Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of ...isocitrate dehydrogenase resulting in an accumulation of the "oncometabolite" 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism. This study aims to assess tumor metabolism using 2D L-COSY at 7T for the detection of 2HG in IDH-mutant gliomas.
Nine treatment-naïve patients with suspected intracranial neoplasms were scanned at 7T MRI/MRS scanner using the 2D L-COSY technique. 2D-spectral processing and analyses were performed using a MATLAB-based reconstruction algorithm. Cross and diagonal peak volumes were quantified in the 2D L-COSY spectra and normalized with respect to the creatine peak at 3.0 ppm and quantified data were compared with previously-published data from six normal subjects. Detection of 2HG was validated using findings from immunohistochemical (IHC) staining in patients who subsequently underwent surgical resection.
2HG was detected in both of the IDH-mutated gliomas (grade III Anaplastic Astrocytoma and grade II Diffuse Astrocytoma) and was absent in IDH wild-type gliomas and in a patient with breast cancer metastases. 2D L-COSY was also able to resolve complex and overlapping resonances including phosphocholine (PC) from glycerophosphocholine (GPC), lactate (Lac) from lipids and glutamate (Glu) from glutamine (Gln).
This study demonstrates the ability of 2D L-COSY to unambiguously detect 2HG in addition to other neuro metabolites. These findings may aid in establishing 2HG as a biomarker of malignant progression as well as for disease monitoring in IDH-mutated gliomas.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Histopathologic assessment routinely provides rich microscopic information about tissue structure and disease process. However, the sections used are very thin, and essentially capture only 2D ...representations of a certain tissue sample. Accurate and robust alignment of sequentially cut 2D slices should contribute to more comprehensive assessment accounting for surrounding 3D information. Towards this end, we here propose a two-step diffeomorphic registration approach that aligns differently stained histology slides to each other, starting with an initial affine step followed by estimating a deformation field. It was quantitatively evaluated on ample (
= 481) and diverse data from the automatic non-rigid histological image registration challenge, where it was awarded the second rank. The obtained results demonstrate the ability of the proposed approach to robustly (average robustness = 0.9898) and accurately (average relative target registration error = 0.2%) align differently stained histology slices of various anatomical sites while maintaining reasonable computational efficiency (<1 min per registration). The method was developed by adapting a general-purpose registration algorithm designed for 3D radiographic scans and achieved consistently accurate results for aligning high-resolution 2D histologic images. Accurate alignment of histologic images can contribute to a better understanding of the spatial arrangement and growth patterns of cells, vessels, matrix, nerves, and immune cell interactions.
Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full ...spectrum of ROS1-fusion positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1-fusion gliomas along with the characterization and meta-analysis of new and published cases. The cohort of 32 new and 58 published cases was divided into three age groups: 19 infants, 40 pediatric patients, and 31 adults with gliomas. Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histological features. GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups, and ten other partner genes were identified. Adult tumors showed recurrent genomic alterations characteristic of IDH-wild-type glioblastoma, including +7/-10/CDKN2A deletion; amplification of CDK4, MDM2, and PDGFRA; and mutations involving TERTp, TP53, PIK3R1, PIK3CA, PTEN, and NF1. Infant tumors showed few genomic alterations, whereas pediatric tumors showed moderate genomic complexity. The outcomes were significantly poorer in adult patients. Although not statistically significant, tumors in infant and pediatric patients with high-grade histology and hemispheric location appeared more aggressive than tumors with lower-grade histology or those in non-hemispheric locations. In conclusion, this study is the largest-to-date to characterize the clinicopathological and molecular signatures of ROS1-fusion positive gliomas from infant, pediatric, and adult patients. We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or co-driver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy.
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The
gene is among the most commonly deranged genes in GBM and thus an important ...therapeutic target. We report the case of a young female with heavily pretreated
-mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration. We then review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, molecular heterogeneity of GBM and the need for enhanced specificity for the
mutations relevant in GBM.
Accurate differentiation between tumor progression (TP) and pseudoprogression remains a critical unmet need in neurooncology.
