These findings support avapritinib as a promising targeted therapy for PDGFRA-altered pediatric gliomas. Further clinical studies are warranted to validate efficacy and resistance mechanisms. 4/4

Avapritinib reduced tumor growth and improved survival in mouse models. In a small compassionate use cohort, partial responses were observed in 3/7 evaluable patients, with good tolerability. 3/n

This study showed that avapritinib, a selective PDGFRA inhibitor, crosses the blood-brain barrier and potently suppresses PDGFRA-driven signaling in preclinical pHGG models with minimal toxicity. 2/n

Effective targeting of PDGFRA-altered high-grade glioma with avapritinib PDGFRA is commonly altered in pediatric HGG. Mayr et al. report that the PDGFRA/KIT inhibitor avapritinib demonstrates on-target activity, brain penetrance, and survival benefit in pre-clinical H3K27M...

Pediatric high-grade gliomas (pHGG), including H3K27M-DMGs, remain a major cause of cancer mortality in children. ~15% harbor PDGFRA alterations - making this receptor an attractive therapeutic target 🧵 1/n 👇👇

www.cell.com/cancer-cell/...

4. UKALL 2011 confirms strong outcomes: 5-year overall survival of 92% and event-free survival of nearly 84%. Treatment-related mortality is lower than relapse risk

3. Omitting vincristine/dexamethasone pulses during maintenance showed noninferiority for bone marrow relapse, but a slight decrease in event-free survival raises caution

2. High-dose methotrexate during interim maintenance failed to reduce CNS relapse compared to standard Capizzi-style treatment

High-Dose Methotrexate in Children and Young Adults With ALL and Lymphoblastic Lymphoma: Results of the Randomized Phase III Study UKALL 2011 PURPOSEUKALL 2011 randomly assigned children and young adults (younger than 25 years) with ALL or lymphoblastic lymphoma. The aims were to reduce induction toxicity (randomization 1 [R1]), CNS relapse...

Key findings from UKALL2011: 1. Shortening dexamethasone from 28 to 14 days during induction didn’t reduce toxicity or osteonecrosis in children and young adults with ALL👇👇👇
ascopubs.org/doi/full/10....

Adding ifosfamide to MAP chemotherapy didn’t improve outcomes for osteosarcoma patients with poor response to initial treatment, and caused more side effects, says JCOG0905 trial.

ascopubs.org/doi/full/10....

Accelerated Aging in Survivors of Childhood Cancer This decision analytical model study estimates the lifetime risks of 8 treatment-related cancers and cardiovascular conditions among childhood cancer survivors and compares them with the general popul...

Survivors of childhood cancer face aging-related diseases nearly 18 years earlier than the general population, with a 2.7-fold higher risk by age 65. Early cancer and heart disease prevention should start much sooner in this group 👇👇👇

jamanetwork.com/journals/jam...

Safety, Efficacy and Total Cost of Point-of-care Manufactured anti-CD19 CAR T-cell Therapy in India: VELCART trial Point-of-care manufactured CAR T-cell therapy demonstrates a higher complete remission rate and presents a promising therapeutic option for low-middle-income countries like India. The total cost of CA...

Point-of-care CAR T-cell therapy using automated production showed strong results in 10 patients, with lower costs, good safety, and high remission rates—promising for wider access, also in low-resource settings 👇👇

www.cell.com/molecular-th...

Pediatric relapsed/refractory ALK-positive anaplastic large cell lymphoma treatment and outcomes in the targeted-drug era Key PointsALK inhibitor or brentuximab monotherapy achieve excellent responses in pediatric patients with R/R ALK-positive ALCL.Optimal targeted therapy, d

Targeted therapies like ALK inhibitors and brentuximab vedotin show strong responses in young patients with relapsed ALK+ ALCL, but questions remain about treatment duration and the need for stem cell transplant.

ashpublications.org/bloodadvance...

The source of STAT3/5 activation? Not JAK, mTOR, or PI3K. However, proteasome inhibitor bortezomib blocked the signaling response, suggesting a new angle to target therapy-resistant leukemia cells.

Mass cytometry showed that chemotherapy-treated leukemia cells had increased STAT3/5 phosphorylation after pre-BCR stimulation. This hyperactivation was not seen in untreated cells or wild-type controls.

MYC-high leukemic cells were vulnerable to BRD3/4 inhibition. Combining the MYC inhibitor JQ1 with prednisolone improved treatment response, pointing to a potential therapeutic strategy.

Leukemia cells in the spinal cord/CNS showed a unique expression pattern with upregulation of interleukin and anti-apoptotic pathways, and downregulation of metabolism-related genes. The microenvironment matters.

Single-cell analysis revealed two distinct leukemia cell phenotypes: one was more proliferative and expressed higher MYC and oxidative phosphorylation genes - this subtype became dominant after chemotherapy

Dynamic evolution of TCF3‐PBX1 leukemias at the single‐cell level under chemotherapy pressure Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. The translocation t(1;19), encoding the TCF3-PBX1 fusion, is associated with intermediate risk and central nervous system (CNS)...

