Log-rank Test Research Articles

Recruitment and polarization typing of tumor-associated macrophages is associated with tumor progression and poor prognosis in Wilms tumor patients.

Tumor-associated macrophages (TAMs) play a crucial role in shaping various tumor microenvironments. However, their recruitment in Wilms tumor (WT), the predominant malignant renal tumor in children, has been inadequately explored. This retrospective cohort study involved the analysis of 148 WT samples to investigate the recruitment and polarization typing of TAMs in WT tissues. WT tissues underwent Western blotting (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence (IF) to measure the expression of TAM markers CD68, CD86, and CD163. Statistically analyze the relationship between TAM recruitment levels and patient clinical characteristics, and use Kaplan-Meier curves and the log-rank test to evaluate the association between TAM levels and survival outcomes. The findings indicated a positive correlation between the recruitment levels of total macrophages (Mtotal) and M2 tumor-associated macrophages (M2 TAM) in both chemotherapy and non-chemotherapy groups with the clinical stage. Elevated recruitment of Mtotal and M2 TAM in tumor tissues was linked to a poorer prognosis. Notably, patients with persistently higher recruitment of M2 TAM following preoperative chemotherapy exhibited the worst prognosis. The recruitment and polarization typing of TAM exhibit significant differences in WT patients with various stages and prognosis outcomes, suggesting a potential avenue for future diagnosis and treatment of WT.

Real-world outcomes of everolimus-based treatment in a Taiwanese cohort with metastatic HR+/HER2- breast cancer.

Everolimus was the first orally targeted therapy for certain cancers. It was introduced before CDK4/6 inhibitors and is widely used to treat advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. This study presents comprehensive findings including updated data and long-term survival analyses focusing on patients with HR+/HER2- metastatic breast cancer who received everolimus-based treatment. The objectives were to assess the impact of everolimus on overall survival (OS) and progression-free survival (PFS) by treatment line, and to evaluate its role in therapeutic strategies in a real-world setting. We included 299 women aged over 20 years with histologically confirmed HR+/HER2- breast cancer who received everolimus-based treatment from multiple medical centers in Taiwan. Survival curves were generated using the Kaplan-Meier method, with the log-rank test for comparisons. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events version 5.0. The median PFS was 5.6 months, and the median OS was 60.1 months. Patients receiving everolimus treatment in three or more lines and those who underwent chemotherapy prior to everolimus-based treatment had a significantly shorter PFS but longer OS. Patients with liver and central nervous system metastases had significantly shorter PFS and OS. The disease control rate was 51.5%, and the overall response rate was 8.0%. These findings support current guidelines and advocate for the inclusion of everolimus in treatment plans for patients with metastatic HR+/HER2- breast cancer, particularly in late-line treatment, with careful consideration of the benefit-risk profile for each patient.

The Prognostic Role of Pre-Treatment Neutrophil-to-Lymphocyte Ratio in an Asian Cohort of Patients with Oropharyngeal Squamous Cell Carcinoma

Purpose: The neutrophil-to-lymphocyte ratio is a simple biomarker that reflects the balance between the systemic inflammatory and immunity status. Here we investigate the prognostic role of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in an Asian cohort of oropharyngeal squamous cell carcinoma (OPSCC) patients. Methods: A retrospective review of OPSCC patients from a tertiary institution was conducted. The NLR was calculated from the haematological specimen taken within a month before treatment. Survival rates were estimated via the Kaplan–Meier method, and Cox proportional hazards regression was performed for univariable and multivariable analyses. The NLR cutpoint was determined using maximally selected log-rank statistics. Results: In a cohort of 148 OPSCC patients, 43% were p16-positive and 44% were p16-negative, with a median follow-up of 24 months. The p16-positive patients were younger (median age 62 vs. 67 years) and exhibited a lower prevalence of heavy smoking (47% vs. 69%). The p16-negative cases frequently presented at an advanced disease stage (74% vs. 41%), with a history of previous radiotherapy (26% vs. 3%). The p16-negative patients displayed a higher median NLR (2.91 vs. 2.49). The 3-year disease-specific survival (DSS) in p16-positive was higher compared to p16-negative patients (89.9% vs. 41.6%). The optimal NLR cutpoint was determined as 3.56 and predicted for decreased DSS (hazard ratio [HR] 2.59, p = 0.004). Multivariable analysis revealed smoking, high NLR ≥ 3.56, and p16-negativity as independent variables associated with poorer DSS and overall survival (OS) across the cohort. Conclusion: A high NLR is independently prognostic of poorer DSS in OPSCC, independent of p16 and smoking status. A NLR of more than 3.56 was highly prognostic for poorer survival and warrants further validation in larger cohorts of OPSCC.

