WHO grade II-III gliomas affect rather young individuals and are characterized by a heterogenous survival prognosis ranging from months to years. Postoperative treatment prolongs survival but potentially impacts long-term quality of life and cognitive functioning. Therefore, refined prognostic stratification models are needed to guide future treatment studies.
Patients with histological diagnosis of WHO grade II/III glioma (lower-grade glioma, LGG) and treated in 2000 – 2018 at the Medical University of Vienna were identified. Short-term survivors (STS) were defined by OS < 12 months, while long-term survivors (LTS) were defined by OS > 10 years after diagnosis. Histological diagnosis according to the current WHO classification was done by a board-certified neuropathologist. DNA methylation profiling was performed using the Illumina EPIC 850k platform and methylation-based tumor classification was obtained using the Heidelberg Methylation Classifier.
Among 599 LGG patients, 123 LTS (20.5%; 40/123 astrocytic, 44/123 oligodendroglial, 39/123 not otherwise specified or pre-WHO 2016 diagnosis = NOS) and 36 STS (6.0%, 24/36 astrocytic, 1/36 oligodendroglial, 11/36 NOS) were identified. At LGG diagnosis, Karnofsky Performance Scale (KPS) was lower (p < 0.001) and age was higher in STS as compared to LTS (p < 0.001). Epileptic seizures were more frequent in LTS, while motor deficits (p < 0.001), aphasia (p = 0.025) and visual disturbances (p = 0.031) were more common in STS at diagnosis. WHO grade II,
Our data indicate that DNA methylation profiling identifies
The authors.
Has not received any funding.
M. Preusser: Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Bayer; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Bristol-Myers Squibb; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Novartis; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Gerson Lehrman Group (GLG); Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: CMC Contrast; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: GlaxoSmithKline; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Mundipharma; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Roche; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: BMJ Journals; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: MedMedia; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: AstraZeneca; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: AbbVie; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Lilly; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Medahead; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Daiichi Sankyo; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Sanofi; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Merck Sharp & Dohme; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Tocagen; Financial Interests, Institutional, Funding: Boehringer Ingelheim; Financial Interests, Institutional, Funding: Bristol-Myers Squibb; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Institutional, Funding: Merck Sharp & Dohme; Financial Interests, Institutional, Funding: Novocure; Financial Interests, Institutional, Funding: GlaxoSmithKline; Financial Interests, Institutional, Funding: AbbVie. A.S. Berghoff: Financial Interests, Personal, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Roche; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Bristol-Myers Squibb; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Merck; Financial Interests, Personal, Other, Lectures, consultation or advisory board participation: Daiichi Sankyo; Financial Interests, Personal, Funding, Travel support: Roche; Financial Interests, Personal, Funding, Travel support: Amgen; Financial Interests, Personal, Funding, Travel support: AbbVie. All other authors have declared no conflicts of interest.
Medulloblastoma (MB) is extremely rare in adults (1% of CNS tumors). Comparative studies show important biological differences between adult and pediatric patients with implications in clinical behaviour and patient outcomes. Although MB is potentially curable with a multidisciplinary approach comprising a combination of maximal safe resection, craniospinal irradiation (CSI), and chemotherapy (CT), the lack of specific studies in the adult subpopulation forces oncologist to adapt treatment regimens.
GEINO Neuro-oncologists were asked to register MB patients in the GEINO-GETHI National CNS tumor register (pts alive at the time of inclusion gave informed consent).
Between 1996 and 2021, 71pts either diagnosed as adults (median age 32y range 18-71) or referred to adult units (7pts), were identified. 42% were female, common symptoms included headache (69%) and ataxia (31%). Of 14 pts with molecular classification, 10 were SHH+(1 pt p53 mutated) and the others non-WNT non-SHH+ and of 23 patients with histological subtype 19 were desmoplasic-nodular. 70,6% underwent complete resection, 23,5 partial and 5,9 biopsy. 95% received radiotherapy, most commonly to the tumor (61%) with a median dose of 55Gy and to the neuroaxis (48%) with a median dose of 36 Gy. Diverse treatment strategies were used: sequential chemotherapy 42.9% (of wich 29% Vincristine-lomustine-platin), 19% concomitant and sequential (80%concomitant vincristine followed in 50% by Vincristine-lomustine-platin), 14% only concomitant CT (66% with vincristine) 7.9% only neoadjuvant(80% carboplatin-VP16, followed in 40% by the same schema) and 7.9% only CT(66% with a platin-VP16 triplet). Median survival was 14,37y and 70.1% remain relapse free.
