Learning about Neurosurgery and Neurology

11/11/2025

https://www.nature.com/articles/s41598-025-25708-8

New study from our team published in Scientific Reports. Mechanistic studies are following.

An inverse association between the use of platelet inhibitors and the risk of cancer has been reported by numerous epidemiological studies in the past. The effects of antiplatelet agents on the cerebral metastasis formation of non-small cell lung cancer (NSCLC) are largely unknown. We therefore, inv...

11/11/2025

🧠 Selected and debated clinical studies in neuro-oncology (as of 2025)

Studies that have generated scientific, clinical, or ethical controversy — due to design limitations, non-reproducible results, translational gaps, or high public attention.

1. EF-14 Trial (Tumor Treating Fields – TTFields in Glioblastoma)

Publication: Stupp et al., JAMA 2017
Design: Phase III randomized trial evaluating TTFields + temozolomide vs. temozolomide alone in newly diagnosed glioblastoma.
Controversy: Demonstrated improved median survival (20.9 vs. 16.0 months), but lack of blinding, limited external validity, unclear mechanistic basis, and very high cost (>€20,000/month).
Discussion: In Europe, adoption has been cautious; in the U.S., rapid integration and commercial promotion.
Status 2025: Standard of care for newly diagnosed glioblastoma and CNS WHO grade 4 astrocytoma, though long-term real-world adherence remains variable.

2. CheckMate 498 & 548 (Nivolumab in Glioblastoma)

Publications: Lim et al., Neuro-Oncology 2022; Omuro et al., Neuro-Oncology 2023
Design: Phase III trials of PD-1 blockade (nivolumab) in newly diagnosed glioblastoma (MGMT-methylated vs. unmethylated).
Controversy: No improvement in overall survival.
Discussion: Checkpoint inhibition remains largely ineffective in “cold” tumors like GBM.
Nonetheless, the trials fuel persistent public and patient optimism about immunotherapy.
Note: Pre-operative or neoadjuvant checkpoint blockade remains experimental; off-label requests continue.

3. NOA-16 (IDH1 Peptide Vaccine in Astrocytoma WHO Grade 2/3)

Publication: Platten et al., Nature 2021
Design: Phase I/II study on safety and immunogenicity of an IDH1(R132H)-targeted vaccine.
Controversy: Highly promising immunogenic results but no proven survival benefit. The trial sparked media overenthusiasm, leading to unrealistic patient expectations of a “cancer vaccine.”
Discussion: Valuable scientific proof of principle, but still translationally premature for broad clinical use.

4. CODEL vs. CATNON (Therapy Strategies in IDH-Mutant Grade 3 Gliomas)

Publications: CATNON: van den Bent et al., NEJM 2017; CODEL: ongoing (ASCO abstracts)
Design: Comparative trials evaluating PCV vs. temozolomide in IDH-mutant anaplastic gliomas.
Controversy: CATNON showed temozolomide benefit but did not account for IDH mutation; CODEL challenges the role of temozolomide in favor of PCV.
Discussion: Discordance between guidelines and real-world practice; significant inter-center variation in treatment choice.

5. German Glioma Network (MGMT Promoter Methylation Substudies)

Publications: e.g., Weller et al., JCO 2015
Design: Translational analyses of MGMT promoter methylation as a predictive biomarker for temozolomide efficacy.
Controversy: MGMT is a well-established marker, but test reproducibility varies between labs; cutoff thresholds are inconsistent.
Discussion: Debate continues whether MGMT is predictive only or also prognostic.
Clinical dilemma: “Borderline MGMT” cases—should temozolomide be offered?

6. Real-World Personalized Neoantigen Peptide Vaccine (Nature Communications 2024)

Publication: Latzer et al., Nature Communications 2024
Design: Retrospective real-world analysis of 173 GBM patients receiving personalized neoantigen-derived peptide vaccines (Germany, 2015–2023).
Findings:

Median overall survival: 31.9 months; 54% of patients alive at cutoff.

Strong vaccine-induced T-cell responses in 90% of monitored patients.