Survival After Shunt Therapy in Normal-Pressure Hydrocephalus: A Meta-Analysis of 1614 Patients

Background: Ventriculoperitoneal (VP) shunt therapy is a crucial intervention for normal-pressure hydrocephalus (NPH). This meta-analysis delves into survival time and the impact of baseline symptom burden on survival after VP shunt therapy for NPH, employing reconstructed pooled survival curves and a one-stage meta-analysis. Methods: IPD regarding overall survival (OS) were acquired from published Kaplan–Meier charts, utilizing the R package IPDfromKM in R (Version 4.3.1, the R Foundation for Statistical Computing). Reconstructed Kaplan–Meier charts were then generated from the pooled IPD data. Both one-stage and two-stage meta-analyses were executed, with hazard ratios (HRs) employed as metrics to evaluate effectiveness. Results: From the initial screening of 216 records, five articles encompassing 1614 patients met the eligibility criteria for inclusion. In two of the five included studies, overall survival was stratified by gait score (1–4 vs. ≥4) in 1043 patients, continence score (1–3 vs. ≥4) in 1022 patients, and mRS (0–2 vs. ≥3) in 956 patients. Patients with good gait demonstrated a mean survival of 8.24 years, while those with poor gait had a mean survival of 6.19 years (log-rank test: p < 0.001). The HR for gait was 2.25 (95% CI: 1.81–2.81, p < 0.001). Continence score stratification revealed a significant difference in survival time (log-rank test: p < 0.001), with an HR of 1.66 (95% CI: 1.33–2.06, p < 0.001). Similarly, mRS stratification demonstrated a significant survival difference (log-rank test: p < 0.001), with an HR of 2.21 (95% CI: 1. 74–2.80, p < 0.001). The reconstructed survival curves for all NPH patients treated with VP shunt therapy, pooling data from five studies, revealed a median survival time of 8.82 years (95% CI: 8.23–9.40). Survival rates at 1, 3, 5, 7, 9, 11, and 13 years were 95.7%, 83.8%, 70.5%, 59.5%, 48.7%, 35.8%, and 25.4%, respectively. Comparison with a general control population showed an HR of 1.79 (95% CI: 1.62–1.98, p < 0.001). Conclusions: This comprehensive meta-analysis underscores the influence of baseline symptom burden on survival after VP shunt therapy in NPH. Therapy in the early stages for those without significant comorbidities may enhance survival.

BIOM-30. NOVEL HISTOLOGIC AND MOLECULAR BIOMARKERS FOR OLIGODENDROGLIOMA

Abstract Oligodendrogliomas are progressive, infiltrative gliomas. While new molecular criteria were introduced in 2016 for diagnosing oligodendroglioma, the grading criteria remains largely unchanged. We evaluated histologic and molecular features for new biomarkers of aggressive behavior, using a cohort of 184 specimens diagnosed as low grade oligodendroglioma within the Duke Brain Tumor Center Biorepository. To identify tumors meeting current molecular criteria for oligodendroglioma, IDH1/2 status was confirmed by whole exome sequencing and 1p/19q codeletion confirmed using inferred copy number variation. First, we assessed for a histologic feature called hypercellular nodules (HCN), which are foci of increased cellularity in regions of otherwise lower cellularity tumor. In patients with newly diagnosed grade 2 oligodendroglioma, 16% (15/92) had HCN. While the median overall survival (OS) was 24.1 years without HCN, the median OS with HCN was only 13.6 years (p<0.02, Mantel-Cox test). We then assessed for homozygous deletion of CDKN2A. Cases with potential CDKN2A homozygous deletion by inferred copy number variation were validated by fluorescence in situ hybridization. In patients with newly diagnosed grade 2 oligodendroglioma, 2% had homozygous CDKN2A deletion (2/107). While the median OS with intact or hemizygous CDKN2A loss was 21 years, it decreased to 3.8 years with homozygous CDKN2A deletion (p<0.0001, Mantel-Cox test), although interpretation is limited given the rarity of homozygous CDKN2A loss at initial diagnosis. For recurrent grade 2 oligodendroglioma, 6% had homozygous deletion (5/77). While the median OS with intact or hemizygous CDKN2A loss in recurrent oligodendroglioma was 25.4 years, it decreased to 6.7 years with homozygous CDKN2A deletion (p< 0.04, Mantel-Cox test). These studies provide support for using HCN and CDKN2A homozygous deletion as grading criteria for oligodendroglioma. Further studies are ongoing, including covariate analysis, expanded cohorts, and ongoing analysis of whole exome sequencing data to identify additional genetic alterations correlated with overall survival.

PATH-27. MOLECULAR, IMAGING, AND SURVIVAL MANIFESTATIONS IN MOLECULAR GLIOBLASTOMAS: INSIGHTS FROM A MULTI-NATIONAL STUDY

