Glioblastoma (GB), classified as a grade 4 astrocytoma by the World Health Organization (WHO) (Louis et al., 2021; Obrador et al., 2024), is the most prevalent, aggressive, and lethal primary brain tumor in adults. Known for its rapid growth, high invasiveness, and significant molecular diversity (Louis et al., 2021), it typically arises in the cerebral hemispheres (Price et al., 2024; Thakkar et al., 2014). Despite advances in treatment, including extensive surgical resection, radiotherapy, and temozolomide-based (Valenzuela-Fuenzalida et al., 2024) chemotherapy (Stupp protocol) (Stupp et al., 2005), the median survival remains dismally poor at 12–15 months post-diagnosis. This reflects the urgent need for novel therapies that effectively target the biological and molecular complexity (Davis, 2016; Vehlow and Cordes, 2013).

Glioblastoma exhibits extensive heterogeneity and plasticity at the cytopathological, transcriptional, and genetic levels (Becker et al., 2021; Perrin et al., 2019; Brennan et al., 2013; Kim et al., 2015). Moreover, the blood–brain barrier (BBB) and altered tumor permeability represent additional major obstacles to effective therapy, further limiting drug delivery and treatment efficacy (Ahmed et al., 2023; Davis, 2016; Wu et al., 2021). Within this highly complex microenvironment, glioblastoma stem-like cells (GSCs) have emerged as key drivers of tumor progression, therapeutic resistance, and recurrence (Loras et al., 2023; Stiles and Rowitch, 2008; Safa et al., 2015; Xie et al., 2022; Hu et al., 2023; Singh et al., 2004). GSCs exhibit marked resistance to apoptosis, contribute to angiogenesis and immunosuppression, and play a central role in both radio- and chemo-resistance (Di Nunno et al., 2022; Schaff and Mellinghoff, 2023; Furnari et al., 2007; Atkins et al., 2015). These properties are further reinforced by hypoxic conditions within the tumor microenvironment, which promote the maintenance of stem-like phenotypes and enhance tumor adaptability (Yalamarty et al., 2023; Eckerdt and Platanias, 2023). The persistence of therapy-resistant GSC populations is widely regarded as a major reason why glioblastoma almost invariably recurs following standard treatment (Bao et al., 2006).

Recent advances in genomic profiling have provided deeper insights into the genetic alterations driving GB. IDH1/2 mutations are predominantly found in grade 4 astrocytomas that evolve from lower-grade gliomas (secondary GBs) (Ichimura et al., 2009), which differ molecularly and clinically from primary GBs (Ichimura et al., 2009). Secondary GBs are different from primary GBs because they develop from pre-existing lower-grade gliomas (classified as WHO grades 2 or 3) instead of appearing out of nowhere, like primary GBs do (Delgado-Martín and Medina, 2020). Lower-grade gliomas tend to grow more slowly and have better survival rates initially, but over time, they can pick up additional genetic changes, such as mutations in TP53 or loss of ATRX, which can eventually lead to their progression into secondary GBs (Claus et al., 2015). This distinction between primary and secondary GBs is crucial because it highlights the differences in their molecular and clinical pathways (Mao et al., 2012). In contrast, EGFR amplification, present in approximately 40% of GB cases, is linked to worse outcomes by promoting aggressive tumor behavior through constitutive activation of growth signaling pathways (Verhaak et al., 2010). TP53 mutations, affecting the p53 pathway in 87% of cases, significantly contribute to disease progression, while alterations in CDKN2A, a key cell cycle regulator gene, further impair apoptosis and disrupt cell cycle control (Campbell et al., 2016). RTK/PI3K/PTEN pathway alterations are observed in 88% of GB cases, emphasizing their role in tumourigenesis. Additionally, loss of heterozygosity on chromosome 10 is one of the most common chromosomal abnormalities identified (Fujisawa et al., 2000). These genetic insights not only enhance our understanding of GB biology but also have potential to improve diagnosis, predict outcomes, and inform personalized therapies. For example, IDH mutations offer prognostic value, while EGFR, TP53, and CDKN2A alterations highlight the molecular complexity and therapeutic resistance of GB (Dunn et al., 2012).

In addition to genetic drivers, clinical and lifestyle factors such as age, sex, overall health, smoking, family history, and viral infections may influence prognosis, though their roles in GB remain underexplored. Some studies suggest sex-based survival differences, with longer survival in females (Yang et al., 2013). Lifestyle factors such as smoking, family cancer history, and viral infections (e.g., hepatitis B, COVID-19) may also influence disease progression and treatment response, although their roles in GB remain underexplored (Travers and Litofsky, 2021).

Tumor location relative to brain ventricles has emerged as a critical prognostic factor, though evidence in mixed impact on overall survival (OS) have been inconsistent (Mistry et al., 2020). While GB distance from the subventricular neural stem cell niche has not been correlated with survival (Mistry et al., 2017), a recent meta-analysis reported that GBs in contact with the lateral ventricle are associated with lower survival. This effect may be independent of established survival predictors, emphasizing the clinical relevance of the ventricular-subventricular zone contact in GB biology (Mistry et al., 2017; Travers and Litofsky, 2021). Furthermore, tumor location near the third ventricle and the contrast-enhancing tumor border has been identified as a prognostic factor, particularly in elderly patients (Fyllingen et al., 2021). Understanding these spatial relationships and their biological implications is crucial for devising more effective therapies and improving GB prognosis.

