Radiation-induced amphiregulin drives tumour metastasis

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Amphiregulin (AREG)

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Amphiregulin (AREG) is a transmembrane glycoprotein and a member of the epidermal growth factor (EGF) family. It functions primarily as a ligand for the epidermal growth factor receptor (EGFR).

General Characteristics

  • Protein type: Transmembrane, EGF-like growth factor
  • Gene: AREG (Chromosome 4q13.3)
  • Activation: Cleaved by metalloproteases (e.g., ADAM17) to release soluble form
  • Receptor binding: Binds EGFR (ErbB1/HER1)

Biological Functions

  • Promotes cell proliferation, survival, and migration
  • Involved in organ development (lung, mammary gland)
  • Key role in wound healing and epithelial regeneration
  • Modulates immune responses and inflammation

Role in Cancer

AREG is frequently upregulated in various cancers and is associated with:

Key Finding (Nature, 2025)

1)

  • Title: Radiation-induced amphiregulin drives tumour metastasis
  • Main result: Radiotherapy induces AREG expression in tumor cells, which activates EGFR on myeloid cells → immunosuppression and reduced phagocytosis, facilitating distant metastasis.
  • Therapeutic implication: Combining radiotherapy with AREG/EGFR inhibitor may improve metastatic control.

Signaling Pathways

Clinical Relevance

Background

Radiotherapy (RT) is a key modality in cancer treatment, traditionally associated with local tumor control and systemic immune activation (e.g., the abscopal effect). However, the pro-metastatic potential of RT is underexplored.

This study identifies amphiregulin (AREG) as a critical factor induced by RT that promotes distant metastasis by reprogramming EGFR-positive myeloid cells into an immunosuppressive phenotype.

Key Findings

  • RT induces expression of AREG in tumor cells.
  • AREG acts on EGFR-expressing myeloid cells, inhibiting phagocytosis.
  • This reprogramming suppresses immune surveillance and supports distant metastatic outgrowth.
  • Inhibition of AREG or EGFR reduces metastasis in preclinical models.

Strengths

  • Mechanistic insight: RT ➝ AREG ➝ EGFR+ myeloid cells ➝ immunosuppression ➝ metastasis.
  • Multimodal design: Combines in vitro, in vivo, and clinical observations.
  • Translational relevance: Suggests therapeutic potential of AREG or EGFR blockade post-RT.
  • Paradigm shift: Challenges the assumption that RT is solely antitumoral.

Limitations

  • Tumor heterogeneity not addressed: Unclear whether the mechanism is universal across tumor types.
  • Simplified immunological view: Focuses on myeloid cells; limited analysis of T-cell responses.
  • Lacks clinical trial data: Proposes interventions not yet validated in humans.
  • Short-term perspective: No data on long-term effects of AREG inhibition (e.g., on wound healing).
  • Potential oversimplification: Other radiation-induced cytokines may also contribute to metastasis.

Clinical Implications

  • Reframes RT as a double-edged sword: antitumoral locally, potentially protumoral systemically.
  • Encourages exploration of RT + anti-EGFR/anti-AREG combinations.
  • Reinforces the importance of immune monitoring during radiotherapy.

Conclusion

This study presents robust evidence that RT can promote metastasis via radiation-induced AREG, which suppresses innate immunity. It introduces a compelling mechanism with therapeutic and conceptual implications, though further clinical validation is needed.

Related Topics

1)

Piffkó A, Yang K, Panda A, Heide J, Tesak K, Wen C, Zawieracz K, Wang L, Naccasha EZ, Bugno J, Fu Y, Chen D, Donle L, Lengyel E, Tilley DG, Mack M, Rock RS, Chmura SJ, Vokes EE, He C, Pitroda SP, Liang HL, Weichselbaum RR. Radiation-induced amphiregulin drives tumour metastasis. Nature. 2025 May 14. doi: 10.1038/s41586-025-08994-0. Epub ahead of print. PMID: 40369065.

Congress of Neurological Surgeons Guidelines

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Congress of Neurological Surgeons Guidelines

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https://www.cns.org/guidelines/browse-guidelines

Congress of neurological surgeons systematic review and evidence-based guidelines for the role of imaging in newly diagnosed WHO grade II diffuse glioma in adults: update 1)

Updated Emerging Therapies Chapter! Brain Tumor Treatment Guidelines of adults with brain metastases Developer: Congress of Neurological Surgeons

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Chiari Malformation Developer: Congress of Neurological Surgeons

Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines Developer: Brain Trauma Foundation

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Perioperative Spine: Preoperative Sponsored by: Congress of Neurological Surgeons (CNS) and the Section on Disorders of the Spine and Peripheral Nerves

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Deep Brain Stimulation for Obsessive Compulsive Disorder: Update of the 2014 Guidelines Developer: Congress of Neurological Surgeons

Guidelines on Neuroablative Procedures for Patients with Cancer Pain Developer: Congress of Neurological Surgeons

Pediatric Hydrocephalus: Systematic Literature Review and Evidence-based Guidelines Developer: Congress of Neurological Surgeons

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Pediatric Myelomeningocele Developer: Congress of Neurological Surgeons

Guidelines on the Evaluation and Treatment of Patients with Thoracolumbar Spine Trauma Developer: Congress of Neurological Surgeons

Guidelines on Subthalamic Nucleus and Globus Pallidus Internus Deep Brain Stimulation for the Treatment of Patients with Parkinson Developer: Congress of Neurological Surgeons

Guidelines on the Management of Patients with Vestibular Schwannoma Developer: Congress of Neurological Surgeons

Guidelines for the Management of Severe Traumatic Brain Injury, 4th ed. Brain Trauma Foundation Severe Traumatic Brain Injury

Guidelines on the Management of Patients with Nonfunctioning Pituitary Adenomas Developer: Congress of Neurological Surgeons

Guidelines for the Management of Patients With Positional Plagiocephaly Developer: Congress of Neurological Surgeons

2020 Update of the Decompressive Craniectomy Recommendations in Guidelines for the Management of Severe Traumatic Brain Injury, 4th ed. 2020 Update Decompressive Craniectomy

Low Grade Glioma Guidelines Developer: Congress of Neurological Surgeons

Occipital Nerve Stimulation for the Treatment of Patients With Medically Refractory Occipital Neuralgia Developer: Congress of Neurological Surgeons

Lumbar Fusion Guideline Developer: Congress of Neurological Surgeons

Update to the Guidelines for the Management of Progressive Glioblastoma Developer: Congress of Neurological Surgeons

Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries Developer: Congress of Neurological Surgeons

Guideline for the Surgical Management of Cervical Degenerative Disease Developer: Congress of Neurological Surgeons

Guidelines for the Management of Newly Diagnosed Glioblastoma Developer: Congress of Neurological Surgeons

In 2013 the American Association of Neurological Surgeons and the Congress of Neurological Surgeons released updated management guidelines for the acute cervical spine injury and spinal cord injury SCI.

