Endoscopic transorbital approach in children: surgical technique and early results.

OBJECTIVE: In this study, the authors aimed to describe the endoscopic transorbital approach (ETOA) in children. METHODS: Six pediatric patients (2 girls and 4 boys) underwent the ETOA for paramedian skull base lesions at a single institution between September 2016 and February 2023. RESULTS: The median age at the time of surgery was 7.5 (range 4-18) years. The median follow-up period was 33 (range 9-60) months. In this series, the ETOA level of difficulty included stage 1 (n = 2, 33.3%), stage 3 (n = 3, 50%), and stage 5 (n = 1, 16.7%). The ETOA was performed for tumor resection in 4 cases; the final pathology consisted of fibrous dysplasia, pilocytic astrocytoma, metastatic neuroblastoma, and choroid plexus papilloma. The procedure was also performed for repair of a petrous apex meningocele and for lateral orbital wall decompression of traumatic lateral rectus muscle entrapment. One patient experienced a transient cranial nerve III palsy after the procedure. There were no operative deaths in this series. CONCLUSIONS: In select cases, the ETOA can be considered a minimally invasive alternative for conventional skull base approaches in the armamentarium of pediatric skull base surgery. Further investigation and the accumulation of experience are warranted in the future to enhance the efficacy and applicability of the ETOA in pediatric patients.

Limitations of outcome prediction based on interfractional volume changes of large (≥ 10cm3) brain metastases during fractionated gamma knife radiosurgery.

PURPOSE: This study investigated the interfractional volume changes of large (≥ 10 cm3) brain metastases (BMs) during fractionated gamma knife radiosurgery (FGKRS) to assess its predictive value for tumor control outcomes. METHODS: The patients who underwent FGKRS for large BMs between January 2017 and December 2022 in our center were reviewed. The interfractional volume change was defined as the disparity in tumor volume (TV) measured between the magnetic resonance images acquired on the first treatment day and those obtained after 2 or 3 fractions during the course of FGKRS. RESULTS: A total of 73 lesions in 70 patients with various primary pathologies were included. Over a median follow-up period of 11 months (range 1-77), the tumor control rate was 63%. Initial TV (cm3) was associated with progression free survival (PFS) and overall survival (OS) in both univariate and multivariate analyses (p = 0.01). Interfractional TV changes revealed an increase in 13 (17.8%) lesions, no change in 14 (19.2%) lesions, and a decrease in 46 (63.0%) lesions, with a mean volume reduction of 5% ± 0.12. Three cut-offs (5%, 10% and 15% volume decrement) were established and patients were divided into two groups based on each reference point. However, there were no significant differences in PFS and OS between the two groups, irrespective of the chosen cut-off value used. CONCLUSION: Interfractional volume changes of large BMs were not found to be associated with tumor control outcomes. Neither significant interfractional volume reduction nor significant volume increase necessarily predicts the tumor control, making early close monitoring essential after FGKRS.

Early Cranioplasty in an Apert's Syndrome Infant With Occipital Encephalocele.

Apert's syndrome (AS) is a rare congenital malformation characterized by distinctive clinical manifestations such as syndactyly of the extremities and midface retrusion, which set it apart from other syndromes. This condition often presents with craniosynostosis and, less commonly, central nervous system abnormalities like encephalocele. In this report, we present a typical case of Apert syndrome with an occipital encephalocele. The infant had plagio-brachycephaly due to craniosynostosis and required urgent repair of the occipital encephalocele. At 1 month of age, we performed both the encephalocele repair and early cranioplasty for autologous bone grafting. This case underscores the importance of early diagnosis and surgical interventions in Apert's syndrome cases with encephalocele.

Impact of boost sequence in concurrent chemo-radiotherapy on newly diagnosed IDH-wildtype glioblastoma multiforme.