Patients with robust immune responses (immunological responders) achieved median OS of 53 months vs. 27 months in non-responders.

Minimal toxicity (mostly Grade 1–2).
Controversy:

Non-randomized design; self-selected and self-funded cohort.

Confounding by socioeconomic bias and selection of long survivors.

No control arm; only propensity-matched comparison with historical datasets.
Discussion: Despite methodological limitations, this large-scale real-world dataset rekindles enthusiasm for personalized vaccine approaches.
However, experts urge caution until prospective randomized trials confirm causality.

7. ACT IV (Rindopepimut – EGFRvIII Vaccine in Glioblastoma)

Publication: Weller et al., Lancet Oncology 2017
Design: Phase III, double-blind, randomized trial of an EGFRvIII-targeted vaccine plus standard therapy in newly diagnosed EGFRvIII-positive GBM.
Controversy: The trial was terminated early due to futility—no difference in survival.
Discussion: Highlighted the heterogeneity and immune escape of glioblastoma; many tumor cells lose EGFRvIII expression during therapy.
Lesson: “Target loss” and intra-tumoral evolution remain major challenges in glioma immunotherapy.

8. BELOB / EORTC 26101 (Bevacizumab in Recurrent Glioblastoma)

Publications: Taal et al., Lancet Oncology 2014; Wick et al., Lancet Oncology 2017
Design: Phase II–III studies of bevacizumab ± lomustine in recurrent glioblastoma.
Controversy: Improved progression-free survival, but no overall survival benefit.
Discussion: Bevacizumab remains widely used for symptom control (reducing edema, steroid-sparing) but lacks disease-modifying effect.
Ethical discussion: Costly therapy with limited benefit — still part of individualized salvage therapy in 2025.

9. GAPVAC-101 (Actively Personalized Vaccine in Newly Diagnosed GBM)

Publication: Hilf et al., Nature 2019
Design: Phase I personalized multi-peptide vaccine (mutated + non-mutated antigens) in 15 patients post-chemoradiation.
Results:

Feasible production within 12 weeks.

Induced broad T-cell responses.

Median PFS: 14.2 months; median OS: 29 months.
Discussion: Landmark early trial for active personalization — technically feasible but complex and costly; remains a prototype concept for individualized immunotherapy.

10. H3K27M Vaccine in Diffuse Midline Glioma

Publication: Grassl et al., Nature Medicine 2023
Design: Compassionate-use study of an H3K27M-targeted peptide vaccine in adult diffuse midline glioma.
Findings: Strong tumor-specific T-cell responses; early signals of clinical benefit.
Controversy: Small uncontrolled cohort (n=8); heterogeneous background therapy.
Discussion: One of the few promising vaccine strategies for midline gliomas; supports ongoing immunotherapy trials in pediatric-type tumors.

Summary and Outlook (2025)

The field of neuro-oncological immunotherapy is undergoing a paradigm shift:

From standard cytotoxic and radiation-based regimens toward individualized molecular and immunologic strategies.

Yet, most trials show biological activity without robust survival benefit.

Major challenges: patient selection, biomarker validation, tumor heterogeneity, and trial design.

Consensus (2025):
Clinical translation of glioma vaccines and immunotherapies requires controlled, biomarker-guided, randomized studies and international collaboration to move from “promising signals” to true standards of care.

07/11/2025

Citation: Chih YC et al. Nature Communications 2025;16:1262.
Topic: Vaccine-induced TCR-T cells targeting PTPRZ1, a glioblastoma stemness antigen.

Why it matters: Glioblastoma (GBM) resists standard therapies. TCR-engineered T cells can recognize intracellular tumor antigens presented on HLA, potentially overcoming some CAR-T limitations.

What the team did

Identified an HLA-A*02–restricted, PTPRZ1-reactive TCR from a vaccinated GBM patient.

Confirmed PTPRZ1 overexpression in malignant GBM cells—especially glioblastoma stem cells (GSCs) and astrocyte-like tumor cells—via bulk and single-cell datasets.

Engineered PTPRZ1-TCR-T cells and tested:

In vitro: Specific killing of all tested HLA-A*02+ primary GBM lines, with preference for GSC/AC-like states; minimal off-target reactivity.