1)

Badve C, Nirappel A, Lo S, Orringer DA, Olson JJ. Congress of neurological surgeons systematic review and evidence-based guidelines for the role of imaging in newly diagnosed WHO grade II diffuse glioma in adults: update. J Neurooncol. 2025 May 8. doi: 10.1007/s11060-025-05043-8. Epub ahead of print. PMID: 40338482.

Adagrasib for Non-small cell lung cancer intracranial metastases

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Adagrasib for Non-small cell lung cancer intracranial metastases

Adagrasib (Krazati) is a selective, irreversible inhibitor of the KRAS G12C mutation. Intracranial metastases (brain metastases, BM) occur in up to 40% of Non-small cell lung cancer patients, and KRAS G12C is present in ~13% of Non-small cell lung cancer intracranial metastases cases. The development of brain-penetrant KRAS G12C inhibitors like adagrasib offers a major therapeutic advance.

🔍 Evidence for Intracranial Efficacy

1. Preclinical Evidence

Christian Migliarese et al. (2025) showed that adagrasib crosses the blood-brain barrier (BBB) in orthotopic brain metastasis mouse models.

Brain exposure confirmed through pharmacokinetic assays.

In adagrasib-resistant SW1573 cells, the combination with abemaciclib (a CDK4/6 inhibitor) induced apoptosis and extended survival.

Monotherapy with adagrasib prolonged survival in adagrasib-sensitive H2122 BM models.

2. Clinical Evidence

Early-phase trials (e.g., KRYSTAL-1) reported intracranial responses:

Objective intracranial response rate (ORR): ~33–42%

Some patients with measurable brain metastases showed partial responses or stable disease.

CNS penetration confirmed by CSF concentration data in limited cohorts.

Well-tolerated at 600 mg BID, though GI side effects and QTc prolongation may occur.

📊 Key Strengths

✅ Selective targeting of KRAS G12C

✅ Oral administration

✅ BBB penetration

✅ Durable CNS activity

✅ Synergy with agents like CDK4/6 inhibitors in resistant clones

⚠️ Limitations

⚠️ Not all patients respond; resistance via bypass pathways (e.g., MET, EGFR) occurs.

⚠️ Limited efficacy in KRAS wild-type or non-G12C tumors.

⚠️ CNS toxicity, although manageable, must be monitored—particularly in combination regimens.

⚠️ Long-term CNS efficacy is still being investigated in larger, controlled trials.

🧪 Ongoing Trials

Several trials are evaluating adagrasib for NSCLC with brain metastases:

KRYSTAL-1: Phase 1/2 study evaluating adagrasib as monotherapy or in combination.

KRYSTAL-10: Combining adagrasib with checkpoint inhibitors (e.g., pembrolizumab).

Trials incorporating abemaciclib, EGFR inhibitors, and MEK inhibitors are also underway.

🧠 Conclusion

Adagrasib represents a significant step forward in treating NSCLC with brain metastases harboring KRAS G12C mutations, especially due to its oral availability, brain penetration, and target selectivity. While promising, combination strategies and biomarker-guided patient selection will be critical to maximize its CNS efficacy and overcome resistance.

Co-existing genomic alterations such as homozygous deletion of CDKN2A/B may impact the utility of adagrasib. Migliarese et al., therefore, explored the combination therapy employing adagrasib and abemaciclib, a brain-penetrant CDK4/6 inhibitor, in NSCLC BM models driven by KRAS-G12C and CDKN2A loss. In both adagrasib-resistant SW1573 cells and adagrasib-responsive H2122 cells, the combination of adagrasib and abemaciclib was slightly synergistic in inhibiting cell viability in vitro through targeting the KRAS-ERK and CDK4/6-Rb signaling pathways. Combination treatment was necessary to activate caspase 3/7-mediated apoptosis in SW1573 cells, while adagrasib alone and in combination comparably elicited apoptosis in H2122 cells. In vivo, combination treatment with adagrasib (75 mg/kg) twice daily and abemaciclib (50 mg/kg) daily was associated with body weight loss (about 10%) in mice bearing orthotopic BM derived from SW1573 or H2122 cells, requiring a 50% dose reduction of adagrasib in some animals. Notably, combination treatment, but neither monotherapy, extended animal survival in the SW1573 model. On the other hand, adagrasib monotherapy and combination were similarly effective at prolonging survival, while abemaciclib monotherapy was ineffective in the H2122 model. Pharmacokinetic studies confirmed brain-penetrant properties of both agents and revealed drug-drug interactions as abemaciclib exposures in the plasma and brains were increased by the presence of adagrasib. Immunohistochemistry demonstrated on-target pharmacodynamic effects of both agents in BM in mice. The work thus supports that the combination therapy of adagrasib and abemaciclib can offer a therapeutic strategy in NSCLC BM genomically characterized by KRAS-G12C and CDKN2A loss 1)

Migliarese et al. provide compelling preclinical evidence that co-targeting KRAS G12C and CDK4/6 pathways may overcome resistance to adagrasib in brain metastases from NSCLC with CDKN2A/B loss. The mechanistic rationale is sound, and the use of brain-penetrant drugs is a major strength. However, toxicity, modest synergy, and pharmacokinetic concerns limit immediate clinical enthusiasm.

📌 Clinical Implications The combination may be most useful in adagrasib-resistant, CDKN2A-deleted BM, but careful dose adjustment and monitoring will be essential.

Future trials must integrate immunotherapy arms and investigate biomarkers of response beyond KRAS/CDKN2A status.

There’s a need for phase I trials with adaptive dosing, especially in patients with CNS involvement.

1)

Migliarese C, Sadeh Y, Torrini C, Turna Demir F, Nayyar N, Yamazawa E, Ishikawa Y, Ijad N, Summers EJ, Elliott A, Rahbaek L, Saechao B, Hallin J, Brastianos PK, Wakimoto H. Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models genomically characterized by KRAS-G12C and homozygous loss of CDKN2A. Acta Neuropathol Commun. 2025 May 2;13(1):88. doi: 10.1186/s40478-025-01993-2. PMID: 40317086.