Abstract Apart from the traditional definition of IDH-wildtype GBM based on histological characteristics, IDH-wildtype diffuse gliomas previously assigned to histological grade 2 or 3 are now defined as IDH-wildtype GBM in the presence of qualifying molecular markers (TERTp mutation, EGFR amplification, or chromosome +7/-10) (“molecular GBM”) in the 2021 WHO classification. However, the clinical significance of molecular GBM is unrevealed. This collaboration aims to comprehensively evaluate the clinical, molecular, imaging characteristics, and prognosis of molecular GBMs in a multi-national dataset and stratify survival. Retrospective chart and imaging review was performed in 258 molecular GBM patients from eight centers across three continents. Clinical, molecular, imaging, and survival characteristics were analyzed. The median age of molecular GBM patients was 58 years (range: 23-83) with 139 males, with TERTp mutation (83 of 214 [38.8%]), EGFR amplification (160 of 204 [78.4%]), and chromosome +7/-10 (82 of 143 patients [57.3%]). The majority of tumors were located at the frontal and temporal lobes (48.4%) and exhibited non-contrast-enhancing (CE) tumors (73.7%). Gliomatosis cerebri pattern was shown with 27 patients (12.4%). The median OS was 28.1 months (95% confidence interval 22.1-34.1). There was significantly shorter survival in patients with high Ki-67 index (> 20) compared to those with low Ki-67 index (median OS 19.3 vs. 31.5 months, log-rank test P = 0.002), while no survival differences were found according to histological grade or molecular diagnostics. Survival was significantly shorter in patients with infiltrative imaging appearance compared to those without (median OS 24.7 vs 41.0 months, log-rank test P = 0.014). In conclusion, survival within molecular GBM patients may be heterogeneous and associated with Ki-67 index and infiltrative imaging appearance.

RBIO-07. IMMUNOMODULATORY PATHWAYS MEDIATE RADIOTHERAPY RESPONSE IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Abstract PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in neurofibromatosis type 1 (NF-1) and are resistant to radiation therapy (RT), yet the mechanisms underlying RT response are poorly understood. Here, we elucidate mechanisms of RT response in NF-1 associated peripheral nerve sheath tumors through genome-wide CRISPRi screens, genomic analysis of mouse models, and molecular analysis of patient-derived tumor specimens. METHODS Patient derived NF1 mutant plexiform neurofibroma (pNF) cells (NF9511b, NF95.6), and MPNST cells (ST88-14; JH2-002) were used to measure RT responses by cell counts and flow cytometry. Genome-wide CRISPRi screens were used to identify functional modifiers of RT response in ST88-14 and JH2-002 MPNST cells. Nf1-/-; Tp53-/- mouse MPNSTs were subcutaneously implanted in immunocompetent C57/B6 mice, irradiated (2Gyx5), and dissociated for single-cell RNA sequencing (scRNA-seq) using 10x Genomics. Human MPNST tumor specimens (n=45) were analyzed with targeted DNA mutation sequencing and methylation arrays for cell type deconvolution. RESULTS Radiation single-dose response curves revealed MPNST cells (IC50 6.85Gy) were radioresistant compared to pNF cells (IC50 3.13Gy). Genome wide CRISPRi screens in ST88-14 and JH2-002 MPNST cells converged on cell cycle, DNA repair, and immunomodulatory gene sets mediating RT sensitivity. Irradiation of subcutaneous mouse Nf1-/-; Tp53-/- MPNSTs significantly decreased tumor growth (p=0.01, t-test). scRNA-seq of 32,763 cells from 4 irradiated and 3 unirradiated mouse Nf1-/-; Tp53-/- MPNSTs identified 8 tumor clusters and 7 non-tumor clusters. Irradiation demonstrated a pro-inflammatory effect with increased T-cell presence (5.8% versus 3.3%, p=0.04, t-test) and greater activation of immunostimulatory genes (Cxcl10, Stat1, Irf7) in T cells. In human MPNSTs, CDKN2A/B deletion (p=0.04, log-rank test) and decreased immune cell composition (p=0.03, log-rank test) were associated with significantly worse overall survival in response to RT. CONCLUSION MPNST RT responses may depend on immunomodulatory mechanisms that could be leveraged to improve clinical RT response.

NCOG-21. ADJUVANT RADIATION THERAPY IN ATYPICAL MENINGIOMA TREATMENT DOES NOT IMPROVE PROGRESSION FREE SURVIVAL OR OVERALL SURVIVAL: A RETROSPECTIVE COHORT STUDY

Abstract Treatment of atypical meningiomas (AMs) presents a challenge due to their aggressive nature and tendency to recur. While there is clear evidence for the role of surgical resection of AMs, the use of adjuvant radiation therapy (ART) is a topic of ongoing debate. The aim of this study is to explore the impact of ART following surgical resection of AMs. The primary outcomes of interest are progression free survival (PFS) and overall survival (OS). Records were reviewed for all patients treated for Ams at our institution between January 1, 2014 and January 1, 2024. Patients were grouped into two cohorts, those who were initially treated with surgical resection only and those who also received adjuvant RT. PFS and OS were compared between the two groups using Kaplan Meier curves and Log Rank test. Additionally, multivariable cox proportional hazard models were used to adjust for age, MIB, and resection Simpson grading. There were 76 patients who were initially treated with surgery only and 23 patients who had surgery and ART. No significant difference in PFS or OS was observed between the groups (p=0.3522 and p=0.3636, respectively); including after adjusting for age, MIB, and Simpson grading (HR= 1.55 [0.64-3.76], p= 0.330; and HR = 0.95 [0.31-2.93] p= 0.934, respectively). On multivariate analysis, MIB >10 was associated with a significant difference in PFS (HR=2.76 [1.15-6.59], p=0.023). With ART, PFS was 91% at 12 and 60% at 36 months (versus 89% and 57%, respectively, with surgery only). OS was 95% at 12 and 88% at 36 months (versus 91% and 85%, respectively, with surgery only). In this series, ART was not observed to significantly improve PFS or OS compared to surgery alone. Larger series are needed to determine if there is a subset of patients who benefit from ART.

