Neuro-oncology最新文献

Abstract: BackgroundPediatric-type low-grade gliomas (PLGG) are the most common central nervous system (CNS) tumor in children. Many are indolent and have excellent outcomes; however, some inexplicably spread throughout the CNS leading to increased morbidity and mortality.

Methods: To better understand this rare and difficult-to-treat entity, as well as the features associated with dissemination in CNS tumors, we assembled a large international cohort (n = 269) of patients with disseminated PLGG with detailed clinical and molecular characterization, including DNA sequencing and methylome profiling.

Results: We identified three subgroups of patients based on the temporal and spatial distribution of dissemination. Tumors with diffuse leptomeningeal spread without a primary tumor mass and those occurring in infants had the worst clinical outcomes. The genetics overlapped substantially with that of non-disseminated PLGG, suggesting that non-genetic mechanisms are an important contributor to dissemination. Therapeutically, targeted RAS/MAPK-pathway inhibition was more effective than conventional chemotherapy as first or second-line treatment.

Conclusions: In sum, this cohort increases our clinical and biological understanding of this rare disease, provides insights for improving patient care, and directs future clinical trials and basic science research.

Background: Dysregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway has been recognized as a pivotal oncogenic driver in Glioblastoma multiforme (GBM) progression. Although PI3K inhibitors have demonstrated initial therapeutic efficacy, the development of resistance through compensatory upregulation of alternative signaling pathways substantially limits their clinical benefits. However, the molecular mechanisms underlying this resistance to PI3K monotherapy in GBM remain incompletely understood.

Methods: Multiple patient-derived glioblastoma models including organoids (GBOs), primary dissociated cells (PDCs) and xenografts (PDCX) were established as clinically relevant platforms to evaluate the feasibility of tailored therapy. Comprehensive molecular profiling and functional analyses were conducted across these patient-derived models. RNA sequencing, mass spectrometry, DNA spreading assays, HR/NHEJ reporter assays and mIF were performed to elucidate the molecular underpinnings of PI3K and cyclin-dependent kinase 4/6 (CDK4/6) co-activation in driving tumor evolution, and to reveal the synthetic lethality efficacy of the concurrent strategy.

Results: Our findings demonstrate that PI3K monoinhibition induces aberrant CDK4/6 activation, and co-activation of PI3K-CDK4/6 signaling positively correlates with monotherapy resistance, which is driven by tumor evolution. The concurrent strategies with PI3K and CDK4/6 inhibition synergistically achieve therapeutic efficacy in suppressing the growth of GBOs, PDCs and PDCX. Mechanistically, insufficient DNA damage response under PI3Ki mono-therapy upregulated CDK4/6, driving aberrant cell cycle progression. The small-molecule inhibitors paxalisib and ribociclib potently suppress tumor proliferation, which induced persistent replication stress and genomic instability.

Conclusions: Employing multiple patient-derived models, our study uncovers clinically relevant PI3Ki resistance mechanisms and advocates a rationale for synthetic lethality through combined PI3K-CDK4/6 inhibition, offering substantial therapeutic potential for GBM patients.

Abstract: BackgroundCurrent treatment strategies for pediatric intracranial ependymoma do not consider molecular heterogeneity. Here, we evaluated molecular group-specific determinants of outcome and developed an improved risk stratification model.

Methods: Patients aged 0-21 years with localized intracranial ependymoma were enrolled into the prospective clinical trial E-HIT2000. Treatment included maximum safe surgery, local radiotherapy, and chemotherapy, stratified according to age, histology and, following a major amendment, residual tumor. Clinical data were analyzed in a pooled molecularly annotated cohort with data from patients treated analogously within subsequent registries.

Results: For 291 trial patients, the 5-year progression-free survival (PFS) and overall survival (OS) were 62 ± 3% and 81 ± 2%, respectively. For the molecularly annotated pooled cohort (n = 228), 5-year PFS/OS were: posterior-fossa group A ependymoma (EPN-PFA) (n = 146): 45 ± 4%/77 ± 4%; posterior-fossa group B ependymoma (EPN-PFB) (n = 19): 90 ± 7%/100%; supratentorial ependymoma, ZFTA fusion-positive (EPN-ZFTA) (n = 59): 64 ± 7%/86 ± 5%; supratentorial ependymoma, YAP1 fusion-positive (EPN-YAP1) (n = 4): 50 ± 25%/100%. Patients with EPN-PFA without molecular risk factors (1q gain, and/or subtype EPN-PFA1c/d/e, 2a), with complete resection, and postoperative radiotherapy showed favorable outcomes (5-year PFS/OS 75 ± 10%/92 ± 7%). For patients with EPN-PFA with molecular risk factors, prognosis was poor irrespective of residual tumor status (5-year PFS/OS: 33 ± 6%/64 ± 6%). Among EPN-ZFTA, 11/59 tumors were classified as EPN-ZFTA with alternative fusions, associated with inferior PFS (5-year PFS/OS: 36 ± 15%/91 ± 9%). For EPN-ZFTA-RELA, homozygous deletions of CDKN2A were associated with unfavorable outcomes (4-year PFS/OS: 19 ± 16%/57 ± 18% vs. 79 ± 7%/97 ± 3%, P = .0001). Finally, we developed a novel stratification model that discriminates standard and intermediate risk patients from those at high risk (P < .0001 for PFS and OS).

Conclusions: These results strongly suggest the inclusion of molecular parameters into stratification and the use of distinct treatment strategies within future ependymoma trials.