IDH-mutant glioma

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IDH-mutant glioma

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IDH-Mutant Glioma Classification (WHO 2021)

The classification of IDH-mutant gliomas according to the World Health Organization Classification of Tumors of the Central Nervous System 2021 is summarized in the table below:

Tumor Type IDH Status 1p/19q Status Key Features Available Grades
Astrocytoma IDH-mutant Mutant Intact ATRX loss, TP53 mutation Grade 2, 3, or 4
Oligodendroglioma IDH-mutant and 1p/19q-codeleted Mutant Codeleted TERT promoter mutation, ATRX retained Grade 2 or 3
Glioblastoma Wildtype — TERT/EGFR amplification or +7/−10 signature, or necrosis/microvascular proliferation Always Grade 4

Additional Notes

  • The term glioblastoma, IDH-mutant is no longer used. These tumors are now classified as Astrocytoma, IDH-mutant, Grade 4.
  • The presence of CDKN2A/B homozygous deletion upgrades astrocytoma, IDH-mutant to WHO Grade 4 even in the absence of necrosis or microvascular proliferation.

Although IDH-mutant glioma generally has a better prognosis than its IDH-wildtype counterparts, considerable prognostic heterogeneity persists among patients with the same IDH mutation. A study of Wang et al. has primarily focused on the different IDH statuses or grades, while the metabolic heterogeneity within IDH-mutant gliomas remains insufficiently characterized. This study aims to identify transcriptomic metabolic subtypes and associated immune microenvironment differences to better understand survival variability and potential therapeutic targets in IDH-mutant glioma.

Patients with IDH-mutant gliomas were included from four public datasets (TCGA, n = 373; CGGA325, n = 167; CGGA693, n = 333; GLASS, n = 100), supplemented by 22 cases from Beijing Tiantan Hospital as an independent cohort. Consensus clustering was used to define novel metabolic subtypes. Clinical features were assessed using chi-square tests and Kaplan-Meier analysis. Metabolic profiles were characterized through enrichment analysis and GSVA; immune infiltration was analyzed using CIBERSORTx and ESTIMATE. Tumor samples from the independent cohort underwent untargeted metabolomics for validation. LASSO regression was applied to select metabolic signatures, and the CGP2014 drug library was used for drug screening.

Three metabolic subtypes (C1-C3) with distinct prognoses (p < 0.05) were identified. C1 exhibited enhanced carbohydrate and nucleotide metabolism; C2 displayed upregulated amino acid and lipid metabolism; and C3 demonstrated elevated lipid, nucleotide, and vitamin metabolism. These patterns were validated in the independent cohort. Subtypes were also correlated with immune infiltration. A 13-gene metabolic signature was established to stratify prognostic risk and suggest subtype-specific drug sensitivities.

The study provided a novel metabolic subtype for IDH-mutant glioma and highlighted these patients’ metabolic heterogeneity and potential therapeutic strategies 1)

Wang et al. provide compelling evidence that metabolic subtyping in IDH-mutant gliomas is biologically meaningful and prognostically informative. Despite the limitations of validation scope and functional depth, the study opens promising avenues for metabolism-guided precision neuro-oncology.

IDH-Mutant Glioma Subtypes

IDH-mutant gliomas, although generally associated with better prognosis, show considerable biological and clinical heterogeneity. Recent transcriptomic and metabolic profiling has revealed distinct subtypes with prognostic and therapeutic implications.

Molecular Subtypes (Traditional WHO Classification)

Subtype IDH Status 1p/19q Status Common Features WHO Grades
Astrocytoma, IDH-mutant Mutant Intact TP53 mutation, ATRX loss Grade 2, 3, or 4
Oligodendroglioma, IDH-mutant Mutant Codeleted TERT promoter mutation, ATRX retained Grade 2 or 3

Metabolic Subtypes (Wang et al., 2025)

Subtype Dominant Metabolism Prognosis Immune Microenvironment Notes
C1 Carbohydrate & nucleotide metabolism Poor Less immune infiltration Higher proliferation signature
C2 Amino acid & lipid metabolism Intermediate Moderate immune activity May benefit from lipid metabolism-targeted drugs
C3 Lipid, nucleotide & vitamin metabolism Favorable Higher immune infiltration Most differentiated; possible immunogenic role

Summary

  • These subtypes are defined by transcriptomic and metabolic profiling, not by histopathology alone.
  • A 13-gene metabolic signature has been proposed to distinguish these subtypes and guide potential treatment.
  • Future therapy may be subtype-specific, focusing on metabolism and immune modulation.
1)

Wang P, Wang J, Fang Z, Chen Q, Zhang Y, Qiu X, Bao Z. Novel metabolic subtypes in IDH-mutant gliomas: implications for prognosis and therapy. BMC Cancer. 2025 Apr 30;25(1):815. doi: 10.1186/s12885-025-14176-y. PMID: 40307749.

ZIP4 in Glioblastoma

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ZIP4 in Glioblastoma

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain.

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Introduction

ZIP4 and ZIP11 are promising molecular diagnostic markers and novel therapeutic targets. Nevertheless, the detailed biological function of zinc transporters and the mechanism of the potential interaction between ZIP11 and IDH1 mutation in gliomagenesis should be further investigated 1)

Glioblastoma (GBM), is characterized by an extremely altered glioblastoma genome, which is characterized by the dysregulation of numerous critical signaling pathways and epigenetic regulations associated with proliferation, cellular growth, survival, and apoptosis. In light of this, genetic alterations in critical signaling pathways and various epigenetic regulation mechanisms are associated with GBM and identified as distinguishing markers. Such GBM prognostic alterations are identified in PI3K/AKT, p53, RTK, RAS, RB, STAT3, and ZIP4 signaling pathways, metabolic pathway (IDH1/2), as well as alterations in epigenetic regulation genes (MGMT, CDKN2A-p16INK4aCDKN2B-p15INK4b). The exploration of innovative diagnostic and therapeutic approaches that specifically target these pathways is of utmost importance to enhance future medication for GBM 2)

* Overexpressed in GBM cells

  • Drives tumor progression by modulating immune microenvironment
  • Regulates microglial plasticity via:
    • Extracellular vesicle (EV)-mediated transfer of TREM1
    • Activation of downstream SYK–PDK–STAT3 signaling in microglia
  • ZIP4 knockout or inhibition:
    • Reduces tumor growth
    • Attenuates microglia-driven immune support for the tumor

Molecular Mechanism in GBM (based on PNAS 2025 study)

  1. ZIP4 increases intracellular zinc in GBM cells
  2. Zinc activates ZEB1 (Zinc Finger E-box Binding Homeobox 1)
  3. ZEB1 promotes production of TREM1-containing EVs
  4. EVs deliver TREM1 to microglia
  5. Microglia are reprogrammed via SYK–PDK–STAT3 → tumor-supportive state