BACKGROUND: The standard of care for glioblastoma multiforme (GBM) is maximal surgical resection followed by conventional fractionated concurrent chemoradiotherapy (CCRT) with a total dose of 60 Gy. However, there is currently no consensus on the optimal boost technique for CCRT in GBM. METHODS: We conducted a retrospective review of 398 patients treated with CCRT between 2016 and 2021, using data from two institutional databases. Patients were divided into two groups: those receiving sequential boost (SEB, N = 119) and those receiving simultaneous integrated boost (SIB, N = 279). The primary endpoint was overall survival (OS). To minimize differences between the SIB and SEB groups, we conducted propensity score matching (PSM) analysis. RESULTS: The median follow-up period was 18.6 months. Before PSM, SEB showed better OS compared to SIB (2-year, 55.6% vs. 44.5%, p = 0.014). However, after PSM, there was no significant difference between two groups (2-year, 55.6% vs. 51.5%, p = 0.300). The boost sequence was not associated with inferior OS before and after PSM (all p-values > 0.05). Additionally, the rates of symptomatic pseudo-progression were similar between the two groups (odds ratio: 1.75, p = 0.055). CONCLUSIONS: This study found no significant difference in OS between SEB and SIB for GBM patients treated with CCRT. Further research is needed to validate these findings and to determine the optimal boost techniques for this patient population.

Atypical induction of HIF-1α expression by pericellular Notch1 signaling suffices for the malignancy of glioblastoma multiforme cells.

Contact-based pericellular interactions play important roles in cancer progression via juxtacrine signaling pathways. The present study revealed that hypoxia-inducible factor-1α (HIF-1α), induced even in non-hypoxic conditions by cell-to-cell contact, was a critical cue responsible for the malignant characteristics of glioblastoma multiforme (GBM) cells through Notch1 signaling. Densely cultured GBM cells showed enhanced viability and resistance to temozolomide (TMZ) compared to GBM cells at a low density. Ablating Notch1 signaling by a γ-secretase inhibitor or siRNA transfection resensitized resistant GBM cells to TMZ treatment and decreased their viability under dense culture conditions. The expression of HIF-1α was significantly elevated in highly dense GBM cells even under non-hypoxic conditions. Atypical HIF-1α expression was associated with the Notch1 signaling pathway in both GBM and glioblastoma stem cells (GSC). Proteasomal degradation of HIF-1α was prevented by binding with Notch1 intracellular domain (NICD), which translocated to the nuclei of GBM cells. Silencing Notch1 signaling using a doxycycline-inducible Notch1 RNA-interfering system or treatment with chetomin, a HIF pathway inhibitor, retarded tumor development with a significant anti-cancer effect in a murine U251-xenograft model. Using GBM patient tissue microarray analysis, a significant increase in HIF-1α expression was identified in the group with Notch1 expression compared to the group without Notch1 expression among those with positive HIF-1α expression. Collectively, these findings highlight the critical role of cell-to-cell contact-dependent signaling in GBM progression. They provide a rationale for targeting HIF-1α signaling even in a non-hypoxic microenvironment.

Efficacy and Safety of Timely Urgent Superficial Temporal Artery-to-Middle Cerebral Artery Bypass Surgery in Patients with Acute Ischemic Stroke: A Single-Institutional Prospective Study and a Pooled Analysis.