Background: Glioblastoma (GBM) is a lethal tumor, actively growing and invading neighboring neural tissue. GBMs appear functionally connected to distributed and spatially distant regions rather than representing an isolated and passive lesion disrupting the brain circuitry. Moreover, increasing evidence suggests that white matter serves as the morphological substrate for GBM to progress and migrate to distant areas in the human brain.

Methods: We hypothesized that the subset of white matter tracts intersecting the tumors depicts the physical substrate for large-scale neuron-glioma interactions and would therefore inform prognosis. Using normative models, we design, analyze, interpret, and test a Lesion-Tract Density Index (L -TDI) marker that considers the distributed white matter pathways interacting with the tumor in 2 independent cohorts of N=367 and N=496 patients, respectively.

Results: First, we show that the tract density within this white matter map robustly stratifies survival rates due to widespread white matter involvement. Second, we demonstrate why tract density-based markers offer critical and necessary insights into the morphology, location, and evolution of human GBM by proving how the proposed L -TDI implicitly considers tumor volume, white matter density, and location. We provide further evidence that the non-uniform distribution of GBMs and their differential prognosis emerge from white matter morphology. Third, we validate the L -TDI marker with multiple Cox survival models and analyze its contribution in relation to other covariates of interest (eg, MGMT promoter methylation). Lastly, by using a simple logistic model, we predict patient death at 12 months with balanced accuracies of 68% and 65%, and areas under the curve of 0.74 and 0.73 when training and testing in separate and independent cohorts.

Conclusions: Overall, we offer a concrete implementation of the emerging paradigm that views GBM not as a focal lesion, but as a network disease sh aped by its complex interactions with distant brain regions.

Intracranial metastases (ICM), specifically parenchymal brain metastases, remain a major clinical challenge in solid tumor oncology, despite recent advances in cancer therapies which have led to improvements in survival for these patients. Improving outcomes even further in this patient population will require a multi-disciplinary approach, including pre-clinical and translational studies, clinical trials, and studies of patient reported outcomes and quality of life. At the 2023 and 2024 joint Society for Neuro-Oncology (SNO) and American Society of Clinical Oncology (ASCO) CNS Metastases Conferences, two ICM collaborative group think tanks convened, composed of diverse, multi-disciplinary stakeholders, including basic and translational researchers, clinical trialists, and clinicians from academia and the community setting. Here we summarize the key knowledge gaps and consensus recommendations put forth by these two think tanks. Advances in ICM research and improvements in patient outcomes will require close inter-specialty and inter-institutional collaboration between stakeholders, including pre-clinical and translational researchers, clinical investigators, industry, and regulatory bodies.

Background: Preclinical studies demonstrate activity of poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors in isocitrate dehydrogenase (IDH) mutant gliomas. We investigated safety, tolerability, pharmacokinetics, and efficacy of the PARP inhibitor pamiparib in conjunction with metronomic low-dose temozolomide in patients with recurrent IDH mutant (IDHmt) gliomas in a multicenter Phase I/II/window of opportunity study.

Methods: Patients received pamiparib in conjunction with daily temozolomide. Following Phase I determination of maximum tolerated dose (MTD), we enrolled 2 patient cohorts (Arm A, multiple prior chemotherapy regimens; Arm B, single prior regimen) in a 2-stage design. Exploratory cohorts examined grade 4 IDHmt patients and intratumoral pharmacokinetics of pamiparib. The primary endpoint was objective radiographic response (ORR) by RANO criteria.

Results: Sixty-six subjects were enrolled. We established pamiparib 60 mg twice daily with temozolomide 20 mg daily as the phase II dose. In non-enhancing and enhancing tumor, pamiparib exhibited an unbound tumor/plasma ratio of 0.92 and 0.98, respectively. 0/15 Arm A and 1/24 Arm B patients achieved a centrally confirmed partial response. Median progression-free survival for Arm A was 5.9 months (95% CI, 1.2-14.8 months), and for Arm B was 9.7 months (95% CI, 5.7-21.7 months). Grade 3+ anemia and neutropenia affected 24% and 33% of patients, respectively. Twenty-two of 66 patients (33.3%) discontinued study treatment for reasons other than tumor progression.

Conclusions: Pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors. While some patients achieved prolonged progression-free survival, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial and impacted long-term tolerability.

Background: Recurrence invariably occurs in patients with high-grade glioma (HGG) despite maximal definitive therapy. Currently, there is no standard-of-care salvage treatment approach and re-irradiation is considered an option for select patients. Various radiotherapy fractionation schedules have been investigated, including the use of stereotactic radiosurgery (SRS). The aim of this study was to provide clinical practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS) specific to salvage SRS for recurrent-HGG. We define SRS as focal radiation in a single fraction and hypofractionated radiosurgery (HFSRS) as focal radiation delivered over 2-5 fractions.

Methods: A literature review and meta-analysis were performed according to PRISMA guidelines. Recommendations were formulated according to DELPHI methodology.

Results: Sixty-two studies met the eligibility criteria for analyses, resulting in 2640 recurrent HGG patients. Stereotactic radiosurgery to a median total dose of 16 Gy was performed in 75% of patients, and HFSRS to the remaining 25% with a median total dose and number of fractions of 25 Gy and 5 fractions, respectively. The median overall survival from re-irradiation was 10.2 months. The pooled neurological toxicity rates were lower with HFSRS compared to SRS (4% vs. 7%, P = 0.001). A cumulative EQD2 greater than 120-130 Gy was significantly associated with a greater risk of radiation necrosis (P = 0.003).

Conclusions: Focal re-irradiation with 16 Gy in single fraction or 24-25 Gy in 3-5 fractions, is safe and appears to be effective for recurrent-HGG. We also present clinical practice recommendations on behalf of the ISRS. Given the limited prospective data, no definitive conclusions can be drawn.