Secondary gliosarcoma: the clinicopathological features and the development of a patient-derived xenograft model of gliosarcoma.

BACKGROUND: Gliosarcoma (GSM) is a distinct and aggressive variant of glioblastoma multiforme (GBM) with worse prognosis and few treatment options. It is often managed with the same treatment modalities with temozolomide (TMZ) as in GBM. However, the therapeutic benefits on GSM from such treatment regimen is largely unknown. Patient-derived xenograft (PDX) models have been used widely to model tumor progression, and subsequently to validate biomarkers and inform potential therapeutic regimens. Here, we report for the first time the successful development of a PDX model of secondary GSM. METHODS: Tissue obtained from a tumor resection revealed a secondary GSM arising from GBM. The clinical, radiological, and histopathological records of the patient were retrospectively reviewed. Samples obtained from surgery were cultured ex vivo and/or implanted subcutaneously in immunocompromised mice. Histopathological features between the primary GBM, secondary GSM, and GSM PDX are compared. RESULTS: In explant culture, the cells displayed a spindle-shaped morphology under phase contrast microscopy, consistent with the sarcomatous component. GSM samples were subcutaneously engrafted into immunocompromised mice after single-cell suspension. Xenografts of serial passages showed enhanced growth rate with increased in vivo passage. We did not observe any histopathological differences between the secondary GSM and its serial in vivo passages of PDX tumors. CONCLUSIONS: Our PDX model for GSM retained the histopathological characteristics of the engrafted tumor from the patient. It may provide valuable information to facilitate molecular and histopathological modelling of GSM and be of significant implication in future research to establish precise cancer medicine for this highly malignant tumor.

Gliosarcoma with PNET features mimicking a metastatic neuroendocrine carcinoma: A diagnostic dilemma.

OBJECTIVE: Gliosarcomas (GS) comprise ~ 2 - 8% of glioblastomas and are associated with a similar poor prognosis. GS have rarely been found with a primitive neuroectodermal component (PNET). We present a case of gliosarcoma with PNET features (GS-PNET) that mimicked a neuroendocrine carcinoma on initial biopsy. MATERIALS AND METHODS: A 68-year-old male presented with 2 weeks of increasing headaches and difficulties with reading, writing, and word-finding. He was found to have a left-sided parieto-occipital heterogeneously enhancing mass. RESULTS: Pathologic analysis after surgical resection initially diagnosed a poorly differentiated carcinoma with neuroendocrine features, and adjuvant therapy was guided by this diagnosis as well as systemic imaging, which was suggestive of gastrointestinal primary malignancy with central nervous system (CNS) metastasis. Subsequent progression and re-resection established a diagnosis of GS with PNET component. Genomic profiling showed shared PTEN, TERT promotor, and TP53 mutations in the original and recurrent tumors. CONCLUSION: There have only been 5 previously reported cases of GS-PNET, to our knowledge, with this case representing the first with comprehensive molecular profiling. The case also highlights the importance of further work-up of presumed metastatic carcinoma with indeterminate immunostaining and/or suspected non-epithelioid component.

Prognostic factors and clinical outcomes in adult primary gliosarcoma patients: a Surveillance, Epidemiology, and End Results (SEER) analysis from 2004 to 2015.

Objective: Gliosarcoma (GSC), a rare malignant brain tumor, is considered as a variant of isocitrate dehydrogenase 1 wild type (IDH1-WT) glioblastoma (GBM). This study aimed to retrospectively analyze the clinical characteristics of GSC and compare whether there are some differences of treatment strategies and outcomes between GSC and GBM patients through Surveillance, Epidemiology, and End Results (SEER) database.Patients and methods: The clinical data of adults diagnosed with primary GSC between 2004 and 2015 were queried from SEER database. The Kaplan-Meier curve and the Cox model were performed to analyze the relationships between clinical parameters and patients' prognosis. Similar analyses were conducted for all primary GBM patients of SEER.Results: In total, 527 GSC and 20,541 GBM patients with complete and valid clinical information were finally enrolled for further analysis. Compared with GBM, GSC owned a proclivity to temporal lobe rather than frontal lobe (p < 0.001), a less conservative extension of resection (EOR) (p < 0.001), and a higher sensitivity to radiotherapy (p < 0.001). As shown by univariate analysis, surgery, radiotherapy and chemotherapy could prolong the overall survival (OS) time of GSC, but EOR did not confer an advantage to the outcomes of patients, no matter whether combined radio/chemotherapy was given. In multivariate analysis, age more than 60 and lack of radio/chemotherapy were identified as independent risk factors for OS of GSC patients.Conclusions: Our study found that although EOR seemed to be important to GBM, the extent of surgery did not show a clear relationship with the improved prognosis of GSC. Additionally, radiotherapy and chemotherapy could prolong patients' survival time significantly, which suggests a more positive role of them in treating GSC and needs further investigations.

