Neuro-oncology advances最新文献

Background: The gold standard for the diagnosis of brain tumors comprises neurosurgical biopsies or resections for tissue acquisition. Depending on the anatomical location of the tumor, this might not always be feasible. The aim of this study was to assess whether targeted sequencing of cell-free DNA (cfDNA) could be applied in a clinical setting for the detection of cancer-specific mutations in cerebrospinal fluid (CSF) and blood using a widely available panel, investigating if this approach would facilitate brain tumor diagnosis.

Methods: Patients with newly suspected or confirmed CNS tumors or suspected leptomeningeal metastasis were included. CSF and blood were sampled for each patient. Using next-generation sequencing (NGS), targeted sequencing was performed on cfDNA. If available, matched tissue samples were also sequenced using the same gene panel.

Results: We investigated 58 samples from 29 patients. Sequencing was successful in 16 CSF samples (55%) and 29 blood samples (100%). On average, more tumor-specific mutations were found in CSF compared to blood. Patients in whom cfDNA sequencing in CSF was successful had tumors with a significantly shorter distance to the CSF space and were larger in size. In 2 cases, where surgeries were not considered because of high surgical risk due to the anatomical locations of the lesions, the diagnosis was aided by CSF sequencing results. One primary CNS lymphoma and 1 H3 K27M diffuse midline glioma were identified, respectively.

Conclusions: NGS-based targeted sequencing in CSF has the potential to facilitate brain tumor diagnosis in patients presenting with new cerebral lesions.

Background: The efficacy of ipilimumab and nivolumab (ipi/nivo) for melanoma brain metastases (MBMs) has been previously reported, leading to uncertainty regarding the optimal role of comprehensive stereotactic radiosurgery (cSRS). We therefore conducted a single-institution retrospective study to compare outcomes of upfront versus deferred cSRS for MBM treated with ipi/nivo.

Methods: We identified patients who started ipi/nivo for newly diagnosed MBMs between 2018 and 2023, with or without upfront cSRS. Patients with >15 MBMs, leptomeningeal disease, or whole-brain radiotherapy at baseline were excluded. Outcomes were compared using multivariable regression and reported as adjusted hazard ratios (aHRs) with 95% CIs.

Results: Of the 132 patients identified, 52.3% received upfront cSRS and 47.7% did not. Patients who received upfront cSRS had larger maximum MBMs (median 2.3 vs 0.7 cm; P < .001), more symptomatic MBMs (59.4% vs 11.1%; P < .001), higher rates of upfront craniotomy (47.8% vs 7.9%; P < .001), and fewer BRAF V600 mutations (34.8% vs 54.0%; P = .035). Upfront cSRS was not associated with longer overall survival (median 47.0 mo vs not reached; aHR = 1.01 [95% CI, 0.60-1.68]; P = .98) but was associated with reduced incidence of intracranial progression (median 37.6 vs 5.5 mo; aHR = 0.40 [95% CI, 0.25-0.64]; P < .001).

Conclusions: In this retrospective study, upfront cSRS was more often used in patients with higher-risk MBM and was associated with improved intracranial control, although no significant survival benefit was observed. These findings suggest that starting ipi/nivo alone may be reasonable for lower-risk MBM, but prospective studies are needed to guide optimal integration of cSRS.

Background: Low-grade or grade 2 diffuse gliomas (LGG) infiltrate the brains leading to significant neurological morbidity. This retrospective observational study evaluates the ability of AI-assisted volumetric analysis to correctly detect tumor growth in longitudinal studies of LGG as compared to the standard clinical method.

Methods: A total of 56 gliomas and 7 stable FLAIR lesions were included; gliomas were classified as clinical progression (n = 34), or clinically stable (n = 22). All gliomas were from radiation-naïve patients; only 2 patients had completed treatment with temozolomide. The dates of tumor growth were gathered from clinical notes. Longitudinal tumor volumes were calculated by the MRIMath FLAIR AI. Golden truths were obtained by physician reviews using the MRIMath Smart contouring system. Growth by significant shifts in tumor volumes was detected by using the statistical method of online change-of-point method.