Clinical Relevance

  • Diseases:
    • Acrodermatitis enteropathica (loss-of-function)
    • Cancers: GBM, pancreatic, prostate, liver (overexpression)
  • Therapeutic implications:
    • ZIP4 is a potential oncologic target
    • Inhibition may reduce tumor–immune crosstalk in GBM
    • Strategies may include:
      • Antisense RNA
      • Zinc chelation
      • Targeted inhibition of ZIP4 or its regulatory axis

—-

Zhang et al. present a compelling study identifying the zinc transporter ZIP4 as a driver of glioblastoma progression through a novel tumor–microglia communication mechanism. The authors show that ZIP4 promotes the release of extracellular vesicles (EVs) enriched with TREM1, which reprograms microglial plasticity via the SYK–PDK–STAT3 signalling axis, thereby fostering a pro-tumor immune microenvironment. Targeting ZIP4 or TREM1 dampens tumor growth and behavioral changes in vivo, highlighting a potential therapeutic axis in GBM 3)

✅ Strengths Novel Mechanistic Insight:

The study uncovers a previously unknown pathway by which ZIP4 regulates microglial behavior, linking metal ion transport to immune microenvironment modulation, which is conceptually innovative.

Use of Orthotopic GBM Mouse Models:

By using clinically relevant in vivo models, the authors strengthen the translational value of their findings.

Multilevel Approach:

The study spans molecular biology (ZIP4, TREM1, STAT3), cell-cell communication (EVs), and behavioral neuroscience, providing a comprehensive view of tumor-host interaction.

Therapeutic Implication:

Demonstrating that ZIP4 knockdown or TREM1 inhibition reduces tumor progression positions these molecules as realistic drug targets.

Relevance of Microglial Plasticity:

The paper builds on current interest in microglial reprogramming in CNS cancers and contributes mechanistic detail that may inform other pathologies involving neuroinflammation.

⚠️ Limitations and Critical Considerations Limited Human Validation:

While the mouse models are strong, the study lacks a robust analysis of ZIP4/TREM1 axis expression in human GBM tissues across multiple subtypes and patients, limiting direct clinical extrapolation.

Overshadowing Other Zinc Transporters:

The exclusive focus on ZIP4 leaves open whether other SLC39A or SLC30A family members may compensate or synergize, an important aspect for drug resistance or redundancy.

Microglia vs. Macrophages:

The study refers to microglia but does not fully distinguish them from peripheral infiltrating macrophages, which are often phenotypically and functionally entangled in GBM. More precise fate-mapping or single-cell RNA-seq would clarify the cellular target.

Behavioral Outcomes:

The behavioral changes attributed to ZIP4 and TREM1 manipulation are mentioned but not deeply characterized. Given the complexity of CNS behavior, these should be more rigorously validated.

Extracellular Vesicle Specificity:

EV characterization is implied but not thoroughly quantified (e.g., EV subtype, cargo validation, dose-response). This affects the confidence in mechanistic claims regarding TREM1 as the key effector.

Therapeutic Translation:

While TREM1 inhibition shows promise in mice, drug delivery to the brain, toxicity, and specificity remain major hurdles not addressed here.

📌 Overall Significance

This study provides a valuable conceptual advance in understanding how GBM co-opts the innate immune system via zinc metabolism and vesicle-based signaling. It bridges metabolic regulation (ZIP4), vesicular communication, and immune reprogramming in a way that few studies have.

Despite some limitations in translational readiness and experimental scope, the paper is strongly hypothesis-generating and lays the groundwork for:

ZIP4 or TREM1-targeted therapy development

Further exploration of metal-ion-dependent immune modulation in CNS cancers

⭐️ Final Verdict:

A high-impact contribution to neuro-oncology and neuroimmunology that warrants further clinical exploration. Its mechanistic clarity, therapeutic potential, and relevance to microglial plasticity make it a noteworthy study, although deeper validation in human samples and advanced immune profiling are needed for full translational impact.

References

1)

Kang X, Chen R, Zhang J, Li G, Dai PG, Chen C, Wang HJ. Expression Profile Analysis of Zinc Transporters (ZIP4, ZIP9, ZIP11, ZnT9) in Gliomas and their Correlation with IDH1 Mutation Status. Asian Pac J Cancer Prev. 2015;16(8):3355-60. doi: 10.7314/apjcp.2015.16.8.3355. PMID: 25921144.
2)

Dakal TC, Kakde GS, Maurya PK. Genomic, epigenomic and transcriptomic landscape of glioblastoma. Metab Brain Dis. 2024 Dec;39(8):1591-1611. doi: 10.1007/s11011-024-01414-8. Epub 2024 Aug 24. PMID: 39180605.
3)

Zhang L, Yang J, Zhou Z, Ren Y, Chen B, Tang A, Zhang K, Li C, Zhou H, Fung KM, Xu C, Kang C, Battiste JD, Bronze MS, Houchen CW, Liu Z, Dunn IF, Cavenee WK, Li M. A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity. Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2427073122. doi: 10.1073/pnas.2427073122. Epub 2025 Apr 30. PMID: 40305049.

Posterior Pituitary Tumor

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Posterior Pituitary Tumor

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A posterior pituitary tumor (PPT) is a rare, often benign neoplasm that originates from the neurohypophysis, also known as the posterior lobe of the pituitary gland.

In 2017, the WHO established that pituicytoma, granular cell tumor (GCT) and spindle cell oncocytoma (SCO) are posterior pituitary tumors (PPT). Data suggests that these tumours probably arise from the pituicytes and may constitute a spectrum of a unique histopathological entity.

Histological Subtypes

Posterior pituitary tumors comprise three main subtypes:

Although histologically distinct, these tumors likely represent a spectrum of a single pathological entity due to shared immunohistochemical markers and origin.

Clinical Presentation

Symptoms are often nonspecific and may resemble those of non-functioning pituitary tumors. Common findings include:

Diagnosis

  • MRI: Typically shows a solid sellar or suprasellar mass, often isointense on T1 and T2, with homogeneous contrast enhancement.
  • Endocrine testing: May reveal hormonal deficiencies or elevations.
  • Histology & Immunohistochemistry:

Treatment and Prognosis

  • Surgical resection is the mainstay of treatment. Approaches include:
  • Complications:
  • Adjuvant therapy: radiotherapy may be used in cases of residual or recurrent tumor.
  • Prognosis:
    • Excellent tumor-specific survival (near 100% at 5 years)
    • Endocrine dysfunction often persists or worsens postoperatively

Retrospective cohort studies

A retrospective cohort study offers a valuable contribution to the limited literature on posterior pituitary tumors (PPTs), analyzing 19 patients treated over 23 years at a single academic center. Despite the rarity of these tumors—pituicytoma (PC), granular cell tumor (GCT), and spindle cell oncocytoma (SCO)—the authors manage to draw meaningful insights into their clinical presentation, surgical management, and long-term endocrine impact 1).