This study aimed to evaluate clinical, surgical and genetic determinants of survival in glioblastoma, with particular emphasis on the spatial relationship between tumor and ventricle.

Univariate survival and exploratory analyses of clinical, tumor-related, genetic, and lifestyle variables are summarized in Table 2. Overall survival was primarily influenced by tumor proximity to the ventricular system, whereas no significant associations were observed for demographic, treatment-related, genetic, or lifestyle variables.

The proximity of the tumor to the lateral ventricle emerged as the most robust prognostic factor. Patients with tumors directly contacting or located closer to the ventricle had markedly shorter survival, whereas those farther away had longer survival. This establishes ventricular proximity as the most robust association observed in this cohort. Importantly, all analyses were restricted to IDH-wildtype glioblastomas, in line with the WHO 2021 classification, thereby avoiding the inclusion of biologically and clinically distinct IDH-mutant astrocytomas.

Surgical resection also showed an effect, though less pronounced than ventricular distance. Patients who underwent gross total resection lived longer than those with subtotal resection or biopsy only, which is consistent with the biological rationale that removing a larger amount of tumor tissue may delay time to recurrence.

However, the distance of the tumor to the ventricles, as well as surgery type, had a strong correlation with survival. Close relationship between ventricular contact and poor outcome raises the hypothesis that cerebrospinal fluid (CSF) dynamics, the neural stem cell niche of the subventricular zone (SVZ), and anatomical structures such as the corpus callosum may contribute to tumor progression and invasiveness. The corpus callosum, a myelin structure that connects the two lateral hemispheres of the brain, is also attached to the lateral ventricle and could act as a conduit for cancer cell invasion. Furthermore, this hypothesis could suggest that a reservoir of neural stem cells is present within the lateral ventricle of the brain, which could act as a reservoir for cancer cells within the tumor. This fact could be assessed by the glioma stem cell marker CD133 (Brescia et al., 2013). Indeed, the SVZ microenvironment has been proposed to foster glioma stem cell maintenance, increasing the likelihood of resistance and recurrence. This biological niche may therefore not only promote initial tumourigenesis but also facilitate repopulation after therapy.

When we examined demographic factors such as age, sex, and BMI, we found that none of them had a significant impact on survival outcomes. This is largely in line with other studies (González Bonet et al., 2022), which suggest that these factors are less critical for predicting overall survival in GB compared to other variables, such as treatment options or tumor behavior (Cabanne et al., 2013), tumor spatial features such as ventricular proximity or surgical extent. As for treatments like radiotherapy and chemotherapy, including the Stupp protocol, they did not seem to significantly impact survival. This could be due to GB complexity, since different patients respond to treatment in very different ways, making it harder to draw clear conclusions. Regarding tumor location, most were in the frontal and temporal lobes. However, surprisingly, specific tumor location did not seem to affect patient survival. Moreover, to rule out the hypothesis that patients undergoing biopsy surgery who tend to have shorter survival rates might have tumors located closer to the ventricle (which would make surgery more difficult), we analyzed the relationship between surgery type and tumor proximity. Our analysis showed no significant association between the distance to the ventricle and the type of surgery performed. This suggests that the poorer survival observed in biopsy patients is not simply explained by tumor location near the ventricle.

This reinforces the idea that the proximity of the tumor to the ventricular system has an intrinsic biological impact on tumor aggressiveness and not merely a mechanical or surgical limitation. Also, our results show no significant association between tumor size and patient survival, despite a non-significant trend toward poorer outcomes with larger tumors. Additionally, tumor volume does not correlate with its distance to the ventricle, indicating size is independent of location. These findings suggest that tumor size and proximity to the ventricle alone are insufficient predictors of prognosis in glioblastoma. Other factors, such as tumor invasiveness or microenvironmental interactions, may have greater influence on patient outcomes. Further research is needed to elucidate these mechanisms and improve prognostic models. Interestingly, while tumor size did not significantly impact survival, tumor proximity to the ventricular system emerged as a strong prognostic factor. This finding suggests that spatial tumor location, reflecting interactions with specific anatomical and biological niches, may be more relevant than tumor burden alone in determining clinical outcome. These results support the concept that glioblastoma aggressiveness is not solely driven by tumor volume but also by its anatomical context and microenvironmental interactions.

