Summary The diagnosis and classification of glioma by liquid biopsy represent a critical unmet need in neuro-oncology. A recent study demonstrates targeted next-generation sequencing of cell-free DNA ...from cerebrospinal fluid as an evolving option for liquid biopsy in patients with glioma. See related article by Iser et al., p. 2974
The ability of diffusion tensor MRI to detect the preferential diffusion of water in cerebral white matter tracts enables neurosurgeons to noninvasively visualize the relationship of lesions to ...functional neural pathways. Although viewed as a research tool in its infancy, diffusion tractography has evolved into a neurosurgical tool with applications in glioma surgery that are enhanced by evolutions in crossing fiber visualization, edema correction, and automated tract identification. In this paper the current literature supporting the use of tractography in brain tumor surgery is summarized, highlighting important clinical studies on the application of diffusion tensor imaging (DTI) for preoperative planning of glioma resection, and risk assessment to analyze postoperative outcomes. The key methods of tractography in current practice and crucial white matter fiber bundles are summarized. After a review of the physical basis of DTI and post-DTI tractography, the authors discuss the methodologies with which to adapt DT image processing for surgical planning, as well as the potential of connectomic imaging to facilitate a network approach to oncofunctional optimization in glioma surgery.
Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a ...pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
Purpose
Since the discovery of
IDH
mutations in glioma over a decade ago, significant progress has been made in determining how these mutations affect epigenetic, transcriptomic, and metabolic ...programs in brain tumor cells. In this article, we summarize current understanding of how
IDH
mutations influence DNA damage in glioma and discuss clinical implications of these findings.
Methods
We performed a thorough review of peer-reviewed publications and provide an overview of key mechanisms by which
IDH
mutations impact response to DNA damage in gliomas, with an emphasis on clinical implications.
Results
The effects of mutant IDH on DNA damage largely fall into four overarching categories: Gene Expression, Sensitivity to Alkylating Agents, Homologous Recombination, and Oxidative Stress. From a mechanistic standpoint, we discuss how mutant IDH and the oncometabolite (
R
)-2HG affect each of these categories of DNA damage. We also contextualize these mechanisms with respect to ongoing clinical trials. Studies are underway that incorporate current standard-of-care therapies, including radiation and alkylating agents, in addition to novel therapeutic agents that exert genotoxic stress specifically in IDH-mutant gliomas. Lastly, we discuss key unanswered questions and emerging data in this field that have important implications for our understanding of glioma biology and for the development of new brain tumor therapies.
Conclusion
Mounting preclinical and clinical data suggest that
IDH
mutations alter DNA damage sensing and repair pathways through distinct mechanisms. Future studies are needed to deepen our understanding of these processes and provide additional mechanistic insights that can be leveraged for therapeutic benefit.
The remarkable heterogeneity of glioblastoma, across patients and over time, is one of the main challenges in precision diagnostics and treatment planning. Non-invasive in vivo characterization of ...this heterogeneity using imaging could assist in understanding disease subtypes, as well as in risk-stratification and treatment planning of glioblastoma. The current study leveraged advanced imaging analytics and radiomic approaches applied to multi-parametric MRI of de novo glioblastoma patients (n = 208 discovery, n = 53 replication), and discovered three distinct and reproducible imaging subtypes of glioblastoma, with differential clinical outcome and underlying molecular characteristics, including isocitrate dehydrogenase-1 (IDH1), O
-methylguanine-DNA methyltransferase, epidermal growth factor receptor variant III (EGFRvIII), and transcriptomic subtype composition. The subtypes provided risk-stratification substantially beyond that provided by WHO classifications. Within IDH1-wildtype tumors, our subtypes revealed different survival (p < 0.001), thereby highlighting the synergistic consideration of molecular and imaging measures for prognostication. Moreover, the imaging characteristics suggest that subtype-specific treatment of peritumoral infiltrated brain tissue might be more effective than current uniform standard-of-care. Finally, our analysis found subtype-specific radiogenomic signatures of EGFRvIII-mutated tumors. The identified subtypes and their clinical and molecular correlates provide an in vivo portrait of phenotypic heterogeneity in glioblastoma, which points to the need for precision diagnostics and personalized treatment.
Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment
. Lysine functions as a biosynthetic molecule, ...energy source and antioxidant
, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8
T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.
5-aminolevulinic acid (5-ALA) is a porphyrin precursor in the heme synthesis pathway. When supplied exogenously, certain cancers consume 5-ALA and convert it to the fluorogenic metabolite ...protoporphyrin IX (PpIX), causing tumor-specific tissue fluorescence. Preoperative administration of 5-ALA is used to aid neurosurgical resection of high-grade gliomas such as glioblastoma, allowing for increased extent of resection and progression free survival for these patients. A subset of gliomas, especially low-grade tumors, do not accumulate PpIX intracellularly or readily fluoresce upon 5-ALA administration, making gross total resection difficult to achieve in diffuse lesions. We review existing literature on 5-ALA metabolism and PpIX accumulation to explore potential mechanisms of 5-ALA-induced glioma tissue fluorescence. Targeting the heme synthesis pathway and understanding its dysregulation in malignant tissues could aid the development of adjunct therapies to increase intraoperative fluorescence after 5-ALA treatment.
Although the use of topical vancomycin has been shown to be safe and effective for reducing postoperative infection rates in patients after spine surgery, its use in cranial wounds has not been ...studied systematically. The authors hypothesized that topical vancomycin, applied in powder form directly to the subgaleal space during closure, would reduce cranial wound infection rates.
A cohort of 150 consecutive patients who underwent craniotomy was studied retrospectively. Seventy-five patients received 1 g of vancomycin powder applied in the subgaleal space at the time of closure. This group was compared with 75 matched-control patients who were accrued over the same time interval and did not receive vancomycin. The primary outcome measure was the presence of surgical site infection within 3 months. Secondary outcome measures included tissue pH from a subgaleal drain and vancomycin levels from the subgaleal space and serum.
Vancomycin was associated with significantly fewer surgical site infections (1 of 75) than was standard antibiotic prophylaxis alone (5 of 75; p < 0.05). Cultures were positive for typical skin flora species. As expected, local measured vancomycin concentrations peaked immediately after surgery (mean ± SD 499 ± 37 μg/ml) and gradually decreased over 12 hours. Vancomycin in the circulating serum remained undetectable. Subgaleal topical vancomycin was associated with a lower incidence of surgical site infections after craniotomy. The authors attribute this reduction in the infection rate to local vancomycin concentrations well above the minimum inhibitory concentration for antimicrobial efficacy.
Topical vancomycin is safe and effective for reducing surgical site infections after craniotomy. These data support the need for a prospective randomized examination of topical vancomycin in the setting of cranial surgery.
Abstract
BACKGROUND
Surgical-site infections (SSIs) are an important cause of morbidity and mortality in neurosurgical patients. Topical antibiotics are one potential method to reduce the incidence ...of these infections.
OBJECTIVE
To examine the efficacy of topical vancomycin applied within the wound during craniotomy in a large prospective cohort study at a major academic center.
METHODS
Three hundred fifty-five patients were studied prospectively in this cohort study; 205 patients received 1 g of topical vancomycin powder in the subgaleal space while 150 matched control patients did not. Patients otherwise received identical care. The primary outcome variable was SSI rate factored by cohort. Secondary analysis examined cost savings from vancomycin usage estimated from hospital costs associated with SSI in craniotomy patients.
RESULTS
The addition of topical vancomycin was associated with a significantly lower rate of SSI than standard of care alone (0.49% 1/205 vs 6% 9/150, P = .002). Based on the costs of revision surgery for infections, topical vancomycin usage was estimated to save $1367 446 per 1000 craniotomy patients. No adverse reactions occurred.
CONCLUSION
Topical vancomycin is a safe, effective, and cost-saving measure to prevent SSIs following craniotomy. These results have broad implications for standard of care in craniotomy.
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