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OBJECTIVES: To evaluate the treatment outcomes in patients with advanced-stage olfactory neuroblastoma (ONB) who received induction chemotherapy (IC). MATERIALS AND METHODS: The clinical data of 38 patients with advanced-stage ONB who received initial IC were retrospectively analyzed. The response was defined using the Response Evaluation Criteria in Solid Tumors version 1.1. Patients with complete remission or partial remission were defined as responders. RESULTS: Seventeen (44.7%) patients responded to IC. The response rate was higher in patients with high Hyams grade tumor (III/IV) compared to those with low-grade tumors (I/II) (60% vs. 22.2%, p = 0.038). Overall, the 5-year cancer-specific survival (CSS) rate was 76.0%. Among nonresponders to IC, a significant difference in 5-year CSS rates was observed between surgery with adjuvant radiotherapy (RT) (100%) versus definitive RT or chemoradiotherapy (CRT) (68.6%) (log-rank p = 0.006). However, for responders, there was no significant difference in 5-year CSS rates between surgery with adjuvant therapy (75%) and definitive RT or CRT (51.1%) (log-rank p = 0.536). When only high-grade tumors were considered among responders, the 5-year CSS rate was significantly higher in patients who received RT or CRT (51.4%) compared to those who underwent surgery with adjuvant therapy (0%) (log-rank p = 0.008). CONCLUSION: In advanced-stage ONB, RT or CRT may be preferable for high-grade tumor responding to IC. Higher response rate and a potential role for induction IC in determining the optimal definitive treatment modality suggest a positive role for advanced-stage high-grade ONB.
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BACKGROUND: Treatment for large (> 10 mL) arteriovenous malformations (AVMs) remains highly challenging. This study evaluated long-term effect of time-staged gamma knife radiosurgery (GKS) for large AVMs. METHODS: For patients with large AVMs treated by time-staged GKS over 10 years, time-staged GKS was repeated every three years targeting the entire nidus if total obliteration was not achieved. Obliteration rate and post-GKS complications were assessed based on 10 mL volume interval of AVMs. Prognostic factors for these outcomes were evaluated using Cox regression analysis. RESULTS: Ninety-six patients were analyzed. For AVMs in the 10-20 mL subgroup, a dose ≥ 13.5Gy yielded higher obliteration rate in the first GKS. In the 20-30 mL subgroup, a second GKS significantly boosted obliteration. AVMs > 30 mL did not achieve any obliteration with the first GKS. Among 35 (36.4%) cases lost to follow-up, 7 (7.2%) were lost due to GKS complications. Kaplan-Meier analysis showed that each subgroup needed different time for achieving 50% favorable obliteration outcome rate: 3.5, 6.5, and 8.2 years for 10-20 mL, 20-30 mL, and > 30 mL subgroup, respectively. Total obliteration rate calculated by intention-to-treat method: 73%, 51.7%, 35.7%, respectively, 61.5% overall. Post-GKS hemorrhage and chronic encapsulated expanding hematoma (CEEH) occurred in 13.5% and 8.3% of cases, respectively. Two patients died. Dose and volume were significant prognostic factors for obliteration. Initial AVM volume was a significant prognostic factor of post-GKS hemorrhage and CEEH. CONCLUSION: Time-staged GKS for large AVMs less than 30 mL has highly favorable long-term outcome and a tolerable complication rate.