Results: In the clinical progression group, automatic AI segmentation followed by human review detected tumor growth at a median of 21 months earlier than visual inspection. In the clinically stable group, AI with human review identified growth in 13/22 cases at a median of 23 months earlier than the last magnetic resonance imaging. AI without human review generated similar results but with a 25% false positive and an 8.33% false negative rate. The median time spent by physicians in reviewing, revising, and approving the AI segmentations is 2 minutes.

Conclusions: These findings highlight the clinical potential of AI-assisted volumetric analysis followed by physician oversight for the timely detection of tumor progression in LGG patients.

Background: This study aims to analyze survival outcomes in patients over 65 years old with a de novo diagnosis of glioblastoma and to identify factors that impact survival to guide management decisions in this population.

Methods: A retrospective single-center cohort study included all patients aged ≥65 years with a de novo histological diagnosis of isocitrate dehydrogenase (IDH)-wildtype glioblastoma treated in our hospital between 2017 and 2024. Patients with incomplete information or loss to follow-up were excluded. Kaplan-Meier curves were used for overall survival analysis. Risk factors were assessed by the Cox proportional hazards regression analyses.

Results: One hundred and fourteen patients were selected with a mean age of 72.5 years old and male preponderance (58/114; 50.9%). A total of 44.7% underwent biopsy only. As far as 17.8% of the patients completed the Stupp protocol. After univariable analysis, a multivariable Cox regression analysis identified the following independent predictors of survival: single lesions at diagnosis, postoperative Karnofsky performance status, lower residual tumor volume, administration of adjuvant therapy according to the Stupp protocol, and administration of a complete radiotherapy schedule. The molecular pattern and the Charlson comorbidity index score were not significantly associated with survival. Age was not identified as an independent survival factor after adjustment by other variables.

Conclusions: Aggressive treatment is also the standard of care for older patients with glioblastoma. Maximal resection followed by the Stupp protocol in patients with a good functional performance predicts better survival. After adjusting by other covariates, age is not independently associated with survival.

Background: Glioblastoma (GB), IDH-wildtype, and low-grade glioma appear indistinguishable in their early pre-symptomatic phase, yet GB follows a far more aggressive clinical course. While genomic studies suggest a "biological birth" of GB years before diagnosis, when GB first becomes radiologically detectable (radiological birth) remains unknown.

Methods: We analyzed longitudinal imaging data from 67 early-stage glioblastoma (earlyGB) cases, characterized by small, asymptomatic lesions that later progressed to classic magnetic resonance imaging appearance of GB (classicGB), comprising 44 institutional and 23 from published reports. A mathematical model integrating tumor volume, radius, imaging intervals, clinical data, and molecular features estimated radiological birth and its modifiers.

Results: The median interval from earlyGB to classicGB was 155 days (range: 35-1557) in our cohort and 113 days (range: 4-854) in the published cohort. Radiological birth occurred 0.83 years (95% CI: 0.66-1.10) before diagnosis in our cohort and 0.15-0.92 years in the published cohort. Rapid progression correlated with age <65 years, MIB1 labeling index ≥30%, and copy-number alterations (CNAs) in EGFR, PTEN, or CDKN2A, but not with TERT promoter status. Absence of these CNAs prolonged the radiological birth to 2.27 years (95% CI: 0.79-100), indicating slower progression. Median overall survival of our cohort was 1.7 years, yielding a radiological-birth-to-death span of 2.8 years.

Conclusions: This largest earlyGB cohort defines the radiological birth and entire clinical trajectory of IDH-wildtype GB. These findings bridge the gap between biological and radiological birth and offer a benchmark for surveillance and early-intervention strategies.

