Glossary — DLGNT & PXA Clinical-Development Summary

The two tumours

Both are MAPK-pathway-driven, which is the whole reason they sit in scope for a pan-RAF inhibitor.

DLGNTDiffuse Leptomeningeal Glioneuronal Tumor

A rare tumour of oligodendrocyte-like cells that spreads diffusely along the leptomeninges rather than forming one mass. Defined molecularly — 1p deletion plus MAPK activation — rather than by appearance alone. Mostly paediatric.

PXAPleomorphic Xanthoastrocytoma

An astrocytoma of varied ("pleomorphic") fat-laden ("xantho-") cells, usually superficial and cystic with an enhancing nodule. Characteristically BRAF-V600E plus loss of CDKN2A/B. Children and young adults.

Glioneuronal

A tumour showing both glial and neuronal features — it does not fit cleanly into either family.

Leptomeninges

The inner two membranes covering the brain and spinal cord. Disease that spreads through them is hard to resect and hard to measure.

Supratentorial

Above the tentorium — the upper part of the brain, including the temporal lobe where most PXA arises.

Mural nodule

A solid lump in the wall of a cyst. On MRI, a cyst with an enhancing mural nodule is the classic PXA picture.

Molecular findings

BRAF

A gene in the MAPK pathway. When altered, it drives continuous growth signalling — the target plixorafenib is aimed at.

BRAF V600E

A single point mutation at codon 600. The common, well-characterised BRAF alteration, typical of PXA.

KIAA1549::BRAF fusion

Two genes joined so BRAF is switched permanently on. Typical of DLGNT and of paediatric low-grade glioma — a different alteration class from V600E, which matters because first-generation inhibitors behave differently against it.

MAPK pathway

The growth-signalling cascade BRAF sits in (RAS → RAF → MEK → ERK). "MAPK-driven" means the tumour depends on it.

Pan-RAF / paradox-breaker

A drug designed to inhibit RAF broadly without the paradoxical activation that first-generation inhibitors cause in some cells — the mechanistic argument for plixorafenib.

Paradoxical activation

The counter-intuitive effect where a BRAF inhibitor switches the pathway ON in cells with normal BRAF, which can drive secondary lesions.

CDKN2A/B deletion

Loss of a tumour-suppressor pair. "Homozygous" means both copies are gone. In PXA it is part of the defining profile and carries grading weight.

TERT alterations

Changes that let cells keep dividing indefinitely. Enriched in higher-grade (anaplastic) PXA.

IDH-wildtype

No IDH mutation present. In CNS tumour classification this is a major branch point, so it is stated explicitly even when negative.

1p deletion / 1q gain

Loss of the short arm / gain of the long arm of chromosome 1. In DLGNT, 1p deletion is part of the definition; 1q gain marks the poorer-outcome group.

Methylation class (MC-1 / MC-2)

Groups defined by DNA-methylation profiling rather than by microscope appearance. In DLGNT they separate outcomes more sharply than histology does — which is why the report leads with them.

Pathology & grading

CNS WHO grade

The World Health Organization's malignancy grade for a CNS tumour (1–4). Increasingly set by molecular features, not appearance alone.

Anaplastic

More aggressive-looking, less differentiated tissue — for PXA, the grade 3 designation.

Mitoses per mm² / per 10 HPF

How many cells are actively dividing, counted per area. HPF = high-power field. The grade 2/3 split for PXA rests on this count.

Ki-67

A stain marking dividing cells; a higher index means faster proliferation.

Eosinophilic granular bodies

Pink granular blobs seen under the microscope — a supportive feature for PXA.

Reticulin

A fibre network highlighted by a special stain; its pattern helps identify PXA.

Evidence & outcomes

OSOverall Survival

Time from a defined start point until death from any cause. "5-yr OS 100%" means all patients in that group were alive at five years.

PFSProgression-Free Survival

Time without the disease worsening or the patient dying.

ORRObjective Response Rate

The share of patients whose tumour shrank by a pre-defined amount.

RWEReal-World Evidence

Evidence from routine care — registries, records, published series — rather than from a controlled trial.

PMID

A PubMed identifier. Every reference in the report carries one so a claim can be traced to its source.

Xenograft

Human tumour tissue grown in an animal model, used to test a drug before human trials.

Preclinical

Laboratory and animal work done before human testing.

Regulatory & development

INDInvestigational New Drug application

The FDA submission that permits human testing to begin.

Tissue-agnostic approval

Approval based on a molecular alteration wherever it occurs, rather than on one tumour type — directly relevant to a BRAF-driven programme spanning several rare tumours.

RACE for Children Act

US law requiring paediatric study of adult cancer drugs aimed at molecular targets on FDA's list. BRAF is on that list.

Rare Pediatric Disease designation / PRV

A designation that can yield a Priority Review Voucher on approval — a transferable, saleable asset. The report flags that the programme's authorization lapsed and reauthorization is pending: verify before relying on it.

EMA

European Medicines Agency — the EU regulator.

PIPPaediatric Investigation Plan

The EMA-agreed plan for studying a medicine in children. Mandatory, and it shapes the European timeline.

Conditional MA

Conditional Marketing Authorisation — EU approval on less complete data, with obligations to complete it afterwards.

Designation

A formal status granted by a regulator (orphan, breakthrough, rare paediatric) carrying specific procedural or commercial benefits.

HITLHuman In The Loop

A required human review step. The report carries a HITL gate: medical and regulatory sign-off before any external use.

Comparator drugs named in the report

Vemurafenib

A first-generation BRAF V600 inhibitor. Approved in melanoma and Erdheim-Chester disease — the report notes it has no CNS or glioma indication.

Dabrafenib

A BRAF V600 inhibitor, usually combined with trametinib.

Trametinib

A MEK inhibitor. MEK sits downstream of BRAF, so blocking both suppresses the pathway more completely and delays resistance.

MEK

The kinase immediately downstream of RAF in the MAPK cascade.