BACKGROUND: Clinical outcome in patients with acute ischemic stroke (AIS) caused by large vessel occlusion (LVO) is not satisfactory if reperfusion treatment fails or is not tried. AIMS: We aimed to assess the efficacy and safety of urgent superficial temporal-to-middle cerebral artery (STA-MCA) bypass surgery in selected patients. METHODS: Patients who were diagnosed with LVO-induced AIS in the anterior circulation but had a failed intra-arterial thrombectomy (IAT) or were not tried due to IAT contraindications were prospectively enrolled. Timely urgent STA-MCA bypass surgery was performed if they showed perfusion-diffusion mismatch or symptom-diffusion mismatch in the acute phase of disease. Clinical and radiological data of these patients were assessed to demonstrate the safety and efficacy of urgent bypass procedures. A pooled analysis of published data on urgent bypass surgery in acute stroke patients was conducted and analyzed. RESULTS: In 18 patients who underwent timely bypass, the National Institutes of Health Stroke Scale (NIHSS) score improved from 12.11 ± 4.84 to 9.89 ± 6.52, 1 week after surgery. Three-month and long-term (9.72 ± 5.00 months) favorable outcomes (modified Rankin Scale [mRS] scores 0-2) were achieved in 50 and 75% of the patients, respectively. The pooled analysis (117 patients from 10 articles, including ours) identified favorable mRS scores in 71.79% patients at 3 months. A significant NIHSS score improvement from 11.51 ± 4.89 to 7.59 ± 5.50 was observed after surgery with significance. Major complications occurred in 3 patients (2.6%, 3/117) without mortality. CONCLUSIONS: Urgent STA-MCA bypass surgery can be regarded as a safe optional treatment to prevent cerebral infarct expansion and to improve clinical and radiological outcomes in highly selected patients.

Clinical Features of Patients With Spontaneous Intracranial Hypotension Complicated With Bilateral Subdural Fluid Collections.

BACKGROUND: Subdural hygromas are often found bilaterally in spontaneous intracranial hypotension (SIH). They frequently progress to chronic subdural hematomas (CSDHs), and if the hematomas are formed, it is difficult to consider SIH as an underlying cause. Whether SIH is underlying or not among the patients presenting bilateral subdural fluid collections (hygromas or CSDHs) is clinically important because the treatment strategy should be different between them. OBJECTIVES: We designed a retrospective case-control study to figure out differential clinical features of the patients presenting bilateral symptomatic subdural fluid collections owing to SIH. METHODS: Sixty-two patients with bilateral symptomatic subdural fluid collections were enrolled, and their data on general demographics, clinical courses, radiological findings, treatments, and outcomes were collected. The patients were divided into "SIH" and "Non-SIH" groups, and a simple logistic regression analysis was performed to clarify the differences between the groups. The consequent receiver operating characteristics (ROC) curve analyses were performed with the significant predictors. RESULTS: Eight patients (13%) were diagnosed with SIH. Young age (odds ratio [OR] = 0.831, 95% confidence interval [CI]: 0.743-0.929, P = .0012), no underlying disease (OR = 0.062, 95% CI: 0.007-0.544, P = .0121), radiological features of brain sagging (OR = 10.36, 95% CI: 0.912-93.411, P = .0017), pseudo-subarachnoid hemorrhage (OR = 15.6, 95% CI: 2.088-116.52, P = .0074), and small amount of fluid collections (OR = 0.719, 95% CI: 0.579-0.893, P = .0029) were significantly associated with SIH group. ROC curve analyses were performed in parameters of age and amount of fluid collection and the cut-off values for each parameter were ≤55 years old and ≤22.08 mm, respectively. Patients diagnosed with SIH underwent epidural blood patches and showed good results, except 1 patient who underwent burr-hole trephinations. CONCLUSION: Bilateral subdural fluid collections due to underlying SIH is associated with young age (≤55 years old), no underlying diseases, smaller amount of fluid collections (≤22.08 mm of depth), and radiological findings of brain sagging or pseudo-subarachnoid hemorrhages.

Unexpected Daily Changes in Tumor Volume during Fractionated Gamma Knife Radiosurgery for Solitary Intraventricular Metastatic Renal Cell Carcinoma: A Case Report.