In vivo (mice): Combined i.v. + intracerebroventricular (ICV) delivery was efficacious in brain tumor models.

Patient tumor organoids (IPTOs): Treatment reduced malignant cell fraction, lowered PTPRZ1 levels, and depleted GSC and AC-like populations.

Key mechanistic/validation points

Antigen dependency: CRISPR PTPRZ1 knock-down (~60%) abolished TCR-T killing, confirming on-target action.

Phenotype: TCR-T cells retained stem-cell memory traits (linked to persistence).

CD4+ component enhanced cytotoxicity and cytokine support.

Safety screen: In-silico/off-target filtering found no problematic cross-reactivity (preclinical).

Limitations & next steps

Preclinical study; HLA-A*02 restriction limits immediate generalizability.

Potential for antigen loss; multivalent TCR repertoires may be needed.

A first-in-human Phase I trial (INVENT4GB) with i.v. + ICV CD4+/CD8+ PTPRZ1-TCR-T is planned to assess feasibility/safety in recurrent GBM.

Takeaway: Proof-of-concept that PTPRZ1-specific TCR-T can selectively debulk GBM stem-like compartments and reshape tumor cell states—supporting clinical translation of TCR-T in GBM.

05/11/2025

Neuro-Oncology Update – Weekly Blog
Perioperative IDH Inhibition in Untreated IDH-Mutant Glioma (Nature Medicine, 2025)

Drummond KJ et al., Nature Medicine, 2025; 31: 3451–3463
ClinicalTrials.gov: NCT05577416

This pilot phase I perioperative study investigated safusidenib (AB-218/DS-1001b), an oral inhibitor of mutant IDH1, in treatment-naive WHO grade 2 IDH-mutant gliomas.

➡️ Study design:

10 patients with IDH1-mutant low-grade gliomas, no prior radiotherapy or chemotherapy

Two-step perioperative design: diagnostic biopsy → 22–36 days of safusidenib → surgical resection

Ongoing postoperative therapy and monitoring

➡️ Main findings:

Feasibility and safety confirmed: 9/10 patients tolerated therapy well; one serious surgery-related event.

Most adverse effects were mild (Grade 1) — fatigue, rash, mild joint pain. One patient had reversible Grade 3 liver enzyme elevation.

Pharmacodynamic proof of target engagement: significant reduction in the oncometabolite 2-hydroxyglutarate (2-HG) and alterations in tumor differentiation and excitability.

Electrophysiological studies confirmed changes in tumor cell function after treatment.

➡️ Interpretation:
This is the first perioperative trial demonstrating that short-term mutant IDH1 inhibition before surgery is safe, biologically active, and feasible in untreated low-grade gliomas.
The design enables direct comparison of pre- and post-treatment tumor tissue, offering new insights into mechanisms of resistance and adaptation.

Conclusion:
Safusidenib effectively targets the metabolic hallmark of IDH-mutant gliomas and sets the stage for larger, biomarker-driven trial

30/10/2025

TERT Expression and Prognosis in Meningiomas – Insights from a Multi-Institutional Cohort Study

(Gui et al., The Lancet Oncology, 2025; Vol. 26, Issue 9, pp. 1191–1203)

A new large-scale analysis from Toronto Western Hospital and collaborating centers across Canada, Germany, and the USA provides crucial insights into the role of TERT activation in meningiomas.

While TERT promoter mutations are known to drive aggressive tumor behavior and early recurrence, this study reveals that high TERT expression can occur even in tumors without these mutations — and still predicts worse clinical outcomes.

➡️ Study design:

Retrospective multi-institutional cohort of 1,241 resected meningiomas (2000–2024)

Assessment of TERT promoter mutation (Sanger sequencing) and TERT mRNA expression (RNA-seq)

Two cohorts: Discovery (n=380, Toronto) and Validation (n=861, international)

➡️ Key findings:

TERT expression was detected in ~30% of meningiomas overall, including ~29% of tumors with wildtype (non-mutated) TERT promoters.