Including three distinct histological subtypes allows for a comparative analysis that reveals intriguing differences, such as the significantly higher preoperative BMI in GCT patients and the sharp postoperative increase in BMI, highlighting possible metabolic derangements associated with this tumor type. The predominance of symptoms like headache, visual impairment, and sexual dysfunction echoes the nonspecific but debilitating nature of sellar pathology.

One of the most striking findings is the persistence or worsening of endocrine dysfunction postoperatively, with minimal recovery over time. This aligns with other literature indicating that surgery for PPTs, though often necessary, rarely restores pituitary function and may even exacerbate deficits. This point emphasizes the need for realistic patient counseling and robust endocrinological follow-up.

Surgical management was nearly evenly split between transsphenoidal and transcranial, a decision likely driven by tumor size and anatomical considerations. Gross total resection (GTR) was achieved in 58% of cases, with a 16% recurrence rate—relatively low, but not negligible, especially considering the benign histology of these tumors. All recurrences were managed with adjuvant radiation therapy, which raises questions about its early use in subtotal resections.

The study’s strengths include its well-defined cohort, detailed subgroup analysis, and long-term follow-up. However, the small sample size and single-center design inherently limit generalizability. Moreover, the retrospective nature introduces potential bias in data collection and outcome assessment.

From a translational perspective, this work underlines a key clinical dilemma: the balance between oncological control and iatrogenic endocrine morbidity. Future prospective multicenter studies with standardized follow-up protocols could help establish evidence-based guidelines for PPTs, including early identification of patients at risk for metabolic deterioration.

This study is a sobering reminder that not all “benign” tumors are benign in consequence. While the tumor-specific survival was excellent (100% at 5 years), the lingering endocrine and metabolic sequelae merit equal attention. Clinicians managing these rare entities must prepare for a dual challenge: surgical precision and long-term systemic management.

Retrospective observational studies

A retrospective observational study was conducted at a single neurosurgical center over 10 years (2013–2023). The authors reviewed medical records and histopathological samples of patients diagnosed with primary TTF1-positive posterior pituitary tumors (PPT) 2).

Summary of Findings

Out of over a decade of surgical activity, only nine PPT cases were identified, reflecting the rarity of this tumor type, which constituted just 0.6% of all sellar/suprasellar operations at the institution.

Breakdown of tumor types:

Key clinical observations:

  • Median patient age: 53 years
  • 66.7% male
  • Frequent symptoms: panhypopituitarism, visual deficits, and headaches
  • Common MRI features: isointense T1 signal, suprasellar extension in GCT and pituicytoma

Notable radiological clue:

  • GCTs demonstrated a “star-like crack” pattern, which may aid in preoperative suspicion.

Critical Appraisal

Strengths

  • The study is one of the few focused exclusively on TTF-1 positive PPTs with confirmed histopathology, adding valuable long-term clinical and imaging data.
  • It provides rare insights into surgical outcomes, emphasizing the challenge posed by the firm and vascular nature of SCO.

Weaknesses

  • As a single-center, retrospective study, external validity is limited. Multicentric studies would be needed to confirm the imaging-histopathology correlations suggested.
  • The sample size is very small (n=9), limiting the statistical power and generalizability of the conclusions.
  • The lack of a control group or comparative data restricts interpretation of surgical or radiotherapeutic outcomes.

Clinical Relevance

  • Preoperative suspicion of SCO or GCT based on radiological features could impact surgical planning and patient counseling, given the tendency for subtotal resection and adjuvant therapy.
  • The report underscores the importance of long-term follow-up due to the limited curative potential of these tumors, even with aggressive intervention.

Conclusion

This study serves as a useful reference for neurosurgeons and endocrinologists managing rare TTF-1-positive PPTs. It highlights the diagnostic difficulty, surgical complexity, and the need for improved strategies to manage these lesions. Future studies should aim to include multicenter cohorts, genetic profiling, and standardized protocols for treatment and surveillance.

Retrospective case series

The aim of Guerrero-Pérez F et al. from the Department of Endocrinology, Department of Pathology, Department of Endocrinology, Hospital Universitari de Bellvitge, Barcelona, Department of Endocrinology, Hospital Universitari Mutua Terrassa, Barcelona, Department of Endocrinology, Hospital Universitario Príncipe de Asturias, Madrid, Department of Neurosurgery, Hospital Universitario Miguel Servet, Zaragoza, Department of Endocrinology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Department of Endocrinology, Hospital General Universitario de Alicante, Spain is to report the clinical findings and surgical outcomes of 16 patients with PPT. They also evaluated the tissue specimens available in light of current knowledge.

PPT were 7 pituicytomas, 3 GCT and 6 SCO. Patients mean age was 55 years old and 75% were female. Basal hormonal study showed hyperprolactinemia (43.7%) and hypopituitarism (37.5%). There was no case of diabetes insipidus (DI). MRI showed sellar/suprasellar masses with mean size of 19.7mm. PPT was not suspected in any patient. Fifteen patients underwent surgery and complications were common: 20% had perioperative bleeding (one patient died because of a massive haemorrhage), 57.1% hypopituitarism, 35.7% permanent DI and 21.4% underwent a second surgery. Pathological findings shown positivity for thyroid transcription factor 1, vimentin and negativity for cytokeratin and chromogranin A in all specimens evaluated. S100 protein was positive in 88.8% of tumours. Ki67 was ≥ 3% in 66.6% and ranged from 4-7% in SCO.

PPT have similar histology, clinical features and are frequently misdiagnosed as nonfunctioning pituitary tumours. However, post-surgical complications including haemorrhage are common. A high clinical suspicion is needed to presume the diagnosis prior surgery and diminish the high morbidity of these tumours 3).

1)

Kremenevski N, Schnell O, Coras R, Buchfelder M, Hore N. Clinical, surgical, and endocrine outcome following treatment of posterior pituitary tumors: a retrospective cohort study. Pituitary. 2025 Apr 5;28(2):45. doi: 10.1007/s11102-025-01518-z. PMID: 40186832.
2)

Lamback E, da Silva Camacho AH, Castro Araujo AC, Wildemberg LE, Cabrera Filho FD, Andreiuolo F, Kasuki L, Ventura N, Chimelli L, Gadelha MR. TTF1-positive posterior pituitary tumors: a single-center experience of 10 years. Endocrine. 2025 Apr 3. doi: 10.1007/s12020-025-04214-x. Epub ahead of print. PMID: 40175820.
3)

Guerrero-Pérez F, Vidal N, Marengo AP, Pozo CD, Blanco C, Rivero-Celada D, Díez JJ, Iglesias P, Picó A, Villabona C. Posterior pituitary tumours: the spectrum of a unique entity. A clinical and histological study of a large case series. Endocrine. 2018 Oct 1. doi: 10.1007/s12020-018-1774-2. [Epub ahead of print] PubMed PMID: 30276594.