Gliosarcoma: a clinical and radiological analysis of 48 cases.

OBJECTIVES: To retrospectively review the radiological and clinicopathological features of gliosarcoma (GSM) and differentiate it from glioblastoma multiforme (GBM). METHODS: The clinicopathological data and imaging findings (including VASARI analysis) of 48 surgically and pathologically confirmed GSM patients (group 1) were reviewed in detail, and were compared with that of other glioblastoma (GBM) cases in our hospital (group 2). RESULTS: There were 28 men and 20 women GSM patients with a median age of 52.5 years (range, 24-80 years) in this study. Haemorrhage (n = 21), a salt-and-pepper sign on T2-weighted images (n = 36), unevenly thickened wall (n = 36) even appearing as a paliform pattern (n = 32), an intra-tumoural large feeding artery (n = 32) and an eccentric cystic portion (ECP) (n = 19) were more commonly observed in the GSM group than in GBM patients. Based on our experience, GSM can be divided into four subtypes according to magnetic resonance imaging (MRI) features. When compared to GBM (group 2), there were more patients designated with type III lesions (having very unevenly thickened walls) and IV (solid) lesions among the GSM cases (group 1). On univariate prognostic analysis, adjuvant therapy (radiotherapy, chemotherapy, and radiochemotherapy) and existence of an eccentric cyst region were prognostic factors. However, Cox's regression model showed only adjuvant therapy as a prognostic factor for GSM. CONCLUSIONS: When compared to GBM, certain imaging features are more likely to occur in GSM, which may help raise the possibility of this disease. All GSM patients are recommended to receive adjuvant therapy to achieve a better prognosis with radiotherapy, chemotherapy or radiochemotherapy all as options. KEY POINTS: • Diagnosis of gliosarcoma can be suggested preoperatively by imaging. • Gliosarcoma can be divided into four subtypes based on MRI. • Paliform pattern and ECP tend to present in gliosarcoma more than GBM. • The cystic subtype of gliosarcoma may predict a more dismal prognosis. • All gliosarcoma patients should receive adjuvant therapy to achieve better prognosis.

Biological characteristics and outcomes of Gliosarcoma.

Gliosarcoma is a highly aggressive primary brain tumour. It is a relatively rare tumour and comprises of two histological components, glial and sarcomatous. Gliosarcomas carry a poorer prognosis than that of Glioblastoma Multiforme (GBM). The current review highlights important histological and radiological features of gliosarcoma in the light of recent literature, and also touches upon the treatment options and outcomes of various types of gliosarcoma.

Primary Gliosarcoma of the Optic Nerve: A Unique Adult Optic Pathway Glioma.

A 90-year-old woman presented with 1-year history of right-sided progressive proptosis, neovascular glaucoma, blindness, and worsening ocular pain. No funduscopic examination was possible because of a corneal opacity. Head CT scan without contrast demonstrated a heterogeneous 4.1 cm (anterior-posterior) by 1.7 cm (transverse) cylindrical mass arising in the right optic nerve and extending from the retrobulbar globe to the optic canal. She underwent palliative enucleation with subtotal resection of the orbital optic nerve and tumor. Pathological examination showed effacement of the optic nerve by an infiltrative high-grade glial neoplasm with biphasic sarcomeric differentiation. Invasion into the uvea and retina was present. The neoplasm was negative for melan-A, HMB45, tyrosinase, synaptophysin, smooth muscle actin, and epithelial membrane antigen. The glioma had strongly intense, but patchy immunopositivity for glial fibrillary acidic protein. Multiple foci of neoplastic cells had pericellular reticulin staining. The overall features were diagnostic of a gliosarcoma (World Health Organization grade IV) of the optic nerve. Postoperative MRI demonstrated postsurgical changes and residual gliosarcoma with extension into the optic chiasm. The patient died 2 and a half months after her enucleation surgery at her nursing home. Autopsy was unavailable due to the caregiver wishes, making a definitive cause of death unknown. Gliosarcoma is a rare variant of glioblastoma, and this is the first documented case presenting as a primary neoplasm of the optic nerve.