Progression-free survival (PFS):

TERT-negative tumors (wildtype): ~16 years

TERT-expressing tumors (wildtype): ~3.2 years

TERT promoter-mutated tumors: ~1.6 years

TERT expression was an independent predictor of shorter PFS, even after controlling for WHO grade, CDKN2A/B loss, and chromosomal alterations (HR 1.85; p = 0.0002).

Within each WHO grade, TERT-positive tumors behaved like tumors one grade higher (e.g., grade 1 → grade 2 behavior).

➡️ Clinical relevance:
These findings challenge current classification systems:
Meningiomas with TERT expression — even without promoter mutation — show biologically more aggressive behavior and may require closer follow-up or adjuvant therapy.

Conclusion:
TERT activation emerges as a robust molecular marker of progression in meningioma. Incorporating TERT expression status into future WHO grading frameworks could refine prognostication and guide treatment intensity.

📄 Reference:
Gui C et al. Analysis of TERT association with clinical outcome in meningiomas: a multi-institutional cohort study. The Lancet Oncology. 2025; 26(9): 1191–1203.

30/10/2025

https://www.youtube.com/watch?v=qpmm1D5X2Ao

The prestigious European Lecture Award for an exceptional and practice-changing contribution to neurosurgery was presented to Professor Jürgen Beck. His grou...

23/10/2025

Tumor Treating Fields (TTFields) in Glioblastoma

(Last updated: October 2025)

🔹 What are Tumor Treating Fields (TTFields)?

Tumor Treating Fields (TTFields, also known as Optune® therapy) are a non-invasive, complementary treatment for patients with glioblastoma.
They use low-intensity, alternating electric fields to disrupt the growth and division of tumor cells, while leaving healthy brain tissue largely unaffected.
TTFields are typically applied after surgery, radiotherapy, and chemotherapy (temozolomide) as part of maintenance therapy.

⚙️ How does the therapy work?
🧩 The process of cell division in the brain

All cells divide to grow and repair tissue.
Tumor cells, however, divide uncontrollably and at a much faster rate, leading to tumor growth.
During division (mitosis), the cell must organize internal structures – especially microtubules, which pull apart the genetic material to form two new cells.

⚡ The mechanism of TTFields

TTFields deliver alternating electric fields at intermediate frequencies (around 200 kHz) directly to the tumor region in the brain.
These fields interfere with mitosis in several ways:

Disruption of microtubule formation:
The electric fields act on charged proteins (e.g., tubulin), preventing proper assembly of the mitotic spindle.
→ The cell cannot complete division and undergoes programmed cell death.

Polarization forces during mitosis:
Differences in electrical charge inside the dividing cell cause physical stress when exposed to TTFields.
→ This mechanical force can damage tumor cells and trigger apoptosis.

Selective effect:
Healthy brain cells are rarely dividing and remain unaffected.
TTFields act specifically on rapidly dividing tumor cells, minimizing systemic side effects.

🕒 How long and how often is the device worn?

TTFields therapy is used daily, ideally for at least 18 hours per day.

Short breaks (e.g., for showering or scalp care) are perfectly fine.

Treatment duration usually spans several months up to a year or longer, depending on response and tolerance.

The system is lightweight and portable (approx. 1.2 kg).
It runs on batteries or AC power and can be worn discreetly in a backpack or shoulder bag during normal daily activities.

📊 Scientific evidence
Study Year n Main result
EF-14 (Stupp et al., JAMA 2017) 695 +4.9 months median overall survival (20.9 vs 16.0 months)
Taphoorn et al., JAMA Oncol 2018 315 No decline in quality of life
Mrugala et al., Semin Oncol 2014 457 20 % long-term survivors > 2 years
Wick et al., Neuro-Oncol Pract 2022 – Confirmed efficacy and safety in real-world use
💡 Benefits of TTFields therapy

Proven survival advantage with maintained quality of life

No systemic side effects (no nausea, fatigue, or blood count changes)

Localized, targeted action within the brain tumor region

Compatible with chemotherapy and bevacizumab

Preserves cognitive function and daily independence

🌞 Everyday life & practical tips
Scalp care

Inspect scalp regularly, especially beneath the arrays.