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Estimación de Kaplan-Meier , Radiocirugia , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Adolescente , Adulto Joven , Malformaciones Arteriovenosas Intracraneales/cirugía , Malformaciones Arteriovenosas Intracraneales/radioterapia , Estudios Retrospectivos , Modelos de Riesgos Proporcionales , Niño , Anciano , Malformaciones Arteriovenosas/cirugía , Estudios de SeguimientoRESUMEN
OBJECTIVES: To investigate the potential relationship between trastuzumab emtansine (T-DM1) treatment and radionecrosis induced by brain stereotactic radiosurgery (SRS) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. MATERIALS AND METHODS: Patients with HER2-positive breast cancer who were diagnosed with brain metastasis and received both SRS and HER2-targeted agents between 2012 and 2022 were retrospectively analyzed. Patients who received T-DM1 within 1 year (either before or after) of SRS were considered as 'T-DM1 exposure (+)'. T-DM1 exposure (-) group had other HER2-targeted agents or received T-DM1 more than 1 year before or after SRS. Symptomatic radionecrosis was defined as Common Terminology Criteria for Adverse Events grade 2 or greater. RESULTS: A total of 103 patients with 535 treatment sessions were included from seven tertiary medical centers in Korea and Italy. The median follow-up duration was 15.5 months (range 1.1-101.9). By per-patient analysis, T-DM1 exposure (+) group had an increased risk of overall radionecrosis after multivariate analysis (HR 2.71, p = 0.020). Additionally, T-DM1 exposure (+) group was associated with a higher risk of symptomatic radionecrosis compared to T-DM1 exposure (-) patients (HR 4.34, p = 0.030). In per-treatment analysis, T-DM1 exposure (+) was linked to higher incidences of overall (HR 3.13, p = 0.036) and symptomatic radionecrosis (HR 10.4, p = 0.013) after multivariate analysis. A higher prevalence of radionecrosis was observed with T-DM1 exposure (+) and a previous history of whole brain radiotherapy. CONCLUSION: An increased risk of radionecrosis was observed in patients receiving T-DM1 with brain SRS. Further research is needed to better understand the optimal sequence and interval for administering T-DM1 and SRS.
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OBJECTIVE: Obsessive-compulsive disorder (OCD) is a psychiatric condition that causes significant distress and social costs and often follows a chronic course with frequent relapses. Approximately 20% of patients do not respond to medication or cognitive behavioral therapy; gamma knife surgery (GKS) has been proposed as a treatment option for these patients. However, research on GKS for OCD patients is rare. METHODS: In this study, 10 patients with treatment-resistant OCD underwent GKS, and the treatment response and side effects were assessed. The improvement in patients' obsessive-compulsive symptoms was evaluated using the Yale-Brown Obsessive Compulsive Scale (YBOCS) scores following GKS. Additionally, the characteristics distinguishing the groups with favorable responses to GKS from those with less favorable responses were examined. RESULTS: GKS was well tolerated, and patients demonstrated a statistically significant reduction in YBOCS scores before and after GKS (p=0.016). Patients that responded to GKS exhibited distinct characteristics from those who did not respond. Patients who responded poorly tended to present an earlier age of onset, a longer duration of illness, more frequent hospitalizations, poorer social functioning, and a greater incidence of suicide attempts/thoughts. CONCLUSION: This study not only demonstrated that GKS is a safe and effective treatment method for intractable OCD but also revealed characteristics distinguishing patients who respond well to GKS from those who do not. These results may aid in the selection of patients for future application of GKS.
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Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.
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Inhibidores de Proteínas Quinasas , Pirazoles , Receptor trkB , Humanos , Masculino , Femenino , Niño , Preescolar , Adulto , Adolescente , Persona de Mediana Edad , Anciano , Lactante , Receptor trkB/genética , Receptor trkB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/uso terapéutico , Receptor trkA/genética , Receptor trkA/antagonistas & inhibidores , Glioma/genética , Glioma/patología , Glioma/tratamiento farmacológico , Pirimidinas/uso terapéutico , Proteínas de Fusión Oncogénica/genética , Benzamidas/uso terapéutico , Glicoproteínas de Membrana/genética , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , IndazolesRESUMEN
Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and NK cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells (MIDSCs), activation of regulatory T cells (Tregs), inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.
