases, however, in spite of the many recurrences, and the enormous size of the tumours, no malignant transformation was noted in either the fibrous dysplasias or the intramuscular myxomas during the long follow-up time (31 years for fibrous dysplasia and 16 years for myxomas). Early wide surgical excision and a carful long-term follow-up for the often very late recurrences of the myxomas is suggested in Mazabraud's syndrome. Received: 27 October 1997 / Accepted: 2 February 1998     

心脏粘液瘤14例临床病理分析

本文对14例心脏粘液瘤作了临床病理分析,其中男性9例,女性5例。发病年龄9～47岁,平均33岁。14例均经手术治疗。其中,1例为四心腔多发性心脏粘液瘤。本文着重讨论了对心脏粘液瘤病理学研究的临床意义。我们认为此病一旦确诊,应立即手术治疗。     

Demonstration of the inner structure of a right atrial myxoma by transoesophageal echocardiography

We report a case of a large right atrial myxoma. With the useof transoesophagal echocardiography, several cysts were idntifieldwithin the tumour and necrotic tissue was differentiated frommyxomatous tissue according to its echo-level. Transoesophagealechocardiography was very useful for the precise diagnosis ofcardiac tumour and demonstration of the inner structure.     

Cardiac myxoma is rich in factor XIIIa positive dendrophages: immunohistochemical study of four cases

Cardiac myxoma is an enigmatic tumour thought to arise from primitive cardiac mesenchymal cells. Factor XIIIa+ dendrophages are tissue histiocytes that are active in tissue repair and thrombosis. To explore whether factor XIIIa+ dendrophages play a role in cardiac myxoma morphogenesis, we stained four cases with an antiserum against coagulation factor XIIIa (FXIIIa). We also used antibodies recognizing CD34, CD31, and S-100 protein. Samples of valvular endocardium from 12 and 16 week fetuses and two adult autopsies were compared with the four myxomas. All cardiac myxomas had rounded and dendritic FXIIIa+ cells admixed with more numerous CD34+ spindle and stellate myxoma cells. The CD34+ cells formed multicellular syncytia and capillary sprouts. Many of these syncytial structures also expressed CD31 and, to a lesser extent, S-100 protein, strongly in two cases and more focally in two. Fetal subendocardium was composed of CD34+ stellate fibroblast-like cells invested with scattered FXIIIa+ histiocytes; no S-100+ cells were detected. Our findings confirm that cardiac myxomas are composed of CD34+ primitive subendocardial cells. These cells show a capacity for CD31+ endothelial differentiation. In cardiac myxoma, the CD34+ myxoma cells are accompanied by numerous FXIIIa+ dendrophages, the presence of which suggests abnormal organizing thrombus-like differentiation in cardiac myxoma morphogenesis.     

Left atrial myxoma presenting with synchronous carotid and femoral embolism

Summary Synchronous embolism of the right femoral and the left internal carotid arteries, occurring in a 39-year-old teacher upon physical effort, was found to be due to a left atrial myxoma. Clinical findings, electrocardiogram and chest radiographs had suggested myocarditis. The patient died of cerebral infarction. In cases of suspected myocarditis, left atrial myxoma has to be considered in the differential diagnosis. Histological examination is recommended of any material obtained by embolectomy.

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Zusammenfassung Ausgehend von einem Myxom des linken Vorhofes, traten bei einem 39jährigen Lehrer unter körperlicher Belastung gleichzeitig embolische Verschlüsse der rechten Arteria femoralis und der linken Arteria carotis interna auf. Der Tumor wurde erst post mortem diagnostiziert. Der klinische Herzbefund ließ im vorliegenden Fall am ehesten an eine Myocarditis denken. In seltenen Fällen ist bei bestehendem Verdacht auf Myocarditis differentialdiagnostisch auch ein Vorhofmyxom in Betracht zu ziehen. Durch Embolektomie gewonnenes Material sollte immer histologisch untersucht werden.

     

The Variations in the Immunologic Features and Interleukin-6 Levels for the Surgical Treatment of Cardiac Myxomas

Purpose In this study, we propose the existence of a relationship between cardiac myxomas and the immunologic features or interleukin-6 (IL-6), while also considering the optimal treatment of cardiac myxoma, especially “familial myxoma.” Methods In a 19-year period at our hospital, 20 patients underwent 21 operations for cardiac myxomas. The immunologic features and the IL-6 levels were measured pre-operatively in 13 cases and post-operatively in 10 cases. A case of “familial myxoma” was diagnosed based on molecular genetic analyses. Results No patients died in the hospital. The tumor size correlated with the preoperative IL-6 and/or α1-globulin values (P < 0.05). In addition, all of the immunologic features and IL-6 levels normalized by 4 weeks after surgery. “Familial myxoma” demonstrated recurrence without showing increases in either the immunologic features, inflammatory signs, or serum IL-6 levels. Conclusions Patients with cardiac myxoma should therefore be operated on immediately because the possibility that the tumor size might be large when IL-6 and/or α1-globulin values are high. In addition, cases of “familial myxoma” require careful observation and periodic echocardiography after surgery to identify any possible recurrence. Recently, molecular genetic analyses are therefore considered to be an important diagnostic tool for cardiac myxoma, especially “familial myxoma.” Our “familial myxoma” case demonstrated a C769T PRKAR1a mutation, which has also been observed in other cases of “familial myxoma.”