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BackgroundDespite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.MethodsComprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.ResultsWhile TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.ConclusionsGlioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.

BACKGROUND: Irinotecan demonstrates anti-tumor efficacy in preclinical glioma models but clinical results are modest due to drug delivery limitations. Convection enhanced delivery (CED) improves drug delivery by increasing intratumoral drug concentration. Real-time magnetic resonance imaging of infusate delivery during CED may optimize tumor coverage. This phase 1 trial examines the safety and tolerability of liposomal irinotecan and gadolinium delivered via CED using real-time MRI guidance in recurrent high-grade glioma patients. METHODS: Initially, a 3 + 3 dose-escalating, single dose trial was planned with 4 cohorts based on a fixed drug dose and volume. After 9 patients, a protocol amendment allowed for variable volume and dose of the study agent based on tumor size. The amended design specified personalized drug volume but fixed concentration of 20 mg/mL of liposomal irinotecan in the first cohort escalating to 40 mg/mL in the second cohort. RESULTS: Eighteen patients with recurrent WHO grade 3 or 4 gliomas (diameter 1-4 cm) were treated. Based on the tumor volume, the total dose of liposomal irinotecan was 20-680 mg in a total volume of 2-17 ml. Technical challenges were overcome by real-time MRI guidance and protocol amendment. The only dose-limiting toxicity (DLT) was a grade 3 stroke. Safety and survival information is presented. CONCLUSIONS: CED of liposomal irinotecan using real-time MRI in patients with recurrent high-grade glioma is feasible. Image-guidance allowed for improved placement of CED cannulas and optimal tumor coverage. Our results warrant further study with repeat CED dosing.

Gliosarcoma (GS) is a rare subtype of glioblastoma multiforme, characterized by a shorter clinical course and poorer prognosis compared to glioblastoma. Here, we report the case of a 50-year-old male patient who presented with episodic loss of consciousness and left-sided limb weakness for one month. MRI revealed a complex neoplastic lesion in the right fronto-parietal region. Postoperative pathology confirmed GS, and the patient underwent adjuvant radiotherapy and chemotherapy. This case highlights the characteristic features of GS through a combination of imaging and pathological findings, providing valuable insights for radiologists.

BACKGROUND: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. METHODS: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. RESULTS: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-β (TGF-β) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-β family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. CONCLUSIONS: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.

Stereotactic radiosurgery (SRS) is widely utilized to treat small- and medium-sized brain arteriovenous malformations (BAVMs); however, radiation-induced malignancies (RIMs) have been reported as extremely rare yet potentially life-threatening complications of SRS. This study aimed to investigate the risk of RIMs after SRS for BAVMs. The outcomes of patients who underwent single-session SRS for BAVMs at our institution and were followed for ≥ 5 years were analyzed to calculate the incidence of RIMs. In addition, a systematic review was conducted using the existing literature reporting RIMs after SRS for BAVMs in compliance with the PRISMA guideline. Regarding the in-hospital analysis, only one (0.18%) RIM (gliosarcoma) was observed among 569 patients, with a median follow-up period of 151 months (interquartile range, 103–255 months). The 15, 20, and 25-year cumulative incidences of RIMs were 0%, 0%, and 1.01%, respectively, whereas the overall incidence rate was 0.12 per 1,000 patient-years. In the systematic review, 14 studies were included, with the incidence of RIMs ranging from 0.00 to 0.24%. Eight patients with RIMs were identified, and the most common pathology was glioblastoma. The median time until the diagnosis of RIM was 7.1 years (range, 4–19 years) after SRS, and their clinical courses were largely dismal, with the post-diagnosis survival periods being 1–10 months. RIM constitutes an extremely rare but potentially fatal complication following SRS for BAVMs, with its incidence rate being at most 0.24%. [ABSTRACT FROM AUTHOR]

Purpose: This study describes oncological outcomes and investigates prognostic factors for patients with gliosarcomas (GSM). Methods: Histopathologically confirmed GSM patients who underwent treatment at five European institutions were retrospectively analyzed. Results: We analyzed 170 patients with a median clinical follow‐up time of 9.2 months. The majority received surgery (94.1%), postoperative radiotherapy (pRT, 81.8%), and temozolomide (TMZ)‐based postoperative chemotherapy (66.5%). The median overall survival (OS) and progression‐free survival (PFS) were 12.3 and 6.6 months, respectively. In the multivariable Cox regression analysis (MVA), the following factors were significantly associated with OS: age per year (hazard ratio (HR): 1.03, p < 0.001), subtotal resection (STR) versus biopsy only (HR: 0.15, p = 0.018), gross total resection (GTR) versus biopsy only (HR: 0.13, p = 0.011), pRT versus no pRT (HR: 0.20, p < 0.001), postoperative TMZ‐based chemotherapy versus no postoperative chemotherapy (HR: 0.44, p = 0.003), MGMT promoter non‐methylated versus methylated (HR: 1.79, p = 0.05), and tumor diameter per cm (HR: 1.15, p = 0.046). For PFS, the following factors were significantly associated in the MVA: GTR versus biopsy only (HR: 0.19, p = 0.026), pRT versus no pRT (HR: 0.36, p = 0.006), postoperative TMZ‐based chemotherapy vs. no postoperative chemotherapy (HR: 0.39, p < 0.001), MGMT promoter status unknown versus methylated (HR: 1.69, p = 0.034), and tumor diameter per cm (HR: 1.18, p = 0.016). Sex, primary or secondary GSM, and TP53 mutational status were not significantly associated with OS or PFS. Conclusions: Trimodal therapy comprising surgical resection, pRT and TMZ‐based chemotherapy appears to have the most beneficial effect on survival in GSM patients. Smaller tumor size, younger age and methylated MGMT promoters are associated with improved survival. To our knowledge, this is the largest multi‐institutional cohort study investigating outcomes and prognostic factors for GSM. [ABSTRACT FROM AUTHOR]