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Estimulación Encefálica Profunda , Servicio de Urgencia en Hospital , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Servicio de Urgencia en Hospital/estadística & datos numéricos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Visitas a la Sala de EmergenciasRESUMEN
Glioblastoma (GBM), the most lethal primary brain cancer, exhibits intratumoral heterogeneity and molecular plasticity, posing challenges for effective treatment. Despite this, the regulatory mechanisms underlying such plasticity, particularly mesenchymal (MES) transition, remain poorly understood. In this study, we elucidate the role of the RNA-binding protein ELAVL2 in regulating aggressive MES transformation in GBM. We found that ELAVL2 is most frequently deleted in GBM compared to other cancers and associated with distinct clinical and molecular features. Transcriptomic analysis revealed that ELAVL2-mediated alterations correspond to specific GBM subtype signatures. Notably, ELAVL2 expression negatively correlated with epithelial-to-mesenchymal transition (EMT)-related genes, and its loss promoted MES process and chemo-resistance in GBM cells, whereas ELAVL2 overexpression exerted the opposite effect. Further investigation via tissue microarray analysis demonstrated that high ELAVL2 protein expression confers a favorable survival outcome in GBM patients. Mechanistically, ELAVL2 was shown to directly bind to the transcripts of EMT-inhibitory molecules, SH3GL3 and DNM3, modulating their mRNA stability, potentially through an m6A-dependent mechanism. In summary, our findings identify ELAVL2 as a critical tumor suppressor and mRNA stabilizer that regulates MES transition in GBM, underscoring its role in transcriptomic plasticity and glioma progression.
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Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype. SIGNIFICANCE: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.
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Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , Humanos , Neoplasias Encefálicas/patología , Epigénesis Genética , Epigenómica , Glioma/patología , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Mutación , Recurrencia Local de Neoplasia/genética , Microambiente TumoralRESUMEN
Patient-derived xenograft (PDX) models, which can retain the characteristics of original tumors in an in vivo-mimicking environment, have been developed to identify better treatment options. However, although original tumors and xenograft tissues mostly share oncogenic mutations and global gene expression patterns, their detailed mutation profiles occasionally do not overlap, indicating that selection occurs in the xenograft environment. To understand this mutational alteration in xenografts, we established 13 PDX models derived from 11 brain tumor patients and confirmed their histopathological similarity. Surprisingly, only a limited number of somatic mutations were shared between the original tumor and xenograft tissue. By analyzing deleteriously mutated genes in tumors and xenografts, we found that previously reported brain tumor-related genes were enriched in PDX samples, demonstrating that xenografts are a valuable platform for studying brain tumors. Furthermore, mutated genes involved in cilium movement, microtubule depolymerization, and histone methylation were enriched in PDX samples compared with the original tumors. Even with the limitations of the heterogeneity of clinical lesions with a heterotropic model, our study demonstrates that PDX models can provide more information in genetic analysis using samples with high heterogeneity, such as brain tumors.
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BACKGROUND: This study aims to elucidate clinical features, therapeutic strategies, and prognosis of pineal parenchymal tumors (PPT) by analyzing a 30-year dataset of a single institution. METHODS: We reviewed data from 43 patients diagnosed with PPT at Seoul National University Hospital between 1990 and 2020. We performed survival analyses and assessed prognostic factors. RESULTS: The cohort included 10 patients with pineocytoma (PC), 13 with pineal parenchymal tumor of intermediate differentiation (PPTID), and 20 with pineoblastoma (PB). Most patients presented with hydrocephalus at diagnosis. Most patients underwent an endoscopic third ventriculostomy and biopsy, with some undergoing additional resection after diagnosis confirmation. Radiotherapy was administered with a high prevalence of gamma knife radiosurgery for PC and PPTID, and craniospinal irradiation for PB. Chemotherapy was essential in the treatment of grade 3 PPTID and PB. The 5-year progression-free survival rates for PC, grade 2 PPTID, grade 3 PPTID, and PB were 100%, 83.3%, 0%, and 40%, respectively, and the 5-year overall survival rates were 100%, 100%, 40%, and 55%, respectively. High-grade tumor histology was associated with lower survival rates. Significant prognostic factors varied among tumor types, with World Health Organization (WHO) grade and leptomeningeal seeding (LMS) for PPTID, and the extent of resection and LMS for PB. Three patients experienced malignant transformations. CONCLUSION: This study underscores the prognostic significance of WHO grades in PPT. It is necessary to provide specific treatment according to tumor grade. Grade 3 PPTID showed a poor prognosis. Potential LMS and malignant transformations necessitate aggressive multimodal treatment and close-interval screening.
