Research Institute in Oncology and Hematology

ObjectiveTo evaluate the effectiveness of early administration of excitatory amino acid (EAA) inhibitors on long-term neurological outcomes in adults with acute moderate to severe traumatic brain injury (TBI).DesignSystematic review and meta-analysis of randomised controlled trials (RCTs).Data sourcesMEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, WHO International Clinical Trials Registry Platform and ClinicalTrials.gov from inception to January 2026.Study selectionRCTs comparing EAA inhibitors with placebo, standard care or any other interventions were included. Trials enrolled adult patients (≥18 years) with moderate to severe TBI (Glasgow Coma Scale score ≤12) receiving the intervention within the acute phase of care (first week).Data extraction and synthesisPairs of reviewers independently screened trials, extracted data, assessed the risk of bias (RoB) with the Cochrane RoB tool 2 and graded the certainty of evidence using the Grades of Recommendation, Assessment, Development and Evaluation approach. Random effects models were used for all effect measures and trial sequential analyses (TSA) were performed for each outcome.Main outcome measuresThe primary outcome was long-term neurological function at 6 months (or the nearest earlier time point), assessed with the Glasgow Outcome Scale (GOS) or extended version (GOS-E), using the classical definitions of an unfavourable outcome (GOS 1–3 or GOS-E 1–4).Results28 trials enrolling 4238 patients were included. Early administration of EAA inhibitors was not associated with reduced unfavourable neurological outcomes (relative risk 0.93 (95% CI (0.84 to 1.03); I²=40%; 15 trials, n=3613, moderate certainty). No statistically significant difference was observed based on EAA inhibitor type, timing or duration of administration, RoB or TBI severity. Mortality, intensive care unit lengths of stay and mean intracranial pressure were not statistically different between groups, but hospital length of stay was reduced in the EAA inhibitors group. The early use of EAA inhibitors was not associated with adverse events (low certainty). TSA showed insufficient power for the primary outcome.ConclusionsIn adults with moderate to severe TBI, the early administration of EAA inhibitors was not associated with a reduction of unfavourable neurological outcomes. Further high-quality and adequately powered RCTs are required to clarify their role in TBI management.PROSPERO registration numberCRD42025635527.

Cervical cancer disproportionately affects HIV-positive women, especially in low- and middle-income countries (LMICs), with a sixfold increased risk due to immunosuppression and persistent HPV infection. This systematic review evaluates the clinical outcomes and toxicities associated with radiotherapy or chemoradiation in HIV-positive compared to HIV-negative women with cervical cancer. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search on August 15, 2023 and an update on June 20, 2025, of Ovid Medline, EMBASE, and ClinicalTrials.gov from database inception to June 2025, as well as a manual review of citations. This process identified 18 cohort studies (11 prospective and seven retrospective), including 2,790 HIV-positive and 4,064 HIV-negative patients treated for cervical cancer with radiation-based treatments. The majority of studies (15 out of 18) were conducted in sub-Saharan Africa. The findings indicated that HIV-positive patients had a 33% lower overall survival (OS) compared to HIV-negative patients (1.33 (95% confidence interval (CI) 1.08-1.63), p = 0.0080). Women living with HIV had an increased risk of mortality, exhibiting a relative risk of 1.27 (95% CI 1.13-1.43, p = 0.0080). They also showed a trend toward lower complete response rates, with a relative risk of 0.92 (95% CI: 0.79-1.06, p = 0.1595). Treatment toxicity was reported in 10 studies, but the grading scales and toxicity reporting differed across studies. Some studies reported differences in toxicities by HIV status, while others found no difference. However, data regarding the impact of concurrent antiretroviral therapy (ART) were not available for assessment on their influence on treatment outcomes and toxicities. The findings underscore the significant research deficiencies in the management of cervical cancer among HIV-positive women undergoing radiation therapy. There is a pressing need for targeted research to elucidate clinical and toxicity outcomes, thereby refining management strategies for this specific patient cohort.

Background/ObjectiveChronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder diagnosed in Canada and is associated with a significant economic burden. This study evaluates the cost effectiveness of fixed-treatment duration venetoclax plus obinutuzumab (VEN + O) for previously untreated, fit CLL patients in Canada, for whom this therapy is not universally reimbursed provincially.MethodsA three-state partitioned survival model was developed using data from the CLL13 trial and a Bayesian network meta-analysis. Health states included progression-free, progressed disease, and death. A lifetime horizon (40-year) was used and a 1.5% discount rate was applied to costs and effects. Costs included drug acquisition, administration, monitoring, adverse events, subsequent treatment, and terminal care. Utility values were derived from previous NICE technology appraisals in CLL. Extensive sensitivity and scenario analyses were conducted.ResultsVEN + O was associated with lower total costs and higher quality-adjusted life years and thus dominant compared with ibrutinib, zanubrutinib, and fludarabine plus cyclophosphamide plus rituximab. Compared with acalabrutinib and venetoclax plus ibrutinib, the incremental cost-utility ratios (ICURs) were in the south-west quadrant and substantially above a CA$50,000/QALY willingness-to-pay threshold, meaning VEN + O was cost effective versus these comparators. VEN + O was cost effective versus bendamustine plus rituximab. Extensive sensitivity and scenario analyses confirmed the robustness of these results.ConclusionsThis analysis demonstrates that VEN + O, a 12-month fixed duration treatment, is a cost-effective option for previously untreated fit CLL patients in Canada. VEN + O offers potential health benefits and cost savings when compared with relevant comparator treatments.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-025-00610-1.

CITATION Chen Y, Ghavami S, Park PC and Irobi J (2025) Editorial: Decoding cell fate: the critical roles of extracellular vesicles.