Background: Spinal chondrosarcomas are rare, aggressive bone tumors with limited data on optimal radiotherapy strategies, particularly regarding the comparison between proton and photon therapies. This study aims to evaluate long-term survival outcomes and identify effective treatments and risk factors using the National Cancer Database.

Methods: Patients diagnosed with spinal chondrosarcomas were categorized into radiation and no-radiation groups. The radiation group was subdivided into proton and photon therapy cohorts. Univariate and Kaplan-Meier analyses assessed demographic, clinical, and survival outcomes. Multivariate Cox proportional hazards models identified prognostic factors, and survival predictive models were evaluated using Area Under the Curve (AUC) metrics.

Results: Of 1971 patients, 343 (17.4%) received radiation. Surgery was less common in the radiation group (53.9% vs 82.6%, P < .001). Combined surgery and radiation had the best survival outcomes, with proton therapy showing superior survival to photons (P < .001). High-dose radiation (Biologically Effective Dose [BED] >70 Gy) and Stereotactic Body Radiation Therapy (SBRT) improved survival (P < .001). Surgery was associated with increased mortality risk (hazard ratio [HR] = 0.35, P < .001), while radiation showed increased risk (HR = 1.31, P = .003). Machine learning identified tumor size thresholds of 75 mm for photon and 70 mm for proton therapy as predictive of mortality. DeepSurv (AUC = 0.708) identified distant metastasis, tumor size, and age as important prognostic factors for 10-year survival.

Conclusion: Gross total resection (GTR) is the most effective treatment for spinal chondrosarcoma. High-dose radiation therapy (BED > 70 Gy) can be combined with surgery to improve survival in advanced cases. Proton therapy offers superior long-term survival compared to photons, and dose-escalated techniques (Stereotactic Radiosurgery [SRS] and Intensity-modulated radiation therapy [IMRT]) show potential in enhancing outcomes.

Background: Altered tumor metabolism has renewed interest in ketogenic strategies, despite limited clinical evidence in glioma. Whereas the ketogenic diet (KD) alone elevates intratumoral amino acids, bevacizumab (BEV) co-administration suppresses these metabolites and curtails tumor growth, pointing to a synergistic therapeutic potential.

Methods: We conducted a clinical pilot study to evaluate the combination of KD and standard therapy, combining BEV, in patients with malignant glioma. A standardized modified ketogenic diet (mKD) regimen was implemented: carbohydrate intake was restricted to 10 g/day in the first week, 20 g/day in the following 2 months, and ≤30 g/day thereafter. MCT oil was administered at ≥50 mL/day, and ketone formula supplements were provided as needed. The primary endpoint was to assess safety and feasibility.

Results: 10 patients were enrolled. The duration of mKD ranged from 63 to 1,954 days, with a median of 185 days. All patients showed a rapid increase in serum ketone levels and achieved therapeutically adequate glucose-ketone index values. All participants met the predefined safety criteria, and no severe adverse events were reported. One patient discontinued the diet owing to moderate abdominal pain. The objective response rate was 50%, and notably, one patient remained on mKD for more than 5 years without tumor recurrence. The median progression-free survival from mKD initiation was 9.5 months, and the median overall survival was 31 months.

Conclusions: The combination of mKD and standard therapy with BEV was safe and feasible in patients with malignant glioma. Larger clinical trials are needed to determine its anti-tumor efficacy and clinical benefit.

Background: Tertiary lymphoid structures (TLSs) correlate with improved survival in various cancers, but their prognostic significance and imaging correlations in glioblastoma (GBM) remain unclear. This study investigated the relationship between TLSs, survival outcomes, and imaging features in GBM patients.

Methods: A retrospective analysis of 190 newly diagnosed GBM patients was conducted. TLSs were identified via hematoxylin-eosin staining, with maturity assessed by multiplex immunofluorescence (CD20/CD3/CD21/CD23) into mature (mTLSs) and immature (imTLSs) subgroups. Survival analysis used Kaplan-Meier method, and TLS predictive models were developed via logistic regression. Clinicopathological and VASARI imaging features were compared.