Prognostic and therapeutic factors of gliosarcoma from a multi-institutional series.

The aims of this multicentre retrospective study were to identify prognostic or therapeutic factors impacting on overall survival in patients with gliosarcoma. The analysis included all patients treated for gliosarcoma between 1998 and 2014 in seven French academic centres. Seventy-five patients with a median age of 60 years (range from 23 to 79 years) were treated with a combination of surgery (n = 66), radiotherapy (adjuvant for 64 patients and exclusive for 8 patients) and temozolomide based chemotherapy (n = 58). Median follow-up was 12 months (range from 2 to 71 months). Two-year overall survival (OS) and disease free survival rates were 12 % (95 % CI 4-20 %) and 2 % (95 % CI 0-6 %), respectively. The median OS was 13 months. Treatment at recurrence consisted of chemotherapy (n = 38) (bevazicumab for 18 patients, repeat temozolomide for 10 patients), salvage surgery (n = 8) and radiochemotherapy (n = 1). In univariate analysis, younger age, higher total dose of radiotherapy, longer time to recurrence and treatment at recurrence significantly increased OS. In multivariate analysis, high total dose of radiotherapy (HR = 0.97, p = 0.007) and treatment at recurrence (HR = 0.28, p < 0.001) were favourable prognostic factors of OS. Radiotherapy at a minimum dose of 54 Gy and salvage treatment increased OS of gliosarcoma. Unlike glioblastoma, in our analysis, TMZ based chemotherapy was not associated with an improvement in OS compared to patients who received radiation therapy only.

An individual patient data meta-analysis on characteristics, treatments and outcomes of the glioblastoma/gliosarcoma patients with central nervous system metastases reported in literature until 2013.

Dissemination of high-grade gliomas (WHO IV) has been investigated poorly so far. We conducted an extensive analysis of the characteristics, treatments and outcomes of the glioblastoma multiforme (GBM)/gliosarcoma (GS) patients with central nervous system (CNS) metastases reported in literature until April 2013. PubMed and Web of Science searches for peer-reviewed articles pertaining to GBM/GS patients with metastatic disease were conducted using predefined keywords. Additionally, we performed hand search following the references from the selected papers. Cases in which the metastases exclusively occurred outside the CNS were excluded. 110 publications reporting on 189 patients were eligible. There was a significant increase in the number of reported cases over the last decades. We calculated a median overall survival from diagnosis of metastasis (from initial diagnosis of GBM/GS) of 3.0 ± 0.3 (11 ± 0.7) months. On univariate analyses, gender, age, the histological subtype, the time interval between initial diagnosis and the occurrence of metastases and the location of CNS metastasis (intracranial versus spinal and parenchymal versus leptomeningeal, respectively) did not influence survival after diagnosis of metastasis. There was no substantial treatment progress over the recent decades. GBM/GS with CNS metastasis are associated with a dismal prognosis. Crucial treatment progress is not evident. A central registry should be considered to consecutively gain more information about the ideal therapeutic approach.

Highly stable polymer coated nano-clustered silver plates: a multimodal optical contrast agent for biomedical imaging.

Here, we present a new optical contrast agent based on silver nanoplate clusters embedded inside of a polymer nano matrix. Unlike nanosphere clusters, which have been well studied, nanoplate clusters have unique properties due to the different possible orientations of interaction between the individual plates, resulting in a significant broadening of the absorption spectra. These nanoclusters were immobilized inside of a polymer cladding so as to maintain their stability and optical properties under in vivo conditions. The polymer-coated silver nanoplate clusters show a lower toxicity compared to the uncoated nanoparticles. At high nanoparticle concentrations, cell death occurs mostly due to apoptosis. These nanoparticles were used for targeted fluorescence imaging in a rat glioma cell line by incorporating a fluorescent dye into the matrix, followed by conjugation of a tumor targeting an F3 peptide. We further used these nanoparticles as photoacoustic contrast agents in vivo to enhance the contrast of the vasculature structures in a rat ear model. We observed a contrast enhancement of over 90% following the nanoparticle injection. It is also shown that these NPs can serve as efficient contrast agents, with specific targeting abilities for broadband multimodal imaging that are usable for diagnostic applications and that extend into use as therapeutic agents as well.