F-fluciclovine is a widely available synthetic amino acid PET ...radiotracer. In this study, we aimed to assess the value of
F-fluciclovine PET for differentiating pseudoprogression from TP in a prospective cohort of patients with suspected radiographic recurrence of glioblastoma.
We enrolled 30 glioblastoma patients with radiographic progression after first-line chemoradiotherapy for whom surgical resection was planned. The patients underwent preoperative
F-fluciclovine PET and MRI. The relative percentages of viable tumor and therapy-related changes observed in histopathology were quantified and categorized as TP (≥50% viable tumor), mixed TP (<50% and >10% viable tumor), or pseudoprogression (≤10% viable tumor).
Eighteen patients had TP, 4 had mixed TP, and 8 had pseudoprogression. Patients with TP/mixed TP had a significantly higher 40- to 50-min SUV
(6.64 + 1.88 vs. 4.11 ± 1.52,
= 0.009) than patients with pseudoprogression. A 40- to 50-min SUV
cutoff of 4.66 provided 90% sensitivity and 83% specificity for differentiation of TP/mixed TP from pseudoprogression (area under the curve AUC, 0.86). A maximum relative cerebral blood volume cutoff of 3.672 provided 90% sensitivity and 71% specificity for differentiation of TP/mixed TP from pseudoprogression (AUC, 0.779). Combining a 40- to 50-min SUV
cutoff of 4.66 and a maximum relative cerebral blood volume of 3.67 on MRI provided 100% sensitivity and 80% specificity for differentiating TP/mixed TP from pseudoprogression (AUC, 0.95).
F-fluciclovine PET uptake can accurately differentiate pseudoprogression from TP in glioblastoma, with even greater accuracy when combined with multiparametric MRI. Given the wide availability of
F-fluciclovine, larger, multicenter studies are warranted to determine whether amino acid PET with
F-fluciclovine should be used in the routine posttreatment assessment of glioblastoma.
Autologous chimeric antigen receptor (CAR) T cells targeted to epidermal growth factor receptor variant III (CAR T-EGFRvIII) have been developed and administered experimentally to treat patients with ...IDH1 wildtype recurrent glioblastoma (rGBM) (NCT02209376). We report the case of a 59-year-old patient who received a single peripheral infusion of CAR T-EGFRvIII cells and survived 36 months after disease recurrence, exceeding expected survival for recurrent glioblastoma. Post-infusion histopathologic analysis of tissue obtained during a second stage surgical resection revealed immunosuppressive adaptive changes in the tumor tissue as well as reduced EGFRvIII expression. Serial brain imaging demonstrated a significant reduction in relative cerebral blood volume (rCBV), a measure strongly associated with tumor proliferative activity, at early time points following CAR T treatment. Notably, CAR T-EGFRvIII cells persisted in her peripheral circulation during 29 months of follow-up, the longest period of CAR T persistence reported in GBM trials to date. These findings in a long-term survivor show that peripherally administered CAR T-EGFRvIII cells can persist for years in the circulation and suggest that this cell therapy approach could be optimized to achieve broader efficacy in recurrent GBM patients.
Purpose
Young adults with isocitrate-dehydrogenase wild-type (
IDH-
WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma,
IDH
-mutant GBM, or
IDH
...-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (
EGFR
CN gain), one of the most common genetic alterations in
IDH
-WT glioma, in young adults with
IDH
-WT GBM.
Methods
We performed a retrospective cohort study of patients 18–45 years old with newly diagnosed,
IDH
-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of
EGFR
CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18–45 years old with
IDH
-WT GBM was analyzed from The Cancer Genome Atlas (TCGA).
Results
Ten of 28 patients (36%) from our institution had
EGFR
CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of
EGFR
CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3–31.0, p = 0.02). In the TCGA cohort (N = 43),
EGFR
CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18).
Conclusions
EGFR
CN gain may be associated with inferior outcomes in young adults with newly diagnosed,
IDH
-WT GBM, suggesting a potential role for targeting EGFR in this population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Stereotactic needle biopsy provides a minimally invasive option for the diagnosis of intracranial lesions but is limited by inconclusive diagnoses on frozen pathology. For rapid pathology, ...5-aminovelunic acid and sodium fluorescein have previously demonstrated potential as diagnostic adjuvants. Stereotactic biopsy with near-infrared (NIR) fluorophores has not been reported. We identified 5 representative cases using NIR fluorescent dye indocyanine green (ICG) administered in a high dose, delayed manner.