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BACKGROUND: Human gliomas are aggressive brain tumors characterized by uncontrolled cell proliferation. Differential expression of Polycomb repressive complex 2 (PRC2) has been reported in various subtypes of glioma. However, the role of PRC2 in uncontrolled growth in glioma and its underlying molecular mechanisms remain to be elucidated. OBJECTIVE: We aimed to investigate the functional role of PRC2 in human glioblastoma cell growth by silencing SUZ12, the non-catalytic core component of PRC2. METHODS: Knockdown of SUZ12 was achieved by infecting T98G cells with lentivirus carrying sequences specifically targeting SUZ12 (shSUZ12). Gene expression was examined by quantitative PCR and western analysis. The impact of shSUZ12 on cell growth was assessed using a cell proliferation assay. Cell cycle distribution was analyzed by flow cytometry, and protein stability was evaluated in cycloheximide-treated cells. Subcellular localization was examined through immunofluorescence staining and biochemical cytoplasmic-nuclear fractionation. Gene expression analysis was also performed on human specimens from normal brain and glioblastoma patients. RESULTS: SUZ12 knockdown (SUZ12 KD) led to widespread decrease in the PRC2-specific histone mark, accompanied by a slowdown of cell proliferation through G1 arrest. In SUZ12 KD cells, the degradation of CDKN1B protein was reduced, resulting from alterations in the MYC-SKP2-CDKN1B axis. Furthermore, nuclear localization of CDKN1B was enhanced in SUZ12 KD cells. Analysis of human glioblastoma samples yielded increased expression of EZH2 and MYC along with reduced CDKN1B compared to normal human brain tissue. CONCLUSION: Our findings suggest a novel role for SUZ12 in cell proliferation through post-translational regulation of CDKN1B in glioblastoma.
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Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Neoplasias/genética , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Proliferación Celular , Glioma/genéticaRESUMEN
Glioblastoma is one of the most malignant primary brain cancer. Despite surgical resection with modern technology followed by chemo-radiation therapy with temozolomide, resistance to the treatment and recurrence is common due to its aggressive and infiltrating nature of the tumor with high proliferation index. The median survival time of the patients with glioblastomas is less than 15 months. Till now there has been no report of molecular target specific for glioblastomas. Early diagnosis and development of molecular target specific for glioblastomas are essential for longer survival of the patients with glioblastomas. Development of biomarkers specific for glioblastomas is most important for early diagnosis, estimation of the prognosis, and molecular target therapy of glioblastomas. To that end, in this study, we have conducted a comprehensive proteome study using primary cells and tissues from patients with glioblastoma. In the discovery stage, we have identified 7429 glioblastoma-specific proteins, where 476 proteins were quantitated using Tandem Mass Tag (TMT) method; 228 and 248 proteins showed up and down-regulated pattern, respectively. In the validation stage (20 selected target proteins), we developed quantitative targeted method (MRM: Multiple reaction monitoring) using stable isotope standards (SIS) peptide. In this study, five proteins (CCT3, PCMT1, TKT, TOMM34, UBA1) showed the significantly different protein levels (t-test: p value ≤ 0.05, AUC ≥ 0.7) between control and cancer groups and the result of multiplex assay using logistic regression showed the 5-marker panel showed better sensitivity (0.80 and 0.90), specificity (0.92 and 1.00), error rate (10 and 2%), and AUC value (0.94 and 0.98) than the best single marker (TOMM34) in primary cells and tissues, respectively. Although we acknowledge that the model requires further validation in a large sample size, the 5 protein marker panel can be used as baseline data for the discovery of novel biomarkers of the glioblastoma.