Competing Risk Model to Determine the Prognostic Factors for Patients with Gliosarcoma.

BACKGROUND: Gliosarcoma (GSM) is a highly aggressive variant of brain cancer with an extremely unfavorable prognosis. Prognosis is not feasible by traditional methods because of a lack of staging criteria, and the present study aims to screen more detailed demographic factors to predict the prognostic factors of the tumors. METHODS: For this study, we extracted data of patients diagnosed with GSM from the SEER (Surveillance Epidemiology and End Results) database between 2000 and 2019. To account for the influence of competing risks, we used a Cumulative Incidence Function. Subsequently, univariate analysis was conducted to evaluate the individual variables under investigation. Specifically for patients with GSM, we generated cumulative risk curves for specific mortality outcomes and events related to competing risks. In addition, we used both univariate and multivariate Cox analysis to account for non-GSM-related deaths that may confound our research. RESULTS: The competing risk model showed that age, marital status, tumor size, and adjuvant therapy were prognostic factors in GSM-related death. The analysis results showed that older age (60-70 years, ≥71 years) and larger tumor size (≥5.3 cm) significantly increased the risk of GSM-related death. Conversely, surgical intervention, chemotherapy, and being single were identified as protective factors against GSM-related death. CONCLUSIONS: Our study using a competing risk model provided valuable insights into the prognostic factors associated with GSM-related death. Further research and clinical interventions targeted at minimizing these risk factors and promoting the use of protective measures may contribute to improved outcomes and reduced mortality for patients with GSM.

Annexin A5-functionalized nanoparticle for multimodal imaging of cell death.

Techniques for visualizing cell death can provide noninvasive assessment of both disease states and response to therapeutic intervention. The purpose of this study was to develop and evaluate a multimodal imaging nanoplatform for the detection of cell death. In this study, we evaluated 111In-labeled annexin A5-conjugated core-cross-linked polymeric micelles (CCPMs) for multimodal imaging of cell death in various disease models. Three different models were conducted, including tumor apoptosis, hepatic apoptosis, and inflammation. Both micro single-photon emission tomography/computed tomography (µSPECT/CT) and fluorescence molecular tomography (FMT) were performed. Biodistribution and immunohistochemistry assays were carried out to validate the selectivity of cell death imaging. In all disease models, cell death was clearly visualized by both µSPECT/CT and FMT. In contrast, there was relatively low signal in the corresponding tissues of control mice. Moreover, the radioactive signal from 111In-labeled annexin A5-CCPM colocalized with its fluorescence signal, and both signals were confined to regions of dying cells. 111In-labeled annexin A5-CCPM allows visualization of cell death by both nuclear and optical techniques at the whole-body level as well as at the microscopic level. It has the potential to aid the diagnosis of disease states or tissue responses involving abnormal cell death.

Prognostic Factors of Gliosarcoma in the Real World: A Retrospective Cohort Study.

Purpose: Gliosarcoma is a histopathological variant of glioblastoma, which is characterized by a biphasic growth pattern consisting of glial and sarcoma components. Owing to its scarcity, data regarding the impact of available treatments on the clinical outcomes of gliosarcoma are inadequate. The purpose of this retrospective cohort study was to analyze the prognostic factors of gliosarcoma. Methods: By screening the clinical database of neurosurgical cases at a single center, patients with gliosarcoma diagnosed histologically from 2013 to 2021 were identified. Clinical, pathological, and molecular data were gathered founded on medical records and follow-up interviews. Prognostic factors were derived using the Cox proportional hazards model with backward stepwise regression analysis. Results: Forty-five GSM patients were included. Median overall survival was 25.6 months (95% CI 8.0-43.1), and median relapse-free survival was 15.2 months (95% CI 9.7-20.8). In multivariable analysis, total resection (p = 0.023, HR = 0.192, 95% CI 0.046-0.797) indicated an improved prognosis. And low expression of Ki-67 (p = 0.059, HR = 2.803, 95% CI 0.963-8.162) would be likely to show statistical significance. However, there might be no statistically significant survival benefit from radiotherapy with concurrent temozolomide (n = 33, 73.3%, log-rank p = 0.99) or adjuvant temozolomide (n = 32, 71.1%, log-rank p = 0.74). Conclusion: This single-center retrospective study with a limited cohort size has demonstrated the treatment of gross total resection and low expression of Ki-67 which are beneficial for patients with GSM, while radiotherapy or temozolomide is not.

