A retrospective analysis of the prognosis of Japanese patients with sarcoma brain metastasis

Abstract Background Bone and soft tissue sarcomas are rare tumors and extremely rarely metastasize to the brain. Previous studies have examined the characteristics and poor prognostic factors in cases of sarcoma brain metastasis (BM). Due to the rarity of cases of BM from sarcoma, limited data exist concerning the prognostic factors and treatment strategies. Methods A retrospective single‐center study was performed on sarcoma patients with BM. The clinicopathological characteristics and treatment options for BM of sarcoma were investigated to identify predictive prognostic factors. Results Between 2006 and 2021, 32 patients treated for newly diagnosed BM at our hospital were retrieved among 3133 bone and soft tissue sarcoma patients via our database. The most common symptom was headache (34%), and the most common histological subtypes were alveolar soft part sarcoma (ASPS) and undifferentiated pleomorphic sarcoma (25%). Non‐ASPS (p = 0.022), presence of lung metastasis (p = 0.046), a short duration between initial metastasis, and the diagnosis of brain metastasis (p = 0.020), and the absence of stereotactic radiosurgery for BM (p = 0.0094) were significantly correlated with a poor prognosis. Conclusions In conclusion, the prognosis of patients with brain metastases of sarcomas is still dismal, but it is necessary to be aware of the factors associated with a relatively favorable prognosis and to select treatment options appropriately

Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies

Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF

Volumetric Analysis of Glioblastoma for Determining Which CpG Sites Should Be Tested by Pyrosequencing to Predict Temozolomide Efficacy

The aim of the present study was to determine which individual or combined CpG sites among O6-methylguanine DNA methyltransferase CpG 74–89 in glioblastoma mainly affects the response to temozolomide resulting from CpG methylation using statistical analyses focused on the tumor volume ratio (TVR). We retrospectively examined 44 patients who had postoperative volumetrically measurable residual tumor tissue and received adjuvant temozolomide therapy for at least 6 months after initial chemoradiotherapy. TVR was defined as the tumor volume 6 months after the initial chemoradiotherapy divided by that before the start of chemoradiotherapy. Predictive values for TVR as a response to adjuvant therapy were compared among the averaged methylation percentages of individual or combined CpGs using the receiver operating characteristic curve. Our data revealed that combined CpG 78 and 79 showed a high area under the curve (AUC) and a positive likelihood ratio and that combined CpG 76–79 showed the highest AUC among all combinations. AUCs of consecutive CpG combinations tended to be higher for CpG 74–82 in exon 1 than for CpG 83–89 in intron 1. In conclusion, the methylation status at CpG sites in exon 1 was strongly associated with TVR reduction in glioblastoma

Clinical Application of Comprehensive Genomic Profiling Tests for Diffuse Gliomas

Next-generation sequencing-based comprehensive genomic profiling test (CGPT) enables clinicians and patients to access promising molecularly targeted therapeutic agents. Approximately 10% of patients who undergo CGPT receive an appropriate agent. However, its coverage of glioma patients is seldom reported. The aim of this study was to reveal the comprehensive results of CGPT in glioma patients in our institution, especially the clinical actionability. We analyzed the genomic aberrations, tumor mutation burden scores, and microsatellite instability status. The Molecular Tumor Board (MTB) individually recommended a therapeutic agent and suggested further confirmation of germline mutations after considering the results. The results of 65/104 patients with glioma who underwent CGPTs were reviewed by MTB. Among them, 12 (18.5%) could access at least one therapeutic agent, and 5 (7.7%) were suspected of germline mutations. A total of 49 patients with IDH-wildtype glioblastoma showed frequent genomic aberrations in the following genes: TERT promoter (67%), CDKN2A (57%), CDKN2B (51%), MTAP (41%), TP53 (35%), EGFR (31%), PTEN (31%), NF1 (18%), BRAF (12%), PDGFRA (12%), CDK4 (10%), and PIK3CA (10%). Since glioma patients currently have very limited standard treatment options and a high recurrence rate, CGPT might be a facilitative tool for glioma patients in terms of clinical actionability and diagnostic value