Antihypertensive Medication After Intracerebral Hemorrhage

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Antihypertensive Medication After Intracerebral Hemorrhage

Latest PubMed Articles

🧠 1. Acute Phase Management (First Hours to Days)

🎯 Goal: Reduce hematoma expansion and improve outcomes

Target Blood Pressure (BP):

  • SBP 150–220 mmHg → Lower to <140 mmHg is generally safe and may improve outcomes (AHA/ASA 2022)
  • SBP >220 mmHg → Consider aggressive reduction with ICU-level monitoring

IV Antihypertensives:

Drug Class Notes
Labetalol α/β-blocker Often first-line; good for rapid BP control
Nicardipine Calcium channel blocker Preferred for titratable infusion
Clevidipine Calcium channel blocker Short half-life, easily adjustable
Esmolol β1-selective blocker Useful for short-term, fast-acting control
Hydralazine Direct vasodilator Less predictable; not first-line

Avoid: Overly rapid BP drops, especially with elevated intracranial pressure (ICP)

🔁 2. Secondary Prevention (Long-Term Management)

🎯 Goal: Prevent recurrent ICH and vascular events

BP Target:

  • Long-term: SBP <130 mmHg
  • Avoid SBP <110 mmHg (risk of hypoperfusion)

Preferred Antihypertensive Classes:

Class Example Notes
ACE inhibitors Enalapril, Ramipril Good stroke prevention evidence
ARBs Losartan, Candesartan Well tolerated alternative to ACEi
Thiazide diuretics Hydrochlorothiazide Often used in combo therapy
Calcium channel blockers Amlodipine Useful as monotherapy or in combinations

Key Trials:

📌 Clinical Pearls

  • Titrate IV to oral meds with continuous monitoring
  • Consider Spontaneous Intracerebral Hemorrhage Etiology (hypertensive vs amyloid-related) for long-term goals
  • Tailor treatment to age, comorbidities, renal function, and prior drug response

TRICH Score

In a prospective cohort study with external validation study components, the authors used data from a longitudinal ICH registry (2011–2022) for score development and validated the model prospectively in three independent hospitals (2020–2022) 1)

The study aims to develop and validate a clinical score (the TRICH score) to predict the need for ≥3 antihypertensive medications three months after intracerebral hemorrhage (ICH), to guide early and individualized blood pressure management.

Clinically Relevant Tool: The TRICH score addresses a clear clinical need: stratifying patients by future antihypertensive needs post-ICH.

– Well-Defined Cohorts: The development and validation cohorts are clearly defined and separate, lending credibility to the generalizability within the studied population.

– Statistical Rigor: The use of multivariate logistic regression, β-coefficients for score construction, and AUC for model performance are standard and appropriate.

– Good Discrimination: The TRICH score achieved a c-statistic of 0.79 in the development and 0.76 in the validation cohort, indicating good predictive performance.

– Subgroup Analyses: The study explores performance in subgroups (e.g., uncontrolled hypertension vs controlled, CAA vs non-CAA), which is useful for clinical interpretation.

Limitations

– Ethnic Homogeneity: All participants were from Hong Kong hospitals, likely representing predominantly Han Chinese patients. This limits external validity, especially in multiethnic or Western populations.

– Short Follow-up: The score is tailored to predict medication needs at 3 months. It remains unclear whether it has predictive power for long-term hypertension control or cardiovascular outcomes.

– Exclusion Criteria Bias: Patients who died before 90 days or lacked follow-up were excluded. These patients might represent a higher-risk group, potentially introducing survivorship bias.

– Simplification Risks: While score simplification (e.g., dichotomizing age or BP ranges) improves usability, it may reduce nuance in individual patient profiles.

The TRICH score has the potential to assist clinicians in initiating early intensive antihypertensive therapy in appropriate post-ICH patients, especially those with a high risk of needing triple therapy. However, caution is warranted to avoid overtreatment in those with transient BP elevation due to acute stress or underlying cerebral amyloid angiopathy.

The model performed better in patients with previously uncontrolled or untreated hypertension, reinforcing its value in guiding care where hypertension is known but uncontrolled. Lack of differentiation in patients with or without CAA suggests that further refinements or adjunct markers may be needed for this subgroup.

Future Directions

– External validation in diverse populations, including Caucasian, African descent, and South Asian cohorts.

– Integration of biomarkers or imaging (e.g., MRI markers of CAA) to refine predictions.

– Evaluation of the TRICH score’s impact on clinical outcome when used in routine care.

Conclusion

This well-conducted cohort study introduces a practical clinical tool—the TRICH score—for anticipating antihypertensive requirements after ICH. Despite its promise, broader validation and studies on downstream outcomes are essential before widespread implementation.

1)

So CH, Yeung C, Ho RW, Hou QH, Sum CHF, Leung W, Wong YK, Liu KCR, Kwan HH, Fok J, Yip EK, Sheng B, Yap DY, Leung GKK, Chan KH, Lau GKK, Teo KC. Triple Antihypertensive Medication Prediction Score After Intracerebral Hemorrhage (the TRICH Score). Neurology. 2025 May 13;104(9):e213560. doi: 10.1212/WNL.0000000000213560. Epub 2025 Apr 4. PMID: 40184593.

Papilledema Differential Diagnosis

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Papilledema Differential Diagnosis

Latest PubMed Articles

Papilledema refers to optic disc swelling due to increased intracranial pressure (ICP). However, when optic disc edema is noted, it’s crucial to distinguish true papilledema from other causes of disc swelling.