Gliosarcoma with extensive extracranial metastatic spread and familial coincidence: A case report.

Gliosarcoma is a rare histopathological subtype of glioblastoma. Metastatic spreading is unusual. In this report, we illustrate a case of gliosarcoma with extensive extracranial metastases with confirmation of histological and molecular concordance between the primary tumor and a metastatic lesion of the lung. Only the autopsy revealed the extent of metastatic spread and the hematogenous pattern of metastatic dissemination. Moreover, the case bared a familial coincidence of malignant glial tumors as the patient's son was diagnosed with a high-grade glioma shortly after the patient's death. By molecular analysis (Sanger and next generation panel sequencing), we could confirm that both patient's tumors carried mutations in the TP53 gene. Interestingly, the detected mutations were located in different exons. Altogether, this case draws attention to the fact that sudden clinical aggravation could be caused by the rare phenomenon of metastatic spread and should therefore be always taken into consideration, even at an early disease stage. Furthermore, the presented case highlights the contemporary value of autoptic pathological examination.

CEST phase mapping using a length and offset varied saturation (LOVARS) scheme.

Chemical exchange saturation transfer MRI is a promising new technique for cellular and molecular imaging. This contrast allows the detection of tumors and ischemia without the use of gadolinium as well as the design of microenvironment-sensitive probes that can be discriminated based on their exchange contrast properties and saturation frequency. Current acquisition schemes to detect and analyze this contrast suffer from sensitivity to spatial B0 inhomogeneity and low contrast-to-noise-ratio, which is an obstacle to widespread adoption of the technology. A new method to detect chemical exchange saturation transfer contrast is proposed here, termed "length and offset varied saturation" which acquires a set of images with the saturation parameters varied so as to modulate the exchange contrast. Either fast fourier transform or the general linear model can be employed to decompose the modulation patterns into separate sources of water signal loss. After transformation, a length and offset varied saturation phase map is generated, which is insensitive to B0 inhomogeneity. When collected on live mice bearing 9L gliosarcomas, and compared to the conventional asymmetry in the magnetization transfer ratio map using offset increment correction, the results show that length and offset varied saturation phase mapping obtains about three to four times contrast-to-noise-ratio and exhibits less B0 artifacts.

[Secondary gliosarcoma: case report]. / Gliosarcome secondaire : à propos d'un cas.

Gliosarcoma is a rare tumor of the central nervous system, consisting of gliomatous and sarcomatous elements. The glioblastoma can undergo a change in phenotype, transforming into a gliosarcoma, especially when the tumor has been treated with radiotherapy. Features unique to gliosarcoma compared to glioblastoma include their potential to appear similar to a meningioma at macroscopy, repeated reports of metastases and infrequency of EGFR mutations. We present a case of secondary gliosarcoma to emphasize on the specificities, essentially diagnostical of this rare entity.

Gliosarcoma of the pineal region with cerebellar metastasis: case illustration.

A very rare case of gliosarcoma of the pineal region with cerebellar metastasis is presented. A few cases of glioblastoma and fibrosarcoma have already been published however there was no reported case with gliosarcoma at the pineal region even with cerebellar metastases.

Primary intramedullary spinal gliosarcoma: An unusual presentation.

Gliosarcoma is a biphasic central nervous system malignancy composed of glial and mesenchymal components. It is recognized as a rare variant of glioblastoma with unique histology, immunostaining properties, and natural history. Although usually described to primarily involve the brain, a search of the published literature revealed four reported cases of gliosarcoma arising in the spinal cord. This report describes the case of a 35-year-old woman with progressive back pain with loss of sensation and power of both lower limbs. Magnetic resonance imaging showed an intramedullary unifocal space-occupying lesion in her thoracolumbar spinal cord. Subtotal resection and subsequent histopathological and immunohistochemical studies confirmed the diagnosis of gliosarcoma of the spinal cord. This report further establishes the clinical entity of primary spinal gliosarcoma and proposes the need to consider this possibility among the differential diagnoses of a space-occupying spinal lesion.