Significant heterogeneity is present in the management of adult MB in Spain. Although treatment in MB should be individualized and treatment outcomes are in line with published series, differences in treatment schemas and availability of molecular diagnostic tools highlight the importance of collaborative groups to standardize management.
GEINO-GETHI.
GEINO, GETHI.
All authors have declared no conflicts of interest.
Radio- and immunotherapy were postulated to have synergistic efficacy in brain metastasis (BM) treatment due to the immune modulating properties of radiation. Therefore, we aimed to investigate changes in the inflammatory microenvironment after local radiation treatments in BM specimens.
Formalin fixed and paraffin embedded BM samples from treatment naïve patients (group 1) and from patients treated whole brain radiotherapy (WBRT) (group 2) or stereotactic radiosurgery (SRS) (group 3) or combined WBRT and SRS (group 4) or prophylactic cranial irradiation (group 5) before BM resection were identified from the Vienna Brain Metastasis Registry. T cell subsets (CD3+, CD8+, CD45RO+, FOXP3+ and LAG3) as well as expression of PD-L1 were investigated.
Specimens from 81 patients (55 lung cancer, 15 breast cancer, 4 renal cell cancer, 1 melanoma, 1 colorectal cancer & 5 other tumor types) were available for analysis. Group 1 presented with statistically significantly higher CD3+ (median: 492.6 cells/mm2), CD8+ (median: 116.3 cells/mm2) and LAG3+ (median: 17.6 cells/mm2) TIL densities than group 2 (CD3+ median:55.5 cells/mm2; LAG3+ median: 4.6 cells/mm2), group 3 (CD3+ median: 67.7 cells/mm2; CD8+ median: 40.6 cells/mm2) and group 4 (CD3+ median: 38.28 cells/mm2; p-value <0.05; Kruskal Wallis test). No significant changes of the inflammatory microenvironment in group 5 compared to the other groups, and in PD-L1 expressions between the groups were observed (p-value >0.05; Kruskal Wallis test). Of 24/81 (29.6%) patients matched samples of initial resected BM and recurrent BM were available. All investigated T cell subsets were numerically lower in recurrent BM from patients treated with radiation therapy between resections than in recurrent BM from patients without radiation treatment between BM resections (p > 0.05; Mann-Whitney U-test).
Our data indicate an immunosuppressive effect of radiotherapy on BM, as evidenced by decreased T cell infiltration in radiated versus non-radiated BM specimens. Future clinical studies should focus on the optimal timely sequencing of immune modulating therapies and radiotherapy.
The authors.
Has not received any funding.
G. Widhalm: Financial Interests, Personal, Other: NX Development Corp. M. Preusser: Financial Interests, Personal, Funding: Boehringer Ingelheim; Financial Interests, Personal, Funding: GlaxoSmithKline; Financial Interests, Personal, Funding: Merck Sharp & Dome ; Financial Interests, Personal, Funding: Roche; Financial Interests, Advisory Board: Bristol-Myers Squibb; Financial Interests, Advisory Board: Novartis; Financial Interests, Advisory Board: Gerson Lehrman Group ; Financial Interests, Advisory Board: CMC Contrast; Financial Interests, Advisory Board: GlaxoSmithKline; Financial Interests, Advisory Board: Mundipharma; Financial Interests, Advisory Board: Roche; Financial Interests, , Advisory Board: AstraZeneca; Financial Interests, Advisory Board: AbbVie; Financial Interests, Advisory Board: Lilly; Financial Interests, Advisory Board: Medahead; Financial Interests, Advisory Board: Daiichi Sankyo; Financial Interests, , Advisory Board: Merck Sharp & Dohme. A.S. Berghoff: Financial Interests, Personal, Funding: Daiichi Sankyo; Financial Interests, Personal, Funding: Roche Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Roche Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: AbbVie. All other authors have declared no conflicts of interest.
Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumour in adults (>60%), with very poor prognosis. First-line standard of care (SoC) treatment for patients involves surgery/surgical resection along with radiation therapy (RT) and concomitant adjuvant temozolomide (TMZ). Idroxioleic acid (2-hydroxyoleic acid sodium salt; 2-OHOA), a new class of orally bioavailable fatty acid that modulates the lipid composition and structure of the membranes, has shown specific effects against cancer due to a dual-mode molecular mechanism of action (cell cycle arrest and programmed cell death by non-protective autophagy in glioma). The aim of this study was to determine the safety, tolerability and maximum tolerated dose of 2-OHOA added to first-line SoC for newly diagnosed GBM patients.