For most fractionated stereotactic radiosurgery treatment plans, daily imaging is not routinely performed, because there is little expectation that lesions will change significantly in the short term. However, here, we present the case of an abrupt increase and decrease in tumor volume during fractionated gamma knife radiosurgery (GKRS) for metastatic brain cancer. A 65-year-old man with a history of nephrectomy due to renal cell carcinoma was admitted to our hospital because of mild cognitive disorder and gait disturbance. An initial MRI of the brain demonstrated a 5 × 3 × 4.5 cm-sized, heterogeneously well-enhanced tumor with a large cystic component compressing the left thalamus and corpus callosum near the lateral ventricle. Owing to its large size and proximity to critical structures, we decided to perform 3 fractionated GKRSs over 3 consecutive days. After the first fraction of 9 Gy with 50% isodose, follow-up MRI the next day revealed an unexpected increase in tumor volume up to 30%. Therefore, the radiosurgical plan was adjusted, and GKRS was performed again using the same dose for the second fraction. The image taken on the third day showed rapid shrinkage of the tumor volume. This case shows that a tumor may change its shape and volume unexpectedly even during the short period of a fractionated GKRS session. Hence, for optimal fractionated GKRS treatment of tumors with the likelihood of an abrupt change in the short term, interval imaging should be considered.

Defining "early" cranioplasty to achieve lower complication rates of bone flap failure: resorption and infection.

BACKGROUND: Although cranioplasty (CP) is a frequently performed and simple procedure, complications are common, particularly bone flap resorption and infection. The timing of surgery is as an important contributory factor, but the optimal timing has not been clearly determined. OBJECTIVE: We retrospectively investigated bone flap resorption and surgical site infection after CP to determine the optimal timing of surgery for reduction of complications. METHODS: The study enrolled 126 patients who underwent decompressive craniectomy (DC) and subsequent CP. Patients with bone flap resorption or surgical site infection were analyzed as the "complication" group. Receiver operating characteristic curve analysis was performed and the Youden index was used to dichotomize "early CP" and "late CP" groups. Univariate and multivariate survival analyses were performed. RESULTS: The complication group included 42 patients. The Youden index was used to identify a cutoff value for the DC-CP interval of > 44 days, and this was used to define early (< 45 days) and late (≥ 45 days) CP. Late CP was a significant risk factor in univariate and multivariate Cox regression analyses. CONCLUSION: This study showed that early CP before 45 days after DC is associated with a lower rate of bone flap resorption and surgical site infection than late CP.

Minimally invasive molecular delivery into the brain using optical modulation of vascular permeability.

Systemic delivery of bioactive molecules in the CNS is hampered by the blood-brain barrier, which has bottlenecked noninvasive physiological study of the brain and the development of CNS drugs. Here we report that irradiation with an ultrashort pulsed laser to the blood vessel wall induces transient leakage of blood plasma without compromising vascular integrity. By combining this method with a systemic injection, we delivered target molecules in various tissues, including the brain cortex. This tool allows minimally invasive local delivery of chemical probes, nanoparticles, and viral vectors into the brain cortex. Furthermore, we demonstrated astrocyte-mediated vasodilation in vivo without opening the skull, using this method to load a calcium indicator in conjunction with label-free photoactivation of astrocytes.

Assessing the Suitability of Artificial Intelligence-Based Chatbots as Counseling Agents for Patients with Brain Tumor: A Comprehensive Survey Analysis.

OBJECTIVE: The internet, particularly social media, has become a popular resource for learning about health and investigating one's own health conditions. The development of artificial intelligence (AI) chatbots has been fueled by the increasing availability of digital health data and advances in natural language processing techniques. While these chatbots are more accessible than before, they sometimes fail to provide accurate information. METHODS: We used representative chatbots currently available (Chat Generative Pretrained Transformer-3.5, Bing Chat, and Google Bard) to answer questions commonly asked by brain tumor patients. The simulated situations with questions were made and selected by the brain tumor committee. These questions are commonly asked by brain tumor patients. The goal of the study was introduced to each chatbot, the situation was explained, and questions were asked. All responses were collected without modification. The answers were shown to the committee members, and they were asked to judge the responses while blinded to the type of chatbot. RESULTS: There was no significant difference in accuracy and communication ability among the 3 groups (P = 0.253, 0.090, respectively). For empathy, Bing Chat and Google Bard were superior to Chat Generative Pretrained Transformer (P = 0.004, 0.002, respectively). The purpose of this study was not to assess or verify the relative superiority of each chatbot. Instead, the aim was to identify the shortcomings and changes needed if AI chatbots are to be used for patient medical purposes. CONCLUSION: AI-based chatbots are a convenient way for patients and the general public to access medical information. Under such circumstances, medical professionals must ensure that the information provided to chatbot users is accurate and safe.