EXTH-12. POTENTIATING THE EFFICACY OF IMMUNE CHECK-POINT INHIBITORS IN GLIOBLASTOMA BY INHIBITION OF CXCL12

Abstract BACKGROUND The tumor immune microenvironment (TIME) in glioblastoma (GBM) is rich in CXCL12, a chemokine known for stimulating angiogenesis. CXCL12 also controls immune cell trafficking and promotes polarization to an immunosuppressive phenotype. We postulated that inhibiting CXCL12 will modulate the immunosuppressive TIME in GBM, thereby augmenting the efficacy of immunotherapy agents like immune checkpoint inhibitors (ICIs). We examined the immunomodulatory and therapeutic efficacy of CXCL12 inhibition, using a small molecule NOX-A12, with and without ICIs in pre-clinical murine GBM models. METHODS B6 immunocompetent mice bearing intracranial (i.c.) or subcutaneous (s.c.) SB28 tumors received either vehicle, NOX-A12, anti-PD1 and anti-CTLA4 (dual ICI) or NOX-A12 + dual ICI (combination). Tumor growth was measured by IVIS imaging and immune cells in brain were analyzed using high dimensional flow cytometry. Survival was analyzed using Kaplan-Meier curves and log rank test. RESULTS Combination treatment resulted in tumor regression and long-term survival in 40% of s.c. tumor bearing mice compared to 10% treated with dual ICI only. Three of 4 mice rechallenged with contralateral s.c. tumor remained tumor free while all naive mice reached endpoint. TIME from treated s.c. tumors revealed increase in CD4 and effector memory CD8 T cells by combination treatment compared to dual ICI. In i.c. GBM tumors, while no survival benefit or growth inhibition was seen, combination treatment induced an early increase in effector memory CD8 T cells and PD-L1+ B cells, and a later increase in MHC-II+ microglia compared to dual ICI. CONCLUSION Inhibition of CXCL12 enabled the increase of effector cytotoxic T cells by ICI, improving survival in the s.c. GBM model, but not in i.c. GBM model. This might be due to differences in CXCL12 effect between extra and intra-CNS tumor or due to robust immune response causing excessive brain edema and death. These will be further explored in ongoing and future studies.

Comparison of efficacy and safety of regorafenib and anti-EGFR targeted therapy in metastatic colorectal cancer: A retrospective study

Aim. To compare the efficacy of regorafenib and the combination of chemotherapy (CT) with anti-EGFR (cetuximab/panitumumab) in the third-line treatment of metastatic colorectal cancer (mCRC). Materials and methods. A retrospective analysis of a prospective database of patients with mCRC from two clinics in the Russian Federation was conducted. Overall survival was considered the primary efficacy criterion. Additional criteria were progression-free survival (PFS), objective effect (OE), and incidence of toxicity. No statistical hypothesis was assumed. Statistical analysis was performed using SPSS (IBM SPPS Statistics v. 20). Results. The database identified 51 patients with morphologically confirmed left-sided mCRC with wild-type RAS and BRAF genes who received more than two lines of antitumor drug therapy from 2010 to 2021, one of which included anti-EGFR antibodies in the third and subsequent lines of treatment. Thirty patients who received regorafenib in the third line and 21 patients who received CT in combination with anti-EGFR in the third line were selected, of which 7 patients had a history of anti-EGFR use, and 14 patients received anti-EGFR for the first time. The median overall survival from the third line initiation date in the CT group in combination with anti-EGFR was numerically higher (21 months, CI 9.0–32.9 months) than in the regorafenib group (10 months, CI 2.4–17.5 months); p=0.1 by log-rank test (Mantel–Cox test); p=0.2 by Breslow–Wilcoxon test; p=0.3 (Tarone–Ware test). PFS was also higher in the anti-EGFR CT group (6 months, CI 3.8–8.2 months) than in the regorafenib group (3 months, CI 1.2–4.7 months); p=0.05 according to Breslow–Wilcoxon test. OE of third-line therapy was reported in 57.1% (n=12) of patients in the CT with anti-EGFR group and significantly less often in the regorafenib group – 10.3% (n=3) of patients (p=0.001). The toxicity of drug therapy of all grades in the regorafenib group was reported in 86.2% (n=25) of patients, while in the CT anti-EGFR group, it was significantly less common – in 52.4% (n=11) of patients (p=0.01). Conclusion. Compared with regorafenib, combining CT with anti-EGFR agents in the third-line treatment of patients with left-sided mCRC with wild-type RAS and BRAF genes is associated with better PFS and the frequency of OE with significantly less toxicity.