Structured differential diagnosis

🔴 True Papilledema (due to increased ICP)

Caused by elevated pressure in the cerebrospinal fluid (CSF):

Intracranial Mass Lesions Tumors (gliomas, metastases, meningiomas)

Abscesses

Hematomas

Cerebral Edema Trauma

Hypoxic-ischemic injury

Hypertensive encephalopathy

Hydrocephalus Obstructive (e.g., aqueductal stenosis)

Communicating (e.g., post-meningitic)

Idiopathic Intracranial Hypertension (IIH) Especially in young obese females

Cerebral Venous Sinus Thrombosis May mimic IIH

Meningitis/Encephalitis Infectious or inflammatory processes causing brain swelling

⚠️ Disc Edema NOT Due to Raised ICP

Unilateral or BilateralOptic Neuritis

Multiple sclerosis

Neuromyelitis optica (NMOSD)

MOG-antibody associated disease

Ischemic Optic Neuropathy

Non-arteritic (NAION): common in elderly, associated with vascular risk

Arteritic (AAION): e.g., giant cell arteritis

Infiltrative or Neoplastic Optic Neuropathy

Lymphoma

Leukemia

Sarcoidosis

Toxic/Nutritional Optic Neuropathy

Methanol, ethambutol

Vitamin B12 deficiency

Congenital Pseudopapilledema

Optic disc drusen

Hypermetropic crowded discs

Other Mimickers

Papillophlebitis (in young patients with retinal vein congestion)

Uveitis (posterior)

Hypertensive retinopathy (Grade IV with disc edema)

🧪 Workup

Neuroimaging: MRI/MRV to rule out mass lesion, thrombosis

Lumbar Puncture: Measure opening pressure, CSF analysis (after imaging)

OCT: Assess retinal nerve fiber layer thickness

Visual fields: Enlargement of blind spot common in papilledema

Fundus autofluorescence/ultrasound: To detect optic disc drusen

Review

A comprehensive review_article by Susan P. Mollan offers a timely update on the diagnosis and management of papilledema, a condition characterized by bilateral optic disc swelling due to raised intracranial pressure. The article is particularly relevant in the context of increasing cases of idiopathic intracranial hypertension (IIH), strongly correlated with the global rise in obesity 1)

A standout strength of this review lies in its emphasis on differentiating true papilledema from pseudopapilledema, a common diagnostic pitfall. The discussion on the role of optical coherence tomography (OCT) is especially valuable. The inclusion of recent imaging biomarkers and structural OCT changes improves clinical accuracy in distinguishing optic disc edema from congenital anomalies like buried optic nerve head drusen.

The article also highlights the multidisciplinary nature of papilledema care. Effective management relies on collaboration between ophthalmologists and neurologists, with shared responsibilities in both diagnosis and treatment—especially crucial when symptoms such as visual field defects and chronic headache are present.

However, the review could have benefitted from a more in-depth exploration of emerging therapies for cerebrospinal fluid (CSF) regulation. Although newer treatment pathways are mentioned, details on pharmacologic or surgical innovations are limited. Further commentary on the role of neuroimaging advancements, particularly with high-resolution MRV (magnetic resonance venography), would have added a more complete clinical picture.

In conclusion, this article is an essential read for any clinician managing patients with suspected raised intracranial pressure. It combines updated diagnostic strategies with practical insights into team-based care, although it leaves room for more discussion on therapeutic frontiers.

Difficulties occur in the differential diagnosis of papilledema against similar changes of the optic nerve head seen during ophthalmoscopy 2)

Causes of papilledema include intracranial tumors, idiopathic intracranial hypertension (pseudotumor cerebri), subarachnoid hemorrhage, subdural hematoma and intracranial inflammation. Optic disc edema may also occur from many conditions other than papilledema, including central retinal artery or vein occlusion, congenital structural anomalies, and optic neuritis 3).

References

1)

Mollan SP. Papilledema. Continuum (Minneap Minn). 2025 Apr 1;31(2):436-462. doi: 10.1212/CON.0000000000001556. PMID: 40179403.
2)

Serova NK, Eliseeva NM. Zastoinyi disk zritel’nogo nerva kak priznak vnutricherepnoi gipertenzii [Papilledema as a sign of intracranial hypertension]. Vestn Oftalmol. 2022;138(4):87-93. Russian. doi: 10.17116/oftalma202213804187. PMID: 36004596.
3)

Whiting AS, Johnson LN. Papilledema: clinical clues and differential diagnosis. Am Fam Physician. 1992 Mar;45(3):1125-34. PMID: 1543098.

Incidental meningioma active surveillance

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Incidental meningioma active surveillance

Active surveillance is a non-interventional management strategy where the tumor is closely monitored with regular imaging and clinical assessments instead of immediate treatment.

Indications for Active Surveillance

Asymptomatic patients

Tumor discovered incidentally

Small size (< 2–3 cm)

No mass effect or brain edema

No radiological signs of aggressiveness (e.g., brain invasion, rapid growth)

The patient has significant comorbidities or advanced age

The tumor is located in an eloquent or high-risk area for surgery

Surveillance Protocol (Typical Schedule)

Baseline MRI with contrast to characterize the tumor

Follow-up MRI at 6 months

If stable → annual imaging for 5 years

If still stable → consider imaging every 2–3 years

Lifelong monitoring is most cases, especially in younger patients

Clinical Follow-up

Regular neurological exams

Monitor for new symptoms: headache, seizures, focal deficits, cognitive changes

Reassess management if:

Tumor grows (commonly defined as >2 mm/year)

New or worsening symptoms appear

Advantages of Active Surveillance Avoids risks of surgery or radiation

Preserves the quality of life in asymptomatic individuals

Many meningiomas remain stable for years or a lifetime

When to Reconsider Treatment Radiological progression (volume increase, edema, mass effect)

Symptom development

Patient preference changes

Tumor in surgically accessible location with low expected morbidity

Cohort studies

A population-based study explores the prevalence and symptomatology of incidentally found meningiomas in a specific aging population—the 70-year-olds participating in the Gothenburg H70 Birth Cohort Study. The authors analyzed MRIs from 792 individuals and found a 1.8% prevalence of incidental meningiomas, with a notable gender skew (12 of the 14 cases were female) 1)

One of the key strengths of this work is its community-based sampling, which reduces the referral bias often present in hospital-based series. It also adds valuable information to the growing body of literature supporting a more conservative treatment approach in asymptomatic or minimally symptomatic individuals, especially in the elderly.

The study challenges the reflexive assumption that nonspecific symptoms like headache or dizziness are attributable to small, incidentally found meningiomas. This is crucial, as overattribution can lead to unnecessary neurosurgical interventions, with accompanying risks and psychological burden.

On the flip side, the small absolute number of identified meningiomas (n=14) limits the statistical power to detect nuanced associations between clinical variables and tumor presence. Furthermore, the authors did not perform longitudinal follow-up to assess tumor growth or symptom progression, which could be relevant in determining the true clinical impact of these incidental findings.

In summary, this study provides solid evidence that supports watchful waiting in many cases of incidental meningioma, particularly in elderly women. It underscores the need for clinical restraint and careful consideration before attributing symptoms or deciding on intervention.