Five patients underwent second window indocyanine green (SWIG)-guided stereotactic biopsy for diagnosis of suspected glioma or tumor recurrence. Up to 5 mg/kg ICG was administered approximately 24 hours prior to surgery. Biopsies were conducted in the standard fashion, targeting regions of suspected tumor using intraoperative frameless navigation. Samples were examined intraoperatively under standard visible light and for fluorescence using conventional NIR imaging platforms. Findings were correlated with frozen and final tumor pathology for all cases.
A total of 10 biopsy specimens were obtained. Three did not fluoresce and did not demonstrate tumor on preliminary or final pathology, including a non-gadolinium-enhancing sample taken proximal to the final target. The remaining 7 fluoresced, of which 6 contained tumor and 1 contained necrosis. Fluorescence was also noted in a patient with radiation treatment effect. Overall fluorescence characteristics were highly concordant with preliminary and final diagnoses.
SWIG provides rapid intraoperative confirmation of pathologic brain tissue by permeating neoplastic or inflammatory brain tissue via a mechanism similar to that of gadolinium enhancement. SWIG-guided stereotactic biopsy can improve surgical efficiency by enhancing confidence in acquisition of target tissue.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND:Meningiomas are well-encapsulated benign brain tumors and surgical resection is often curative. Nevertheless, this is not always possible due to the difficulty of identifying residual ...disease intraoperatively. We hypothesized that meningiomas overexpress folate receptor alpha (FRα), allowing intraoperative molecular imaging by targeting FRα with a near-infrared (NIR) dye.
OBJECTIVE:To determine FRα expression in both human and canine meningioma cohorts to prepare for future clinical studies. Present a case study of a meningioma resection with intraoperative NIR fluorescence imaging.
METHODS:Tissue samples of 27 human meningioma specimens and 7 canine meningioma specimens were immunohistochemically stained for FRα along with normal dura, skeletal muscle, and kidney tissue. We then enrolled a patient with a pituitary adenoma and tuberculum sella meningioma in a clinical trial in which the patient received an infusion of folate-linked, NIR fluorescent dye prior to surgery.
RESULTS:In the cohort of human meningiomas, 9 WHO grade I, 12 grade II, and 6 grade III tumors were identified. Eighty-nine percent of WHO grade I, 67% of grade II, and 50% of grade III tumors overexpressed FRα. In the 7 canine meningioma samples, 100% stained positively for FRα. Both human and canine normal dura from autopsy samples demonstrated no evidence of FRα overexpression. In the case study, the meningioma demonstrated a high NIR signal-to-background-ratio of 4.0 and demonstrated strong FRα immunohistochemistry staining.
CONCLUSION:This study directly demonstrates FRα overexpression in both human and canine meningiomas. We also demonstrate superb intraoperative imaging of a meningioma using a FRα-targeting dye.
Glioblastoma (GBM) is an immunologically "cold" tumor characterized by poor responsiveness to immunotherapy. Standard of care for GBM is surgical resection followed by chemoradiotherapy and ...maintenance chemotherapy. However, tumor recurrence is the norm, and recurring tumors are found frequently to have acquired molecular changes (e.g., mutations) that may influence their immunobiology. Here, we compared the immune contexture of de novo GBM and recurrent GBM (rGBM) using high-dimensional cytometry and multiplex IHC. Although myeloid and T cells were similarly abundant in de novo and rGBM, their spatial organization within tumors differed and was linked to outcomes. In rGBM, T cells were enriched and activated in perivascular regions and clustered with activated macrophages and fewer regulatory T cells. Moreover, a higher expression of phosphorylated STAT1 by T cells in these regions at recurrence was associated with a favorable prognosis. Together, our data identify differences in the immunobiology of de novo GBM and rGBM and identify perivascular T cells as potential therapeutic targets. See related Spotlight by Bayik et al., p. 787.
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