NIMG-58. MACHINE LEARNING-GENERATED WHOLE-BRAIN RADIO-PATHOMIC TUMOR PROBABILITY MAPS WITHIN CONTRAST-ENHANCEMENT STRATIFY SURVIVAL IN GLIOBLASTOMA PATIENTS UNDERGOING GROSS-TOTAL RESECTION

Abstract BACKGROUND Even for those undergoing gross total resection (GTR), patients with WHO grade 4 glioblastoma (GBM) have poor overall survival (OS). Stratifying those who will have better OS vs. those that will not remains challenging, with conventional imaging and radiomic models falling short. This study utilizes machine learning (ML)-generated radio-pathomic models based on autopsy tissue as ground-truth to enhance prognostication through tumor probability maps (TPM) within preoperative contrast-enhancing (CE) regions of GBM. METHODS Data from the UCSF-PDGM-v2 and UPenn-GBM databases were analyzed, focusing on patients who underwent GTR with WHO 4 IDH-wildtype glioblastoma (n = 528). Preoperative tumor cellularity within CE was quantified using ML-generated TPMs, with a median threshold of 0.7242. Kaplan-Meier survival curves were employed to compare OS between patients with low (≤ 0.7242) and high (> 0.7242) TPM values in CE regions. Statistical significance was evaluated using log-rank tests. RESULTS Kaplan-Meier curves demonstrated significant stratification in survival outcomes based on TPM values. Patients with lower TPM values in CE regions had a median OS of 567 days, compared to 457 days for those with higher TPM values (log-rank p-value: < 0.001). These findings suggest that lower tumor cellularity in CE regions as assessed by TPMs correlates with improved survival, offering a more nuanced stratification than current MRI-based methods. CONCLUSION This study underscores the potential of TPM metrics as a powerful prognostic tool in GBM. The significant correlation between lower TPM values in CE regions and better median OS indicates that TPM can effectively stratify patients, aiding in clinical decision-making and personalized treatment planning. Future research is necessary to validate these findings in larger, diverse patient populations and to explore the biological mechanisms underlying these survival differences.

Predicting first-line VEGFR-TKI resistance and survival in metastatic clear cell renal cell carcinoma using a clinical-radiomic nomogram.

This study aims to construct predicting models using radiomic and clinical features in predicting first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) early resistance in metastatic clear cell renal cell carcinoma (mccRCC) patients. We also aim to explore the correlation of predicting models with short and long-term survival of mccRCC patients. In this retrospective study, 110 mccRCC patients from 2009 to 2019 were included and assigned into training and test sets. Radiomic features were extracted from tumor 3D-ROI of baseline enhanced CT images. Radiomic features were selected by Lasso method to construct a radiomic score. A combined nomogram was established using the combination of radiomic score and clinical factors. The discriminative abilities of the radiomic, clinical and combined nomogram were quantified using ROC curve. Cox regression analysis was used to test the correlation of nomogram score with progression-free survival (PFS) and overall survival (OS). PFS and OS were compared between different risk groups by log-rank test. The radiomic, clinical and combined nomogram demonstrated AUCs of 0.81, 0.75, and 0.83 in training set; 0.79, 0.77, and 0.88 in test set. Nomogram score ≥ 1.18 was an independent prognostic factor of PFS (HR 0.22 (0.10, 0.47), p < 0.001) and OS (HR 0.38 (0.20, 0.71), p = 0.002), in training set. PFS in low-risk group were significantly longer than high-risk group in training (p < 0.001) and test (p < 0.001) set, respectively. OS in low-risk group were significantly longer than high-risk group in training (p = 0.003) and test (p = 0.009) set, respectively. A nomogram combining baseline radiomic signature and clinical factors helped detecting first-line VEGFR-TKI early resistance and predicting short and long-term prognosis in mccRCC patients.

DDDR-14. IMPROVED ANTI-GLIOBLASTOMA EFFICACY BY BRG399, A NOVEL ORAL MICROTUBULE BINDING AGENT

Abstract Glioblastoma (GBM) is a highly malignant form of brain tumor with a poor prognosis despite advances in treatments. Therapeutic resistance/relapse remains a significant challenge necessitating the development of novel approaches. BRG399 is a brain permeant, non P-gp substrate, microtubule-targeting agent that displays anti-cancer activity in vitro and in vivo. BRG399 was well tolerated in rat and dog toxicology studies. Anti-cancer activity (IC50) of BRG399 in in vitro models of GBM was assessed to have potency ranging from 42nm to 89nM in the 3 cell lines tested. Here, in vivo tumor activity of BRG399 was assessed in Sprague Dawley rats implanted with 3x105 C6 rat glioma cells into the right entorhinal cortex/subiculum region. 14 days post successful implantation tumors were assessed by MRI, rats were randomized to receive vehicle (2% Labrasol) or BRG399 (5, 10, 20 mg/kg groups) twice daily by oral gavage for 16 days, and MRIs were performed on survivors on days 31 and 45 post implantation. BRG399 administration resulted in a marked improvement in survival (from 7.7 ± 2.6 days to 25.5 ± 15.6 days, log-rank test, p:0.007) compared to controls. Six animals receiving BRG399 remained alive beyond day 60 of post-treatment initiation. To assess biodistribution of BRG399 in the brain, rats were implanted with C6 cells and tumor establishment assessed 12 days later by MRI. Animals were treated with vehicle or BRG399 (10, 20, 25 mg/kg) and plasma and brains were collected for bioanalytical assessment. Tissue single cell biodistribution was performed using TIMSTOF FLEX spatial OMICS. These results demonstrate a therapeutic effect of BRG399 on intracranial glioma-bearing rats with survival of the BRG399 treatment groups of strong statistical significance over the control group. Analysis of drug levels in plasma and brain will serve as guidance for dose and scheduling decisions for further therapeutic development.