Retrospective Comparative Cohort Study with Propensity Score Matching

Hallak et al. employ a retrospective study design with propensity score matching to balance confounding factors between patients undergoing stereotactic radiosurgery (SRS) and those under active surveillance 2)

Key findings include:

  • Superior radiological control in the SRS group (97.37%) compared to observation (71.93%), with a statistically significant advantage (p < 0.01).
  • Neurological safety appears slightly compromised in SRS (1.39% new deficits), while no new deficits occurred under surveillance.
  • The need for surgical resection was low in both arms, slightly higher in the observation group (3.5% vs 0.9%), though not statistically significant (p = 0.063).
  • A trend toward lower mortality in the SRS group (9.65% vs 18.42%) was noted, yet without reaching statistical significance (p = 0.06). Notably, no deaths in the observation group were directly attributed to meningioma progression.

From a clinical decision making perspective, the study underscores the value of personalized management. While SRS offers more robust tumor control, the marginal increase in risk of neurological complication, coupled with a non-significant impact on survival or surgical rescue, suggests watchful waiting remains a valid approach—especially in patients with limited life expectancy or comorbidities.

Future prospective trials with functional outcomes, quality-of-life metrics, and cost-effectiveness analyses are needed to refine treatment algorithms. Nevertheless, this article adds weight to current trends toward de-escalation in certain low-risk neurosurgical cases.

1)

de Dios E, Näslund O, Choudhry M, Berglund M, Skoglund T, Sarovic D, Rydén L, Kern S, Skoog I, Thurin E. Prevalence and symptoms of incidental meningiomas: a population-based study. Acta Neurochir (Wien). 2025 Apr 3;167(1):98. doi: 10.1007/s00701-025-06506-7. PMID: 40178655.
2)

Hallak H, Mantziaris G, Pikis S, Islim AI, Peker S, Samanci Y, Nabeel AM, Reda WA, Tawadros SR, El-Shehaby AMN, Abdelkarim K, Emad RM, Mathieu D, Lee CC, Liscak R, Alvarez RM, Kondziolka D, Tripathi M, Speckter H, Bowden GN, Benveniste RJ, Lunsford LD, Jenkinson MD, Sheehan J. A retrospective comparison of active surveillance to stereotactic radiosurgery for the management of elderly patients with an incidental meningioma. Acta Neurochir (Wien). 2025 Feb 6;167(1):37. doi: 10.1007/s00701-025-06452-4. PMID: 39912992; PMCID: PMC11802698.

Fourth ventricle tumor surgery complications

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Fourth ventricle tumor surgery complications

Fourth ventricle tumor surgery is delicate and carries specific risks due to the complex anatomy of the region. The fourth ventricle lies in the posterior fossa of the brain, nestled between the brainstem and cerebellum. Because of this, complications can involve vital neurological structures.

🔴 Neurological Complications

Cranial Nerve Deficits

Especially CN VI (abducens), CN VII (facial), and CN VIII (vestibulocochlear).

May cause diplopia, facial weakness, or hearing loss.

Cerebellar Dysfunction

Ataxia, dysmetria, intention tremor.

Can be transient or permanent.

Brainstem Injury

Risk of respiratory or cardiovascular instability.

It can lead to coma or death in extreme cases.

Mutism / Cerebellar Cognitive Affective Syndrome

Especially in pediatric patients after resection of medulloblastomas or ependymomas.

Characterized by mutism, emotional lability, and executive dysfunction.

💧 CSF-related Complications

Hydrocephalus (pre- or post-operative)

Due to obstruction of CSF pathways (aqueduct or outlets of the fourth ventricle).

May require an external ventricular drain (EVD) or VP shunt.

CSF Leak / Pseudomeningocele

From poor dural closure or pressure buildup.

Risk of infection or wound healing issues.

Meningitis / Ventriculitis

Especially if there’s a CSF leak or prolonged drain use.

💉 Vascular Complications

Hemorrhage

Intraoperative bleeding from a tumor or surrounding vessels.

Postoperative hematoma causing brainstem compression.

Ischemia

Injury to perforating arteries (e.g., branches of the posterior inferior cerebellar artery – PICA).

It can cause infarcts in the brainstem or cerebellum.

🛌 Systemic and General Complications

Infection

Seizures (rare for the posterior fossa)

Respiratory compromise (especially in children or after brainstem manipulation)

Wound complications

🧠 Tumor-specific factors

Ependymomas: Adherence to the floor of the 4th ventricle increases brainstem injury risk.

Medulloblastomas: prone to CSF spread, so thorough surgical and oncologic planning is key.

Choroid plexus tumors: highly vascular, bleeding risk.

Cohort studies

In a large multicenter cohort study Persson et al. investigate postoperative word-finding abilities in children undergoing posterior fossa tumor surgery (PFTs), with data from 184 children across Europe. The authors address a critical yet understudied postoperative complication—word-finding difficulty, which goes beyond classic cerebellar mutism syndrome (CMS) and focuses on more subtle higher-order language impairments 1)

The study’s key strength lies in its pre- and postoperative comparisons using a speeded picture-naming test, providing quantitative insights into word retrieval speeds. Interestingly, the results reveal no significant change between pre- and postoperative performance on average. This means that while some children improved, others declined, underscoring the heterogeneous outcomes in PFT surgeries.

A striking finding is that 95% of children performed more than two standard deviations slower than age norms after surgery, despite no aggregate decline. This discrepancy suggests that even without a gross drop in individual scores, the cohort as a whole demonstrates clinically significant delays, potentially overlooked in standard assessments.

The study identifies fourth ventricle tumor as a specific risk factor (B = -4.09, p < 0.05), linking it to possible damage of the dentato-thalamo-cortical pathway. This aligns with previous neuroanatomical models implicating cerebellar-thalamo-cortical circuits in language function, not just motor planning.

From a clinical perspective, these findings call for routine postoperative language screening—even in patients who do not develop mutism—to detect subtle deficits that may affect communication and academic performance. Furthermore, early intervention strategies may be needed, particularly for children with tumours in higher-risk locations.

This study contributes valuable evidence supporting the existence of subtle yet functionally important postoperative language impairments in children with PFTs. It urges the neurooncology and neuropsychology communities to broaden the scope of postoperative assessments to include not only mutism but also word-finding and higher cognitive-linguistic functions.

1)

Persson K, Grønbæk J, Tiberg I, Fyrberg Å, Castor C, Andreozzi B, Frič R, Hauser P, Kiudeliene R, Mallucci C, Mathiasen R, Nyman P, Pizer B, Sehested A, Boeg Thomsen D; CMS study group. Postoperative word-finding difficulties in children with posterior fossa tumours: a crosslinguistic European cohort study. Childs Nerv Syst. 2025 Mar 12;41(1):128. doi: 10.1007/s00381-025-06787-4. PMID: 40075014; PMCID: PMC11903548.