Endoscopic transorbital approach for resection of mediobasal temporal lesions using an optic radiation-sparing strategy.

OBJECTIVE: The endoscopic transorbital approach (ETOA) has emerged as a promising minimally invasive technique for resection of lesions in the mediobasal temporal region (MTR) due to its potential to preserve the integrity of the optic radiation (OR). This study evaluated the safety and efficacy of ETOA using an OR-sparing surgical strategy for mediobasal temporal lesions. METHODS: A retrospective review was conducted of the medical records of 15 patients (7 females and 8 males) who underwent ETOA for lesions in the MTR between November 2017 and November 2022. Preoperative diffusion tensor imaging (DTI) tractography of the OR was utilized in all cases for surgical planning to visualize the spatial relations between the OR and the target mediobasal temporal lesion. RESULTS: The median age of the treated patients was 43 years (range 22-76 years), with a median follow-up duration of 12 months (range 6-35 months). Eleven lesions (73.3%) involved only the anterior segment of the MTR, while 4 lesions (26.7%) affected both the anterior and middle segments. Gross-total resection was achieved in 13 patients (86.7%) and subtotal resection in 2 (13.3%). The final pathologies included low-grade glioma (n = 5), cavernous malformation (n = 3), glioblastoma multiforme (n = 2), multinodular and vacuolating neuronal tumor (n = 1), pleomorphic xanthoastrocytoma (n = 1), anaplastic oligodendroglioma (n = 1), adenoid cystic carcinoma (n = 1), and metastatic renal cell carcinoma (n = 1). Postoperative neuro-ophthalmological examinations revealed that all patients maintained their previous visual function. Follow-up DTI tractography further confirmed the preservation of the preoperative ORs in the treated patients. No postoperative CSF leaks, infections, or cosmetic problems occurred in this series. CONCLUSIONS: The combined use of ETOA and OR tractography appears to be a feasible approach for resecting lesions involving the MTR, especially in the anterior segment. In the authors' experience, this surgical strategy enables maximal safe resection while minimizing the risk of postoperative visual dysfunction. Further studies with larger sample sizes are warranted to validate these findings and assess long-term outcomes.

Nomogram for radiation-induced lymphopenia in patients receiving intensity-modulated radiotherapy based-chemoradiation therapy for newly diagnosed glioblastoma: A multi-institutional study.

Purpose: Severe lymphopenia (SLP) has emerged as a significant prognostic factor in glioblastoma. Intensity-modulated radiation therapy (IMRT)-based radiation therapy (RT) is suggested to minimize the risk of SLP. This study aimed to evaluate SLP incidence based on multi-institutional database in patients with GBM treated with IMRT and develop a predictive nomogram. Patients and methods: This retrospective study reviewed data from 348 patients treated with IMRT-based concurrent chemoradiation therapy (CCRT) at two major hospitals from 2016 to 2021. After multivariate regression analysis, a nomogram was developed and internally validated to predict SLP risk. Results: During treatment course, 21.0% of patients developed SLP and SLP was associated with poor overall survival outcomes in patients with GBM. A newly developed nomogram, incorporating gender, pre-CCRT absolute lymphocyte count, and brain mean dose, demonstrated fair predictive accuracy (AUC 0.723). Conclusions: This study provides the first nomogram for predicting SLP in patients with GBM treated with IMRT-based CCRT, with acceptable predictive accuracy. The findings underscore the need for dose optimization and radiation planning to minimize SLP risk. Further external validation is crucial for adopting this nomogram in clinical practice.

Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM).

PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.

Potential Risk of Choline Alfoscerate on Isoflurane-Induced Toxicity in Primary Human Astrocytes.

Objective: Isoflurane, a widely used common inhalational anesthetic agent, can induce brain toxicity. The challenge lies in protecting neurologically compromised patients from neurotoxic anesthetics. Choline alfoscerate (L-α-Glycerophosphorylcholine, α-GPC) is recognized for its neuroprotective properties against oxidative stress and inflammation, but its optimal therapeutic window and indications are still under investigation. This study explores the impact of α-GPC on human astrocytes, the most abundant cells in the brain that protect against oxidative stress, under isoflurane exposure. Methods: This study was designed to examine changes in factors related to isoflurane-induced toxicity following α-GPC administration. Primary human astrocytes were pretreated with varying doses of α-GPC (ranging from 0.1 to 10.0 µM) for 24 hours prior to 2.5% isoflurane exposure. In vitro analysis of cell morphology, water-soluble tetrazolium salt-1 assay, quantitative real-time polymerase chain reaction, proteome profiler array, and transcriptome sequencing were conducted. Results: A significant morphological damage to human astrocytes was observed in the group that had been pretreated with 10.0 mM of α-GPC and exposed to 2.5% isoflurane. A decrease in cell viability was identified in the group pretreated with 10.0 µM of α-GPC and exposed to 2.5% isoflurane compared to the group exposed only to 2.5% isoflurane. Quantitative real-time polymerase chain reaction revealed that mRNA expression of heme-oxygenase 1 and hypoxia-inducible factor-1α, which were reduced by isoflurane, was further suppressed by 10.0 µM α-GPC pretreatment. The proteome profiler array demonstrated that α-GPC pretreatment influenced a variety of factors associated with apoptosis induced by oxidative stress. Additionally, transcriptome sequencing identified pathways significantly related to changes in isoflurane-induced toxicity caused by α-GPC pretreatment. Conclusion: The findings suggest that α-GPC pretreatment could potentially enhance the vulnerability of primary human astrocytes to isoflurane-induced toxicity by diminishing the expression of antioxidant factors, potentially leading to amplified cell damage.

Fibronectin Type III Domain Containing 3B as a Potential Prognostic and Therapeutic Biomarker for Glioblastoma.

Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and resistance to anticancer therapy. In this report, we explore the role of fibronectin type III domain containing 3B (FNDC3B) and its potential as a prognostic and therapeutic biomarker in GBM. GBM exhibited a significantly higher cancer-to-normal ratio compared to other organs, and patients with high FNDC3B expression had a poor prognosis (p < 0.01). In vitro studies revealed that silencing FNDC3B significantly reduced the expression of Survivin, an apoptosis inhibitor, and also reduced cell migration, invasion, extracellular matrix adhesion ability, and stem cell properties in GBM cells. Furthermore, we identified that FNDC3B regulates PTEN/PI3K/Akt signaling in GBM cells using MetaCore integrated pathway bioinformatics analysis and a proteome profiler phospho-kinase array with sequential western blot analysis. Collectively, our findings suggest FNDC3B as a potential biomarker for predicting GBM patient survival and for the development of treatment strategies for GBM.

Treatment Outcomes after Dose-Escalated Moderately Hypofractionated Radiotherapy for Frail Patients with High-Grade Glioma.