Clonorchis sinensis infection contributes to hepatocellular carcinoma progression via enhancing angiogenesis.

Clonorchis sinensis (C. sinensis) infection plays an important role in the progression of hepatocarcinogenesis. However, its specific role in HCC progression remains unclear. This study aimed to investigate whether C. sinensis contributes to angiogenesis in HCC. A comprehensive clinical analysis was conducted on 947 HCC patients, divided into two groups: C. sinensis (-) HCC and C. sinensis (+) HCC. Kaplan-Meier survival curves and log-rank tests were utilized to assess survival outcomes. Microvessel density (MVD) was evaluated through CD34 immunohistochemistry on hepatectomy specimens. A chemistry analyzer and blood analyzer were employed to measure the concentration of circulating angiogenesis-related biomarkers. Quantitative reverse transcription-PCR (qRT-PCR) was used to analyze the expression of angiogenesis-related genes (CD34, Ang1, Ang2, VEGF, PDGF) in HCC tissues. C. sinensis infection was associated with poorer outcomes in HCC patients, with significantly shorter overall survival (OS) (p = 0.014) and recurrence-free survival (RFS) (p<0.001). Notably, C. sinensis infection led to an upregulation of MVD in HCC tissues (p = 0.041). C. sinensis (+) HCC patients exhibited significantly higher levels of circulating angiogenesis-related biomarkers, including MONO (p = 0.004), EOSO (p < 0.001), C3 (p = 0.001), FIB (p = 0.010), PLT (p = 0.003), LDH (p = 0.004), GLDH (p = 0.003), compared to C. sinensis (-) HCC patients. Moreover, qRT-PCR analysis revealed that most angiogenesis-related genes were overexpressed in patients with C. sinensis infection. C. sinensis infection is closely associated with inflammatory responses and may promote metabolic reprogramming in HCC, thereby enhancing its malignant characteristics.

Effect of dyslipidemia on HBsAg clearance in nucleos(t)ide analogues-experienced chronic hepatitis B patients treated with peginterferon alfa.

While previous reports have shown that hepatitis B virus (HBV) infection affects lipid metabolism and vice versa, the impact of dyslipidemia on the functional cure of HBV infection following peginterferon alfa (PegIFNα) therapy remains unknown. Hence, this study aimed to investigate the effect of dyslipidemia on hepatitis B surface antigen (HBsAg) clearance and develop a nomogram model for predicting patients for whom PegIFNα therapy is indicated. A total of 160 nucleos(t)ide analogues (NAs)- experienced chronic hepatitis B (CHB) patients treated with PegIFNα (180µg/week) were enrolled in this study. The relationship between serum lipid and HBsAg clearance was analysed. Univariate and multivariate COX analyses were used to construct and plot the nomogram model. The area under the receiver operating characteristic curve (AUC) and calibration curve were used to evaluate the discrimination and calibration of the model, respectively. After 48 weeks of PegIFNα therapy, a total of 33 patients in the cohort achieved HBsAg clearance. Univariate and multivariate COX analyses indicated that dyslipidemia was significantly associated with HBsAg clearance and was an independent predictor of HBsAg clearance (HR = 0.243, P = 0.001). Kaplan-Meier survival analyses show that cumulative HBsAg clearance was significantly higher in the normolipidemic group than in the dyslipidemia group (log-rank test, P = 0.007). During the treatment, triglyceride showed an increasing trend, while the levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, apolipoprotein A1 and apolipoprotein B decreased. Dyslipidemia and other indicators independently associated with HBsAg clearance were used to construct the nomogram model. The AUC of the model at 36-week and 48-week were 0.879 and 0.856, and the model demonstrated good discrimination and calibration. Dyslipidemia can affect the antiviral efficacy of PegIFNα in NAs-experienced CHB patients. Our findings suggest that the nomogram model constructed using serum lipid has good predictive power and may help physicians to identify the superior patients for PegIFNα therapy.

RADT-09. CHEMORADIOTHERAPY WITH TEMOZOLOMIDE VS. RADIOTHERAPY ALONE IN PATIENTS WITH IDH WILD-TYPE AND TERT PROMOTER MUTATION HISTOLOGICAL GRADE 2/3 GLIOMAS: A POSTHOC ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL

Abstract PURPOSE In 2016, we initiated a signal center prospective randomized trial to compare chemoradiotherapy (CRT) with temozolomide (TMZ) to radiotherapy (RT) alone in patients with IDH wild-type and TERT promoter mutation histological grade 2/3 gliomas. This study demonstrated patients who received CRT had a longer median OS than those who received RT alone and found no statistical difference in PFS between the two groups. Now, we recruited more patients in the CRT group to further explore whether there were differences in PFS between patients treated with CRT and RT. Besides, we explored the effect of MGMT promoter (MGMTp) methylation status on OS and PFS in patients receiving CRT therapy in the STUPP schedule. METHODS We expanded the scope by enrolling 21 participants in the CRT group and extending the follow-up period. OS and PFS were analyzed using the log-rank test, and high-risk factors were explored through Cox regression analysis. RESULTS Patients’ median follow-up is 21.9 months. CRT group has a longer median OS (25.3 vs 17.2 months; P = 0.029, HR = 0.443) and PFS (14.6 vs 8.3 months; P = 0.0008, HR = 0.387) than the RT group. Multivariate analysis identified CRT as a favorable prognostic variable for both OS (P = 0.003) and PFS (P = 0.002). The status of MGMTp methylation did not affect OS (P = 0.560, HR = 1.30) and PFS (P = 0.75, HR = 0.88) in patients with IDH-wt/TERTp-mut receiving TMZ chemotherapy. CRT with TMZ did not significantly increase grade 3 or higher toxicities. CONCLUSIONS The long-term results confirmed that the OS and PFS benefits of the RT plus TMZ regimen exceeded those of the RT alone group in patients with IDH-wt/TERTp-mut gliomas.

CNSC-35. TEMOZOLOMIDE POTENTIALLY POSTPONES THE DEVELOPMENT OF SUBSEQUENT METASTASES IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PATIENTS

Abstract OBJECTIVE Surgical intervention is thought to increase the likelihood of subsequent dissemination in diffuse intrinsic pontine glioma (DIPG) patients. However, there is no study evaluating the factors influencing the timing of metastasis development. Hence, the present analysis was conducted to shed light on factors associated with subsequent dissemination timing. METHODS This analysis included 28 pediatric (age≤12) DIPG cases with metastasis treated at Sanjiu Brain Hospital between June 1, 2017 and June 30, 2023. The clinical data were retrospectively collected following the initial diagnosis. The diagnosis was established by typical imaging features of DIPG. The same three radiologists analyzed the imaging data independently. Time to subsequent metastasis was estimated using Kaplan–Meier analysis, and a log-rank test evaluated the differences between groups. RESULTS Of 28 patients, 13 (46.4%) were males and 15 were females. 23 (82.1%) underwent surgical intervention, while 5 (17.9%) did not receive surgery. The patients’ median age was 7 years (2-12 yrs.). The Kaplan-Meier method showed that the median time to metastasis was 5.8 months (95%CI 4.2-9.1). The log-rank test demonstrated that adjuvant temozolomide was the only variable that could significantly delay metastasis in the pediatric DIPG population (P=0.03). The median time to metastasis from the day of initial diagnosis for those who received adjuvant temozolomide was 6.8 months (95%CI 5-10.7) vs. 3 months for those who did not receive adjuvant temozolomide (95%CI 2.3-NA). Sex, age, surgical intervention, and concurrent irradiation and temozolomide were not associated with metastasis timing. CONCLUSION Adjuvant temozolomide administration might benefit DIPG patients by delaying metastasis, especially in those who are at higher risk for subsequent metastasis, such as those who underwent surgical intervention. However, prospective studies are warranted to confirm these results.

RADT-47. CLINICAL OUTCOMES AFTER SURGICAL RESECTION OF BRAIN METASTASES IN SMALL CELL LUNG CANCER PATIENTS

Abstract Small cell lung cancer (SCLC) has a high propensity to metastasize to the brain. Radiotherapy is the primary treatment for SCLC brain metastases. Whole brain radiotherapy (WBRT) has been the standard of care, but recent studies show similar overall survival (OS) in patients treated with upfront stereotactic radiosurgery (SRS). Surgery does not typically have a role in SCLC although it can provide relief of neurologic symptoms and pathologic diagnosis. We sought to determine the clinical outcomes of patients who underwent surgical resection of SCLC brain metastases. A retrospective chart review of SCLC patients treated at UPMC from 2010 – 2022 was performed. OS after resection was estimated using the Kaplan-Meier method with log-rank test. 4,213 patients were diagnosed with SCLC, of which 715 patients (17%) had synchronous brain metastases at initial diagnosis. Forty patients underwent resection of SCLC brain metastases, all of whom were symptomatic. The median diameter of the resected brain metastases was 3.8 cm (range 1.7 – 8 cm). Seventy-five percent (n=30) had resection of synchronous brain metastases and 25% (n=10) had resection of metachronous brain metastases. Median OS for the surgical cohort was 13.6 months (interquartile range (IQR), 3.4 – 21.9 months). Patients with metachronous and synchronous brain metastases had median OS of 6.8 months (IQR, 2.8 – 24.6 months) and 14.3 months (IQR, 3.6 – 20.4), respectively. Of patients with synchronous brain metastases (n=30), 53% (n=16) received post-operative WBRT, 40% (n=11) received post-operative SRS and 10% (n=3) died within 7 weeks of surgery. Median OS of patients with synchronous brain metastases treated with WBRT and SRS were 11.9 months (IQR, 3.8 – 21.7) and 19.0 months (IQR, 14.6 – 30.3), respectively, and the difference was not statistically significant (p=0.53). Surgery for SCLC brain metastases is uncommon. Patients who received SRS versus WBRT post-operatively for synchronous brain metastases had no difference in OS.