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We present the clinicopathological and molecular genetic characteristics of a neuroepithelial tumor (NET), EWSR1::PATZ1 fusion-positive with a literature review. This fusion has recently been discovered in rare central nervous system tumors and soft tissue sarcomas and was not included in the fifth edition of the WHO classifications. We identified this fusion in 2 NETs. The first case involved a 7-year-old girl and the second case occurred in a 53-year-old man; both presented with headaches and vomiting. The pediatric case initially showed an intermediate grade of the tumor, but upon recurrences, it transformed into a high-grade tumor with 2 relapses in 8.3 years. This case exhibited high mitotic activity (20/10 high-power fields), and a high Ki-67 index (21%). The TERT promoter (TERTp) mutation was present in both initial and recurrent tumors. In contrast, the adult case was a low-grade tumor with no mitotic activity or recurrence over 13.5 months after subtotal resection and gamma knife surgery. Interestingly, the pediatric case demonstrated a longer survival time compared to conventional glioblastoma. The TERTp mutation, similar to being a molecular signature in adult-type glioblastoma, could also be an indicator of high-grade behavior in PATZ1 fusion NET.
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Glioblastoma , Neoplasias Neuroepiteliales , Sarcoma , Masculino , Adulto , Femenino , Humanos , Niño , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Factores de Transcripción , Neoplasias Neuroepiteliales/genética , Sarcoma/genética , Biomarcadores de Tumor/genética , Proteínas Represoras/genética , Factores de Transcripción de Tipo Kruppel/genética , Proteína EWS de Unión a ARN/genéticaRESUMEN
BACKGROUND: Since the long-term outcomes of 162 patients who underwent gamma knife radiosurgery (GKS) as an initial or adjuvant treatment for acoustic neuromas (ANs) with unilateral hearing loss were first reported in 1998, there has been no report of a comprehensive analysis of what has changed in GKS practice. METHODS: We performed a retrospective study of the long-term outcomes of 106 patients with unilateral sporadic ANs who underwent GKS as an initial treatment. The mean patient age was 50 years, and the mean initial tumor volume was 3.68 cm3 (range, 0.10-23.30 cm3). The median marginal tumor dose was 12.5 Gy (range, 8.0-15.0 Gy) and the median follow-up duration was 153 months (range, 120-216 months). RESULTS: The tumor volume increased in 11 patients (10.4%), remained stationary in 27 (25.5%), and decreased in 68 patients (64.2%). The actuarial 3, 5, 10, and 15-year tumor control rates were 95.3 ± 2.1%, 94.3 ± 2.2%, 87.7 ± 3.2%, and 86.6 ± 3.3%, respectively. The 10-year actuarial tumor control rate was significantly lower in the patients with tumor volumes of ≥ 8 cm3 (P = 0.010). The rate of maintaining the same Gardner-Robertson scale grade was 28.6%, and that of serviceable hearing was 46.4%. The rates of newly developed facial and trigeminal neuropathy were 2.8% and 4.7%, respectively. The patients who received marginal doses of less than 12 Gy revealed higher tumor control failure rates (P = 0.129) and newly occurred facial or trigeminal neuropathy rates (P = 0.040 and 0.313, respectively). CONCLUSION: GKS as an initial treatment for ANs could be helpful in terms of tumor control, the preservation of serviceable hearing, and the prevention of cranial neuropathy. It is recommended to perform GKS as soon as possible not only for tumor control in unilateral ANs with hearing loss but also for hearing preservation in those without hearing loss.