Check out this new study led by Profs Duque-Afonso and Heinaniemi utilizing a mouse model of TCF3-PBX1+ leukemia that mimics human relapse after chemotherapy. About 40% of treated mice survived, with CNS infiltration, similar to clinical setting 👇👇 🧵 1/n

onlinelibrary.wiley.com/doi/10.1002/...

Targeting senescent stemlike subpopulations in Philadelphia chromosome–like acute lymphoblastic leukemia Key PointsOur study discovered new regulators of ruxolitinib response in Ph-like ALL, including c-MYC as a therapeutically targetable codependency.A progno

Multiomics profiling of resistant Ph like ALL cells revealed MYC dependency and a dormant leukemia subpopulation. Dual inhibition of BCL-2 and JAK/STAT or SRC/ABL pathways effectively eradicated these cells, offering a potential therapeutic strategy 👇

ashpublications.org/blood/articl...

Human-correlated genetic models identify precision therapy for liver cancer - Nature As proof of principle, an analysis using a suite of human-aligned immunocompetent mouse models of hepatocellular carcinoma identifies a promising therapeutic candidate, cladribine, which acts in ...

Interesting study using 27 genetically engineered mouse models that closely mimic human hepatocellular carcinoma. 4 subtypes were identified and cladribine, combined with standard therapy, showed promising efficacy for a specific subtype 👇👇

www.nature.com/articles/s41...

The somatic mutation landscape of normal gastric epithelium - Nature Whole-gene sequencing of microdissected gastric glands from individuals with and without gastric cancer reveals distinct patterns of somatic mutations and provides insights into influen...

By age 60, about 60% of the normal oesophageal epithelium is occupied by cell clones with driver mutations. In contrast, this proportion is much lower in the intestines (~1%) and *stomach* (~5%), see new study 👇👇👇

www.nature.com/articles/s41...

The end of the genetic paradigm of cancer Genome sequencing results and single-cell transcriptomics continue to produce findings that challenge the idea that cancer is purely a ‘genetic disease’. This Essay delves into cancer omics data that ...

This article challenges the traditional view that cancer is primarily a "genetic disease", proposing instead that tumorigenesis arises from disruptions in cellular and tissue organization 👇👇👇

journals.plos.org/plosbiology/...

Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma - Nature Medicine A patient with newly diagnosed glioblastoma was safely treated with neoadjuvant nivolumab, relatlimab and ipilimumab before maximal resection, with comprehensive immune profiling showing the induction...

Glioblastoma has a dismal prognosis and resists also immunotherapy. Here, a case report with a neoadjuvant dose of triple checkpoint inhibitors before surgery led to strong immune activation and no recurrence after 17 months 👇👇👇

www.nature.com/articles/s41...

Overall, the findings identify a new, subtype-specific interaction between neurons and glioma cells that could have clinical implications, especially regarding the use of GABA-modulating drugs in DMG patients. 5/5

Importantly, lorazepam, a common GABA-enhancing drug, increased tumor growth and shortened survival in these models. This effect was not seen in hemispheric gliomas, where GABAergic input was minimal and non-stimulatory 4/n

The researchers confirmed that GABAergic signals form functional synapses with tumor cells and drive tumor growth using advanced techniques, including patch-clamp recordings, optogenetics, and mouse models 3/n

Unlike in healthy brain tissue, where GABA usually inhibits activity, in DMG cells, GABA causes depolarization—a state that promotes tumor proliferation. This is due to altered chloride transport in DMG cells via the NKCC1 protein, which raises intracellular chloride levels 2/n

GABAergic neuron-to-glioma synapses in diffuse midline gliomas - Nature Functional, tumour-promoting GABAergic neuron-to-glioma synapses in diffuse midline gliomas are identified.

This study reveals a surprising and tumor-specific mechanism by which GABAergic neurons promote the growth of diffuse midline gliomas (DMGs), particularly those with H3K27M mutations 👇👇 🧵🧵 1/n

www.nature.com/articles/s41...

Urinary Catecholamines Predict Relapse During Complete Remission in High-Risk Neuroblastoma | JCO Precision Oncology PURPOSEUrinary catecholamine metabolites are well-known biomarkers for the diagnosis (Dx) of neuroblastoma, but their clinical significance in determining therapy response during treatment is not well...

In high-risk neuroblastoma, catecholamine positivity at complete remission (CR) predicted worse event-free (38% vs. 80%) and overall survival (52% vs. 86%). 3-methoxytyramine at CR was a strong prognostic marker for poor OS (HR 7.5, 95% CI 2.0–28.6) 👇

ascopubs.org/doi/10.1200/...

Children with predisposition may benefit from variant-specific management. Extended neoadjuvant treatment could be considered for WT1 and TRIM28 mutations, though WT1-driven tumours may require novel agents. Clonal architecture distortions might inform recurrence risk