PATH-36. DO GENE EXPRESSION PROFILES BETTER PREDICT OLIGODENDROGLIOMA SURVIVAL?

Abstract The WHO 2021 classification of oligodendroglioma grade 2 (G2) and grade 3 (G3), is separated by histopathology alone and does not universally reflect survival outcome. DNA methylation-based profiling also fails to separate oligodendroglioma grades. Our aim was to define transcriptome-based molecular subgroups that predict survival of oligodendroglioma (IDH-mutant and 1p/19q-codeleted) patients. Clinical and whole-transcriptome data for oligodendroglioma were obtained from TCGA (n=132), CGGA (n=53), and the Exsegen Genomics Research Biobank (n=16) (CTRI/2021/09/036861); while that of control brain samples (n=9) were obtained from CPTAC. Overall survival (OS) was significantly different in TCGA samples between WHO CNS G2 and G3 oligodendrogliomas (log-rank test, p=0.0001); but, not in CGGA (p=0.1833) or Exsegen (p&amp;gt;0.06) samples. Genes with highly variable expression (Median Absolute Deviation, i.e. MAD&amp;gt;1; 1645 genes) across TCGA oligodendroglioma and CPTAC control brain samples were used to exclude 9 oligodendroglioma samples with Pearson’s correlation&amp;gt;0.75 with control brain samples. Consensus clustering (K-means and spectral) of remaining 124 TCGA oligodendroglioma samples identified three significantly different (SigClust, p&amp;lt;0.05) transcriptomic classes using 1347 highly variable genes (MAD&amp;gt;1) in these samples. Principal component analysis (PCA) on expression of 1347 genes in TCGA samples revealed partial overlap of G2 and G3 tumours; but transcriptomic classes with distinct OS could be identified at both extremes of survival. Gene expression signatures for each transcriptomic class were developed using core TCGA samples from each class. For further validation, gene signatures were used to predict the transcriptomic classes of CGGA and Exsegen samples based on highest cosine similarity between sample gene expression and gene signature of each transcriptomic class. OS was significantly different between the transcriptomic classes in TCGA samples and predicted ones in CGGA samples. Transcriptome profiling separated oligodendrogliomas into distinct classes which can predict survival and potentially augment grading and refine prognostication and treatment options.

Incidence of acute kidney injury and its predictors among neonates admitted at neonatal intensive care unit of, Northwest Ethiopia comprehensive specialized hospitals, 2023.

Acute kidney injury is an acute and reversible increment in serum creatinine (SCr) levels with a reduction in urine output oliguria, or anuria. Acute kidney injury is a major cause of neonatal morbidity and mortality worldwide; it is a serious problem in low and middle-income countries, particularly in sub-Saharan Africa such as Ethiopia. Moreover, there are few studies in developing countries. This study aimed to investigate the incidence and predictors of acute kidney injury in neonates admitted to the neonatal intensive care unit of some specialized hospitals in the Amhara region of northwestern Ethiopia. A facility-based retrospective follow-up study was conducted in the Northwest Amhara Region's comprehensive specialized hospitals with 634 neonates from January 2020 to December 2022. Data were collected by reviewing patient charts using simple random sampling with a pretested checklist, entered using Epi-data 4.6, and analyzed using STATA 14. Median survival time, Kaplan-Meier survival curve, and log-rank test were calculated. Bivariable and multivariable Cox hazard models were used to determine the determinants of acute kidney injury. A hazard ratio with a 95% confidence interval was calculated. Variables with p-values less than 0.05 were considered statistically significant. The incidence of Acute Kidney Injury among Neonates admitted to Neonatal IntensiveCare Unit was 14.9 per 1000 (95% CI: 12.5-17.7) with the proportion of acute kidney injury (20.19%) (95% CI: 17.23-23.50) neonates with sepsis (AHR: 2.59; 95%CI: 1.21-5.56), neonates with perinatal asphyxia [(AHR: 2.70; 95%CI: 1.29-5.65) were taking gentamicin drugs [(AHR = 1.74; 95%CI: 1.03-2.94], neonates were preterm [(AHR; 1.77: 95%CI: 1.05 -2.98], and neonatal-hyponatremia [(AHR: 2.14; 95%CI: (1.00 -4.9)] and hyperkalemia [(AHR: 2.64; 95 CI: (1.11- 6.2)] were statistically found to be significant predictors of acute kidney injury. The incidence of acute kidney injury in neonates was high. Premature infants, neonates with sepsis, who suffered perinatal asphyxia, who received gentamicin drugs, whose sodium levels decreased and potassium levels increased were at higher risk of developing acute kidney injury. All concerned agencies should work to prevent acute kidney injury and pay special attention to multifactorial causes. Therefore, strategies need to be developed and/or strengthened to prevent the occurrence of acute kidney injury in infants with sepsis, neonates who suffered perinatal asphyxia, and preterm infants whose sodium levels decreased and potassium levels increased.