Computed tomography and magnetic resonance features of gliosarcoma: a study of 54 cases.

OBJECTIVE: To investigate the features of pathologically confirmed gliosarcomas using computed tomography (CT) and magnetic resonance (MR) imaging. METHODS: We retrospectively reviewed the cross-sectional CT and MR images of 54 patients (37 males and 17 females; mean age, 44.5 years; range, 13-74 years) with gliosarcomas confirmed by histopathology. RESULTS: Across all patients, there were 59 lesions. On nonenhanced CT and MR images, tumors were predominantly inhomogeneous. On the postcontrast CT and MR images, 50 (84.7%) irregular lesions had thick walls with a strong rim- and ringlike enhancement, whereas the remaining 9 (15.3%) round or oval lesions had even thin walls with an enhanced peripheral ring. Magnetic resonance spectroscopy showed increased choline and lactate values, along with decreased N-acetylaspartate and creatine values. On diffusion-weighted imaging, the tumor was slightly or markedly hyperintense compared with the white matter. CONCLUSION: A well-demarcated mass located peripherally, with rimlike or ring enhancement, is a common presentation of gliosarcoma on CT and MR images. In addition, magnetic resonance spectroscopy and diffusion-weighted imaging can be used to make a differential diagnosis.

Diagnostic utility of IDH1- and p53-mutation analysis in secondary gliosarcoma.

We report on a 47-year-old woman in whom an anaplastic astrocytoma was resected in 2006. Postoperative radiation had to be interrupted because of a wound infection necessitating explantation of the infected bone flap and implantation of a titanium mesh. Subsequently, radiation therapy was completed and temozolomide was administered for 45 cycles. In the beginning of 2010 a new contrast enhancing mass was seen in the former tumor region. The mass was subtotally excised and showed no histomorphological similarity to the first lesion but represented a highly pleomorphic and mainly sarcomatoid differentiated malignant tumor. The lack of expression of GFAP or MAP-2 raised the question of a secondary malignancy, however, molecular genetic analysis of IDH1 and p53 revealed the same mutations in the anaplastic astrocytoma from 2006 as in the sarcomatoid tumor operated in 2010. Furthermore, accumulation of mutated IDH1 and TP53 protein could be demonstrated immunohistochemically. Thus, the second tumor represented the rare instance of recurrence of an anaplastic astrocytoma as a secondary gliosarcoma and a second malignant neoplasm was ruled out. The postoperative therapy and the inflammation might have contributed to the severe change in morphological phenotype of the glioma.

Treatments of gliosarcoma of the brain: a systematic review and meta-analysis.

Gliosarcoma (GSM) is a rare central nervous system tumor. Clinical management of it is similar to glioblastoma (GBM). However, due to a few comparative studies exist, uncertainty and disagreements remain in the literatures. To assess the available evidence on the value of different treatments and to carry out an up-to-date evaluation to summarize the evidence for the optimal treatment in GSM patients. Free words were used to search for the relevant studies without language limitations in electronic databases including PubMed, Ovid EMBASE, Cochrane Central Register of Controlled Trials from inception to September 15, 2019. Pooled hazard ratio (HR) with 95% confidence interval (CI) were calculated using a random-effects model. The main endpoint was all-cause mortality. Overall, 10 studies published between 2008 and 2018 including 803 patients were selected for the meta-analysis. Temozolomide (TMZ)-dominated chemotherapy was associated with a reduced risk of overall survival (OS), with HR 0.49 (95% CI 0.37-0.66). The pooled HR of OS was 0.40 (95% CI 0.29-0.56) between radiotherapy and without radiotherapy. The pooled HR (0.52, 95% CI 0.32-0.85) indicated gross total resection (GTR) had a positive impact on OS in GSM. In patients with GSM, survival benefits as currently performed are associated with TMZ-dominated chemotherapy and high-dose radiotherapy. Our systematic review and meta-analysis also demonstrate GTR is associated with a reduction in all-cause mortality in patients with primary GSM.