Nonetheless, when tumor proximity to the ventricle is combined with other features such as stem cell-like molecular signatures, the predictive value for poor prognosis becomes even more compelling, potentially identifying a more aggressive glioblastoma subtype. Regarding genetic factors, mutations in GB driver genes such as IDH1, EGFR, TP53, and CDKN2A, or CNVs in genes like EGFR and PTEN, did not show strong associations with survival outcomes in this study. However, these findings should be interpreted with caution, as the limited sample size may have reduced the statistical power to detect significant genetic effects. It is likely that the absence of a significant difference in IDH mutation is attributable to the limited size of the mutated group. Furthermore, it should be noted that the current classification of GB does not include IDH mutation as a diagnostic criterion. While other studies (Campbell et al., 2016; Mao et al., 2012; Verhaak et al., 2010) have found links between certain genetic markers and survival in GB, we did not observe the same results. This could be due to patient differences or because our sample size was too small to pick up on subtle effects, but it is clear that we still lack considerable insight on how genetic changes impact GB.

Several studies have shown no consistent association between glioblastoma and common comorbidities such as smoking (Li et al., 2016), type 2 diabetes (Lu et al., 2018), hepatitis B (Cabanne et al., 2013) infection, or a family history of cancer. These observations should be interpreted cautiously, as the analysis of lifestyle and medical history factors was exploratory and the study was not powered to detect subtle effects of these variables on survival (Qi et al., 2023).

Although glioblastoma recurrence rates of up to 70%–80% have been reported in the literature (Weller et al., 2021), recurrence was documented in 43.9% of patients in our cohort, likely reflecting follow-up duration and censoring. Unfortunately, secondary surgeries for recurrent tumors did not seem to improve survival, which really highlights how limited our treatment options are when GB reappears. We need better strategies for dealing with recurrent GB, something that clearly still is a challenge in the field.

On the other hand, when we looked at lifestyle and medical history factors like smoking, past cancer, COVID-19 infection, and conditions like hepatitis B and Type II diabetes, they did not seem to affect survival at all. This suggests that these factors might not matter as much in the context of GB. However, in GB patients who are motivated to make lifestyle adjustments to improve their outcomes, the exciting news is that dietary restriction of sugar and caloric intake in particular seems to show some promise, with better news coming from exercise, vitamin supplementation, and cannabis use showing potential benefits as well (Peeri et al., 2021; Travers and Litofsky, 2021).

A significant challenge in the management of GB is the difficulty neurosurgeons face in accessing the tumor (Brown et al., 2016; Lacroix et al., 2001; Stummer et al., 2008). The primary objective is to achieve complete removal of the tumor without compromising the patient’s life. However, complete eradication of infiltrating tumor cells is not feasible, as glioblastoma diffusely invades surrounding brain tissue, limiting surgical clearance and contributing to inevitable recurrence (Brown et al., 2016; Lacroix et al., 2001; Stummer et al., 2008). This is a consequence of the high invasiveness of brain cells, which renders total surgery a viable option for increasing survival but not preventing relapse.

What remains evident is that tumors close to the ventricular system present a double challenge: not only are they harder to resect completely due to their location, but they may also represent a biologically distinct and more aggressive subtype of glioblastoma. Perhaps the most relevant finding of this work is that tumors located close to the ventricular system are associated with shorter survival. Patients with tumors that were in direct contact with the ventricles had the shortest survival times, which suggests that where the tumor is located in relation to the ventricles might influence tumor growth or treatment efficacy. This spatial relationship is critical and could serve as a valuable addition to current prognostic models. Classifying tumors by their proximity to the ventricle at diagnosis could help stratify patients more accurately and inform treatment decisions, including whether to consider more aggressive or targeted therapies in periventricular tumors (Mistry et al., 2017, 2020). Notably, the association between ventricular proximity and poor survival could not be explained by differences in surgical strategy, as tumor ventricle distance was independent of the extent of resection. This supports the hypothesis that ventricular proximity reflects intrinsic biological aggressiveness rather than a purely surgical limitation.

Extensive resection has consistently been associated with prolonged survival in glioblastoma patients (Brown et al., 2016; Lacroix et al., 2001; Stummer et al., 2008). While genetic factors did not provide us with clear answers, it is still important to keep studying them, as they could hold the key to better treatments in the future. The relationship between tumor proximity to the ventricle and survival is also something that deserves more attention, as it could help us improve prognostic models. Several studies have reported that glioblastomas contacting the subventricular zone (SVZ) are associated with poorer prognosis and increased likelihood of multifocal recurrence. This may be related to the presence of neural stem-like cells in the SVZ microenvironment, which could contribute to tumor aggressiveness and resistance to treatment. Lateral ventricle glioblastomas may represent a more aggressive and invasive tumor subtype and integrating this spatial parameter into clinical assessment could help personalize therapy and ultimately improve patient outcomes. Overall, there is still a lot we need to figure out, but the hope is that by continuing to explore new treatment options and gathering more data, we can find better ways to help patients with GB in the future. Advancements in immunotherapy, tumor-treating fields, and targeted therapies offer promise, yet their integration into standard treatments remains a work in progress, highlighting the need for comprehensive, individualized treatment strategies (Qi et al., 2023; Weller et al., 2021). Given the single-center retrospective design and cohort-specific tertile cut-offs, these findings should be interpreted as exploratory and require validation in independent cohorts.