Use pH-neutral, alcohol-free cleansing and moisturizing products.

Replace the transducer arrays every 3–4 days; allow the skin to recover if irritated.

Shave the scalp regularly to ensure good contact.

Device handling & mobility

Change batteries every 4–6 hours or use wall power when resting.

Remove arrays for showering or swimming; reapply after drying the scalp.

The system is air-travel approved – it can be carried in hand luggage.

Social and emotional aspects

The visible device can feel unusual at first but soon becomes routine.

Many patients describe TTFields as a way to actively participate in their therapy.

Support groups (e.g., Deutsche Hirntumorhilfe or international networks) can provide valuable encouragement.

⚠️ Possible side effects

Most common: mild to moderate local skin irritation (redness, itching, or discomfort)
→ Usually well manageable with proper care and short pauses.

Rare: superficial infection from poor hygiene or prolonged irritation.

No systemic side effects have been observed.

👥 Who is eligible for TTFields therapy?

Adults with newly diagnosed glioblastoma after completion of chemoradiation

Good overall condition (Karnofsky ≥ 70 %)

Willingness to wear the device consistently

Treatment eligibility is discussed within an interdisciplinary tumor board (neuro-oncology, neurosurgery, radiation oncology, palliative care).

📚 Further information

Websites

www.optunetherapy.com

www.novocure.com

www.neuroonkologie-heilversuch.de

Key scientific references

Stupp R et al., JAMA 2017

Taphoorn M et al., JAMA Oncology 2018

Kirson E et al., Cancer Research 2007

Mun E et al., Neuro-Oncology 2018

Wick W et al., Neuro-Oncol Pract 2022

Brem S et al., Frontiers in Oncology 2023

🔎 Summary

Tumor Treating Fields represent a well-established, scientifically validated, and non-invasive therapy for glioblastoma.
They extend survival, maintain quality of life, and can be safely integrated into daily routines.
The more consistently the device is worn, the greater the potential benefit.

Evidenzbasierte Informationen zu Heilversuchen in der Neuroonkologie für Ärzte und Patienten.

23/10/2025

Regorafenib and Other RTK Inhibitors (RTKIs): Mechanism, Evidence in Glioblastoma, and Clinical Considerations

Mechanism of Action
Regorafenib is an oral multi-kinase inhibitor that targets several receptor tyrosine kinases (RTKs) involved in tumor growth, angiogenesis, and cell survival.
It inhibits pathways such as VEGFR, PDGFR, FGFR, KIT, RET, and RAF, thereby reducing tumor vascularization and proliferation.
Other RTK inhibitors with overlapping or related targets include Lenvatinib, Sorafenib, Sunitinib, and Cabozantinib.

Evidence in Glioblastoma

Regorafenib has shown modest but clinically relevant activity in recurrent glioblastoma.

The REGOMA trial (Lancet Oncol. 2019) demonstrated improved overall survival compared with lomustine (median OS ~7.4 vs. 5.6 months).

Responses are typically radiographic and temporary, but some patients experience significant stabilization or symptom improvement.

Based on REGOMA, EANO guidelines consider regorafenib a reasonable option in recurrent glioblastoma, especially when other treatments have failed.

Other RTK inhibitors (e.g., lenvatinib, cabozantinib) are still being studied; results have been mixed, and no clear survival advantage has been proven so far.

Use in Radiation Necrosis
RTKIs are not routinely used for radiation necrosis, as their anti-edema effect is weaker than bevacizumab. However, in individual cases with strong angiogenic activity, limited benefit might be observed.

Corticosteroid-Sparing Effect
Regorafenib may indirectly reduce the need for corticosteroids by decreasing peritumoral edema and vascular permeability, but this effect is less pronounced than with bevacizumab.

Tolerability and Side Effects
Common adverse effects include fatigue, hypertension, hand–foot skin reaction, diarrhea, mucositis, and elevated liver enzymes. Dose adjustments are often needed. Regular monitoring is essential.