For high-grade glioma (HGG) patients with old age or poor performance status, hypofractionated radiotherapy (hypoRT) in 10-15 fractions is recommended. Also, limited data exist on the impact of salvage treatment after progression in frail patients. We retrospectively analyzed the outcomes of dose-escalated hypoRT in 40 frail HGG patients who were treated with hypoRT between 2013 and 2021. With a median biologically effective dose of 71.7 Gy, a total dose of 56 Gy in 20 fractions was the most frequently used regimen (53.7%). The median age and Karnofsky Performance Status of patients were 74 years and 70, respectively. Most patients (n = 31, 77.5%) were diagnosed with glioblastoma, IDH-wildtype, CNS WHO grade 4. Only 10 (25.0%) patients underwent surgical resection, and 28 (70.0%) patients received concurrent temozolomide during hypoRT. With a median follow-up of 9.7 months, the median overall survival (OS) was 12.2 months. Of the 30 (75.0%) patients with disease progression, only 12 patients received salvage treatment. The OS after progression differed significantly depending on salvage treatment (median OS, 9.6 vs. 4.6 months, p = 0.032). Dose-escalated hypoRT in 20 fractions produced survival outcomes outperforming historical data for frail patients.

Radiomic features define risk and are linked to DNA methylation attributes in primary CNS lymphoma.

Background: The prognostic roles of clinical and laboratory markers have been exploited to model risk in patients with primary CNS lymphoma, but these approaches do not fully explain the observed variation in outcome. To date, neuroimaging or molecular information is not used. The aim of this study was to determine the utility of radiomic features to capture clinically relevant phenotypes, and to link those to molecular profiles for enhanced risk stratification. Methods: In this retrospective study, we investigated 133 patients across 9 sites in Austria (2005-2018) and an external validation site in South Korea (44 patients, 2013-2016). We used T1-weighted contrast-enhanced MRI and an L1-norm regularized Cox proportional hazard model to derive a radiomic risk score. We integrated radiomic features with DNA methylation profiles using machine learning-based prediction, and validated the most relevant biological associations in tissues and cell lines. Results: The radiomic risk score, consisting of 20 mostly textural features, was a strong and independent predictor of survival (multivariate hazard ratio = 6.56 [3.64-11.81]) that remained valid in the external validation cohort. Radiomic features captured gene regulatory differences such as in BCL6 binding activity, which was put forth as testable treatment target for a subset of patients. Conclusions: The radiomic risk score was a robust and complementary predictor of survival and reflected characteristics in underlying DNA methylation patterns. Leveraging imaging phenotypes to assess risk and inform epigenetic treatment targets provides a concept on which to advance prognostic modeling and precision therapy for this aggressive cancer.

Differential dependency of human glioblastoma cells on vascular endothelial growth factor­A signaling via neuropilin­1.

Despite the high expression of neuropilin­1 (NRP­1) in human glioblastoma (GB), the understanding of its function as a co­receptor of vascular endothelial growth factor receptors (VEGFRs) in angiogenesis is currently limited. Therefore, the aim of the present study was to elucidate the non­classical function of NRP­1 expression in human GB. Expression patterns of NRP­1 and VEGF­A were determined by sandwich ELISA, western blot analysis, or immunohistochemistry. Differential dependency of GB cells following ablation of VEGF­A signaling was validated in vitro and in vivo. Cellular mechanism responsible for distinct response to VEGF­A signaling was evaluated by western blotting and immunoprecipitation analysis. Prognostic implications were assessed using IHC analysis. GB cells exhibited differing sensitivity to silencing of vascular endothelial growth factor (VEGF)­A signaling, which resulted in a distinct expression pattern of wild­type or chondroitin­sulfated NRP­1. VEGF­A­sensitive GB exhibited the physical interaction between wild­type NRP­1 and FMS related receptor tyrosine kinase 1 (Flt­1) whereas VEGF­A­resistant GB exhibited chondroitin­sulfated NRP­1 without interaction with Flt­1. Eliminating the chondroitin sulfate modification in NRP­1 led to re­sensitization to VEGF­A signaling, and chondroitin sulfate modification was found to be associated with an adverse prognosis in patients with GB. The present study identified the distinct functions of NRP­1 in VEGF­A signaling in accordance with its unique expression type and interaction with Flt­1. The present research is expected to provide a strong basis for targeting VEGF­A signaling in patients with GB, with variable responses.