Results: Of 190 cases, 85 (44.73%) were TLSs+, comprising 47 imTLSs and 38 mTLSs. Mean overall survival (OS) was 11.82 months. Significant OS differences were observed between TLSs+ (14.67 months) and TLSs- (9.51 months) groups, and between mTLSs (19.36 months) and imTLSs (10.87 months) groups (all P < .05). VASARI features f2, f8, f17, and f22 differed significantly between TLSs+/TLSs- groups, while f6, f16, and f18 differed between mTLSs/imTLSs groups (all P < .05). These features were independent predictors of TLS presence and maturity.

Conclusion: TLSs exist at varying maturation stages in GBM and represent favorable prognostic biomarkers. Their presence and maturity significantly correlate with OS and specific VASARI features. Preoperative imaging prediction of TLSs may facilitate risk stratification and individualized treatment for GBM patients.

Glioblastoma (GB) is the most malignant tumor in the adult central nervous system (CNS), presenting substantial treatment challenges due to its infiltrative nature, heterogeneity and immunosuppressive environment it creates. Current therapeutic efforts are focused on enhancing our understanding of GB and developing effective therapies. An emerging area of interest is the bidirectional gut-brain axis, which mediates communication between gut microbiota and CNS. The gut-brain axis allows the microbiota to modulate the immune system and inflammatory pathways through microbial metabolites, such as short-chain fatty acids (SCFAs) and tryptophan derivatives, promoting or suppressing GB progression. Understanding these interactions can lead to microbiota-targeted therapies for GB patients. Novel therapies, such as fecal microbiota transplantation to enhance immunotherapy response and using bacterial toxins to cross the blood-brain barrier, show promise in improving treatment-resistant GB treatment. Additionally, the role of probiotics and antibiotics on GB prognosis is being investigated. While more research is needed to understand the gut microbiota's role in GB, recent findings suggest promising directions for future therapies. This review examines the interplay between key immune system components and the microbiota in GB development and explores how this understanding could facilitate the development of novel therapeutic interventions.

Background: Despite advancements in treatment, 5-year survival for medulloblastoma (MB) remains 60%-70%. Human cytomegalovirus (HCMV) has been implicated as an oncomodulator in MB, but its impact on survival has not been explored. This study evaluates HCMV expression in pediatric MB tissue and its association with molecular risk groups and survival.

Methods: A retrospective study of pediatric MB cases (≤19 years) from 2007 to 2023 was conducted using the WHO 2021 classification, the Northcott brain-tumor classifier, and the SIOP-Europe/ERN PaedCan risk stratification. HCMV immediate-early (HCMV-IE) and late-antigen (HCMV-LA) expression were assessed by optimized immunohistochemistry, and whole-genome sequencing (WGS) data from 20 tumors were analyzed for viral gene expression.

Results: Forty-five patients (mean age 8.2 years; 22% ≤3 years) were included: WNT (18%), SHH TP53-wildtype (18%), and non-WNT/non-SHH (64%). Twenty percent of MB belonged to low-risk, 33% to standard-risk, and 47% to high-risk (HR-MB) groups. Four tumors exhibited MYC/N amplification. HCMV-LA positivity was found in 84% of cases, with 53% showing high expression (≥25% of cells). Cox-regression identified HR-MB (HR = 4.197, p = .021) and high HCMV-LA (HR = 4.334, p = .027) as independent predictors of poor outcomes. WGS revealed UL88 as the most abundantly expressed HCMV gene (log₂[TPM+1] ≈ 14-15), with maximal expression in Group 3 MB.

Conclusions: This study provides the first evidence linking high HCMV-LA expression to adverse outcomes and high-risk molecular features in pediatric MB. UL88 emerged as the most strongly expressed HCMV gene across MB samples. These findings suggest a potential prognostic and therapeutic role for HCMV in MB, warranting validation in larger, prospective cohorts.