A phase 1B, open-label, dose-finding study, 3+3 de-escalating design (starting at 12 g/day). The trial (NCT03867123) recruited newly diagnosed GBM patients with a partial or complete surgical resection of the grade 4 astrocytic tumour in two independent arms: arm 1 (6-week concurrent phase of RT + TMZ + 2-OHOA) and arm 2 (8-week maintenance phase of TMZ + 2-OHOA). Both arms were to be followed by a 4-week safety follow-up.
Nineteen patients were recruited, 10 patients in Arm 1 and 9 in Arm 2. As no DLTs were found, all received 12 g/day of 2-OHOA. All patients from both arms presented at least one AE. The AEs presented in >40% of the patients were diarrhoea (8/10), headache (5/10), nausea (5/10), asthenia (4/10), constipation (4/10) and vomiting (4/10) in Arm 1, and nausea (6/8), diarrhoea (5/8) and vomiting (5/8) in Arm 2. None of the patients suffered any grade 4 or 5 AEs by CTCAE grade in any arm. The only attributed SAE in the study –embolism CTAE 3 in one patient in Cohort 1 (1/10)– was not related to 2-OHOA.
Addition of 12 g daily of 2-OHOA to standard of care (RT/TMZ) in newly diagnosed GBM patients was generally well tolerated, offered a favourable safety profile (no 2-OHOA-related serious or high-grade AEs), and it is the recommended dose of 2-OHOA for phase III trials.
NCT03867123.
Laminar Pharmaceuticals S.A.
Laminar Pharmaceuticals S.A.
C. Balaña: Financial Interests, Institutional, Advisory Board: Laminar Pharmaceutical. A. Cuesta: Financial Interests, Personal, Full or part-time Employment: Laminar Pharmaceutical. J.V. Torres: Financial Interests, Institutional, Project Lead: Laminar Pharmaceutical. J. Roma: Financial Interests, Personal, Advisory Role: Laminar Pharmaceutical. R. Taylor: Financial Interests, Personal and Institutional, Full or part-time Employment: Laminar Pharmaceutical. P.V. Escriba: Financial Interests, Personal, Ownership Interest: Laminar Pharmaceutical. E. Llobet: Financial Interests, Institutional, Project Lead: Laminar Pharmaceutical. A.G. McNicholl: Financial Interests, Personal, Full or part-time Employment: Laminar Pharmaceutical. All other authors have declared no conflicts of interest.
5-aminoleveulinic acid sonodynamic therapy (5-ALA SDT) is a drug-device strategy that exploits the metabolic liabilities of cancer. Following systemic administration of 5-ALA, incomplete tumor metabolism leads to accumulation of a photosensitive intermediary, protoporphyrin-IX (PpIX). Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces cytotoxic reactive oxygen species and tumor cell death. This first-in-human phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in recurrent glioblastoma patients (GBM).
Ascending energy doses of 5-ALA SDT are tested in adult patients with recurrent GBM undergoing planned re-resection. In a Dose-Escalation Arm, 9-18 patients are assigned to one of three dose levels of MRgFUS (200J, 400J, and 800J), followed by a four-day interval to tumor resection. In each patient, half the tumor volume, including Gadolinium-enhancing and nonenhancing tumor, is targeted with MRgFUS and the other half is an internal control. Using tumor pharmacodynamic endpoints, the Minimum Biological Dose (MBD) associated with 5-ALA SDT response is identified. In a subsequent Time-Escalation Arm, 12 patients are treated at the MBD and assigned to one of two time-intervals (two-days vs. six-day) between SDT and resection.
As of May 1, accrual to the 200J dose level was completed (n=3) without significant drug- or device-related adverse events. No cellular or radiographic changes to non-targeted tissue were observed. Following 5-ALA infusion, the median Cmax for 5-ALA and PpIX were 307 μM and 319 nM, respectively. For all patients, the oxidative stress biomarkers 4-hydroxynonenal , glutathione, cysteine, and thiol were elevated in treated tissue vs. internal control. Similarly, the apoptosis biomarker cleaved caspase-3 was increased in treated tumor vs. control (median, 48.6% vs. 29.6%, p=0.05).
This initial, first-in-human experience with a new therapeutic modality for recurrent glioblastoma indicates that 5-ALA SDT is well-tolerated and safe at 200J. Sonodynamic therapy leads to targeted oxidative stress and accompanying cell death in human glioblastoma tissue.
NCT04559685.
Neurotrials LLC.
The Ben and Catherine Ivy Foundation and Barrow Neurological Foundation.
All authors have declared no conflicts of interest.