Summary

Type: Oral multi-target tyrosine kinase inhibitor (anti-angiogenic and anti-proliferative)

Main indication: Recurrent glioblastoma (based on REGOMA trial)

Effect: Modest survival benefit; some radiographic and symptomatic improvement

Steroid-sparing: Possible, but weaker than bevacizumab

Common side effects: Hypertension, fatigue, skin toxicity, diarrhea, liver enzyme elevation

22/10/2025

🔔Registration is open!

👉Celebrating the birthday of Prof. Lars Leksell, also known as the “father of Radiosurgery”, we invite you to Brussels from 21-22 November for the second edition of the symposium on Radiosurgery, organized by the EANS Section of Radiosurgery.

🔎The World Radiosurgery Day Symposium - Multidisciplinary Insights into the Spectrum of Neurosurgical Pathologies, Brussels, Belgium 21/11/2025 - 22/11/2025, has been accredited by the European Accreditation Council for Continuing Medical Education (EACCME®) with 15.5 European CME credits (ECMEC®s).

Attendees will have the opportunity to:
🔹engage with pioneers in the field
🔹share insights, and
🔹discuss the practical challenges and opportunities that arise in the application of advanced radiosurgical techniques.

Register now!
🔗https://www.eans.org/page/2025_World_Radiosurgery_Day_Symposium

21/10/2025

Bevacizumab (Avastin®): Mechanism, Evidence in Glioblastoma and Radiation Necrosis, and Corticosteroid-Sparing Effect
Mechanism of Action
Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF). By blocking VEGF, it inhibits the formation of new blood vessels (angiogenesis) that tumors need to grow and maintain their blood supply. In brain tumors, this also helps reduce abnormal vascular permeability and swelling (edema).

Evidence in Glioblastoma
Bevacizumab is not a curative treatment for glioblastoma but may provide symptomatic and radiographic improvement.

Clinical trials (e.g., AVAglio, RTOG 0825) showed that bevacizumab can prolong progression-free survival (PFS) but does not significantly improve overall survival (OS).

It can improve or stabilize neurological symptoms and quality of life in some patients with recurrent glioblastoma.

The main benefit is often related to the reduction of tumor-associated edema and mass effect.

Use in Radiation Necrosis
In patients with radiation necrosis, bevacizumab can significantly reduce brain swelling and contrast enhancement on MRI. This is because it decreases vascular leakage and inflammation, leading to clinical improvement in symptoms such as headache, cognitive changes, or focal deficits.

Corticosteroid-Sparing Effect
Bevacizumab often allows a reduction or discontinuation of corticosteroids (like dexamethasone), which are commonly used to control brain edema. This “steroid-sparing” effect is important because long-term corticosteroid use can cause side effects such as muscle weakness, infection risk, mood changes, and metabolic issues.

Summary

Type: Anti-VEGF monoclonal antibody (anti-angiogenic therapy)

Main effects: Reduces edema, improves neurological symptoms, may delay progression

Evidence: Improves PFS but not OS in glioblastoma; effective in radiation necrosis

Additional benefit: Reduces steroid dependence and improves quality of life in selected patients

19/10/2025

CAR T cell therapy in glioblastoma – lessons from a decade of trials

📖 Begley SL et al., Molecular Therapy 2025; 33(6): 2454-2461.
🔗 DOI: 10.1016/j.ymthe.2025.03.004

🧠 CAR T cells are entering neuro-oncology.
Between 2015 and 2024, ten phase I trials tested CAR T therapy in recurrent GBM—targeting IL13Rα2, EGFRvIII, and HER2.

📊 Key insights:
• Safe intracranial (ICV/ICT) administration, but variable efficacy
• Occasional transient radiographic responses and cytokine activation
• Challenges: antigen heterogeneity, immunosuppressive microenvironment, and limited persistence
• Next gen approaches: dual-target CARs (EGFR + IL13Rα2), armored CARs blocking TGF-β signaling, and memory-enriched T cells

🚀 Future:
CAR T therapy remains early-phase but represents the next frontier of precision immunotherapy for GBM — linking molecular targets with locoregional delivery and translational innovation.