BackgroundGlioblastoma (GB), an aggressive brain malignancy with a poor prognosis of 1.5–2 years, rarely exhibits extracranial metastasis (ECM). However, metabolic reprogramming has emerged as a key driver of GB progression and invasiveness. This study presents a rare case of recurrent GB with scalp metastasis, exploring how metabolic shifts enable GB cells to evade treatment and adapt to hostile environments, offering insights for developing innovative therapies.MethodsTandem mass spectrometry (MS/MS) was employed to analyze amino acid profiles in both the recurrent and metastatic stages of GB. Systems biology approaches were used to uncover genetic alterations and metabolic reprogramming associated with the progression from recurrence to metastasis.ResultsOur analysis revealed distinct amino acid utilization patterns in a patient with a molecular phenotype of wild-type IDH-1&2, TERT mutation, non-mutated BRAF and EGFR, and non-methylated MGMT. During recurrence and metastasis, significant differences in amino acid profiles were observed between blood and cerebrospinal fluid (CSF) samples. Additionally, protein-protein interaction (PPI) analysis identified key genomic drivers potentially responsible for the transition from recurrent to metastatic GB.ConclusionsBeyond established risk factors such as craniotomy, biopsies, ventricular shunting, and radiation therapy, our findings suggest that metabolic reprogramming plays a crucial role in the transition from recurrent to metastatic GB. Targeting these metabolic shifts could provide new avenues for managing and preventing extracranial metastasis in GB, making this an important focus for future research.

Inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6) are approved for the treatment of locally advanced or metastatic breast cancer, but not for melanoma. In this study, we evaluated the effectiveness of the CDK4/6 inhibitor, palbociclib, the CDK2 inhibitor, PF-07104091, the dual CXCR1 and CXCR2 (CXCR1/2) antagonist, SX-682, and the combination of these inhibitors for effective treatment of melanoma in preclinical models. Both palbociclib and SX-682 inhibited the growth of BRAFWT/NRASWT B16-F10 and NRASmut 1014 melanoma tumors and in both models, SX-682 created a more anti-tumor immune microenvironment. The combination effect was additive in the B16F10 model, but not in the 1014 model. In the B16F10 model, the addition of the CDK2 inhibitor, PF-07104091, overcame B16F10 acquired resistance to CDK4/6 inhibitors by suppressing the induction of cyclin D1 and E1 expression by palbociclib. In the less responsive 1014 cells, cyclin D1 was reduced, but cyclin E1 was induced in response to PF-07104091. However, in both models, combined treatment with palbociclib and PF-07104091 markedly suppressed cyclin A2, cyclin D1, cyclin E1 and pRB-S807/S811. Combining CDK4/6 and CDK2 inhibitors with the CXCR1/2 antagonist, SX-682, halted B16F10 tumor growth by blocking tumor cell proliferation and increasing the anti-tumor immune response in the tumor microenvironment. The combination of all three inhibitors resulted in a tumor microenvironment characterized by increased IFNγ-producing CD4+ T cells, decreased CD4+FOXP3+ T regulatory cells (Tregs), and decreased IL-10-producing CD4+ T cells. This combination also decreased the percentage of CD8+ T cells that expressed PD-1 or TIM-3 and increased the ratio of MHCII+F4/80+ M1-like macrophages to CD206+F4/80+ M2-like macrophages. These data suggest that inhibiting CDK4/6 and CDK2, combined with antagonism of CXCR1/2, may be an effective treatment for BRAF wild-type melanoma tumors and NRAS mutant melanoma tumors that express Rb and are resistant to immune checkpoint inhibitors.

This paper presents a comprehensive comparative analysis of biomarkers for head and neck cancer (HNC), a prevalent but molecularly diverse malignancy. We detail the roles of key proteins and genes in tumourigenesis and progression, emphasizing their diagnostic, prognostic, and therapeutic relevance. Our bioinformatic validation reveals crucial genes such as AURKA, HMGA2, MMP1, PLAU, and SERPINE1, along with microRNAs (miRNA), linked to HNC progression. OncomiRs, including hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-196a-5p, and hsa-miR-200c-3p, drive tumourigenesis, while tumour-suppressive miRNAs like hsa-miR-375 and hsa-miR-145-5p inhibit it. Notably, hsa-miR-155-3p correlates with survival outcomes in addition to the genes RAI14, S1PR5, OSBPL10, and METTL6, highlighting its prognostic potential. Future directions should focus on leveraging precision medicine, novel therapeutics, and AI integration to advance personalized treatment strategies to optimize patient outcomes in HNC care.

Protein arginine N-methyltransferases (PRMT) are a family of S-adenosyl-l-methionine (SAM)-dependent enzymes that transfer methyl-groups to the ω-N of arginyl residues in proteins. PRMTs are involved in regulating gene expression, RNA splicing, and other activities. PRMT1 is responsible for most cellular arginine methylation, and its dysregulation is involved in many cancers. Accordingly, many groups have targeted PRMT1 using small molecules and peptide inhibitors. In this Perspective, we discuss the structure and function of selected peptide and small molecule inhibitors of PRMT1. We examine inhibitors that target the substrate arginyl peptide, SAM, or both binding sites, and the type of inhibition that results. Small molecules, and peptides that are bisubstrate, and/or PRMT transition state mimic inhibitors as well as inhibitors that alkylate PRMTs will be discussed. We define a structure-activity relationship for the aromatic/heteroaromatic N-methylethylenediamine inhibitors of PRMT1 and review current progress of PRMT1 inhibitors in clinical trials.