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Pérdida Auditiva , Neuroma Acústico , Radiocirugia , Enfermedades del Nervio Trigémino , Humanos , Persona de Mediana Edad , Neuroma Acústico/radioterapia , Neuroma Acústico/cirugía , Radiocirugia/efectos adversos , Estudios Retrospectivos , Estudios de Seguimiento , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/etiología , Enfermedades del Nervio Trigémino/etiología , Enfermedades del Nervio Trigémino/cirugía , Resultado del TratamientoRESUMEN
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis and limited treatment options. While 5-fluorouracil (5-FU) has not been widely employed in GBM therapy, emerging research indicates its potential for effectiveness when combined with advanced drug delivery systems to improve its transport to brain tumors. This study aims to investigate the role of THOC2 expression in 5-FU resistance in GBM cell lines. We evaluated diverse GBM cell lines and primary glioma cells for 5-FU sensitivity, cell doubling times, and gene expression. We observed a significant correlation between THOC2 expression and 5-FU resistance. To further investigate this correlation, we selected five GBM cell lines and developed 5-FU resistant GBM cells, including T98FR cells, through long-term 5-FU treatment. In 5-FU challenged cells, THOC2 expression was upregulated, with the highest increase in T98FR cells. THOC2 knockdown in T98FR cells reduced 5-FU IC50 values, confirming its role in 5-FU resistance. In a mouse xenograft model, THOC2 knockdown attenuated tumor growth and extended survival duration after 5-FU treatment. RNA sequencing identified differentially expressed genes and alternative splicing variants in T98FR/shTHOC2 cells. THOC2 knockdown altered Bcl-x splicing, increasing pro-apoptotic Bcl-xS expression, and impaired cell adhesion and migration by reducing L1CAM expression. These results suggest that THOC2 plays a crucial role in 5-FU resistance in GBM and that targeting THOC2 expression could be a potential therapeutic strategy for improving the efficacy of 5-FU-based combination therapies in GBM patients.
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Tumor spheroids are powerful tools for drug screening and understanding tumor physiology. Among spheroid formation methods, the hanging drop method is considered most suitable for high-throughput screening (HTS) of anticancer drugs because it does not require surface treatment. However, it still needs to increase the liquid-holding capacity because hanging drops often fall due to the increased pressure caused by the addition of drugs, cells, etc. Here, we report a multi-inlet spheroid generator (MSG) enabling the stable addition of liquid-containing drugs or cells into a spheroid through its side inlet. The MSG was able to load additional solutions through the side inlet without increasing the force applied to the hanging drop. The volume of the additional liquid was easily controlled by varying the diameter of the side inlet. Furthermore, the sequences of the solution injections were manipulated using multiple side inlets. The feasibility of the MSG in clinical application was demonstrated by testing the efficacy of drugs in patient-derived cancer (PDC) cells and controlling the stromal cell ratio in the tumor microenvironment (TME) containing spheroids. Our results suggest that the MSG is a versatile platform for HTS of anticancer drugs and recapitulating the TME.
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Antineoplásicos , Esferoides Celulares , Humanos , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Bahías , Ensayos Analíticos de Alto Rendimiento/métodos , Microambiente Tumoral , Antineoplásicos/farmacologíaRESUMEN
Currently, research on superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic hyperthermia applications is steadily increasing. In this work, SPIONs were synthesized by the bromide-assisted polyol method and angle-shaped SPIONs were successfully generated with the optimized concentration of bromide. The influence of bromide concentration on the shape of the generated SPIONs as well as the heating characteristics under an alternating magnetic field (AMF) was thoroughly investigated. At a concentration of 20 mg mL-1 of the angle-shaped SPIONs, the highest temperature curve up to 23 °C was observed under AMF with 140 Oe and 100 kHz for 10 min. With the biotoxicity assay, no significant cytotoxicity was observed in the normal fibroblast of HFB-141103 as well as tumor cells of U87MG and FSall treated with the angle-shaped SPIONs at a concentration below 100 µg mL-1. However, significantly decreased cellular viability was observed in tumor cells of U87MG and FSall treated with 100 µg mL-1 of the angle-shaped SPIONs under AMF with 140 Oe and 100 kHz. Based on these results, it is thought that the angle-shaped SPIONs synthesized by the bromide-assisted polyol method will provide highly efficient magnetic hyperthermia therapy for cancers under biologically safe AMF with 140 Oe and 100 kHz.