Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; ...however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.
The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3–21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549–BRAF fusion or the BRAFV600E Val600Glu mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.
Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% 95% CI 18–57) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72–45·59). In stratum 3, ten (40% 21–61) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14–51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five 10%) and maculopapular rash (five 10%). No treatment-realted deaths were reported.
Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.
National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Photon-counting computed tomography (PCCT) offers better high-resolution and noise performance than energy integrating detector (EID) CT. In this work, we compared both technologies for imaging of ...the temporal bone and skull base. A clinical PCCT system and 3 clinical EID CT scanners were used to image the American College of Radiology image quality phantom using a clinical imaging protocol with matched CTDI vol (CT dose index-volume) of 25 mGy. Images were used to characterize the image quality of each system across a series of high-resolution reconstruction options. Noise was calculated from the noise power spectrum, whereas resolution was quantified with a bone insert by calculating a task transfer function. Images of an anthropomorphic skull phantom and 2 patient cases were examined for visualization of small anatomical structures. Across measured conditions, PCCT had a comparable or smaller average noise magnitude (120 Hounsfield units HU) to the EID systems (144-326 HU). Photon-counting CT also had comparable resolution (task transfer function f25 : 1.60 mm -1 ) to the EID systems (1.34-1.77 mm -1 ). Imaging results supported quantitative findings as PCCT more clearly showed the 12-lp/cm bars from the fourth section of the American College of Radiology phantom and better represented the vestibular aqueduct and oval and round windows when compared with the EID scanners. A clinical PCCT system was able to image the temporal bone and skull base with improved spatial resolution and lower noise than clinical EID CT systems at matched dose.
D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a ...subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8
T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6
CD8
T cells with a progenitor phenotype and decreased terminally exhausted CD8
T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8
T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established
up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.
Recombinant human acid α-glucosidase (rhGAA) enzyme replacement therapy (ERT) has prolonged survival in infantile Pompe disease (IPD), but has unmasked central nervous system (CNS) changes.
Brain ...imaging, consisting of computed tomography (CT) and/or magnetic resonance imaging (MRI), was performed on 23 patients with IPD (17 CRIM-positive, 6 CRIM-negative) aged 2–38months. Most patients had baseline neuroimaging performed prior to the initiation of ERT. Follow-up neuroimaging was performed in eight.
Sixteen patients (70%) had neuroimaging abnormalities consisting of ventricular enlargement (VE) and/or extra-axial cerebrospinal fluid accumulation (EACSF) at baseline, with delayed myelination in two. Follow-up neuroimaging (n=8) after 6–153months showed marked improvement, with normalization of VE and EACSF in seven patients. Two of three patients imaged after age 10years demonstrated white matter changes, with one noted to have a basilar artery aneurysm.
Mild abnormalities on brain imaging in untreated or newly treated patients with IPD tend to resolve with time, in conjunction with ERT. However, white matter changes are emerging as seen in Patients 1 and 3 which included abnormal periventricular white matter changes with subtle signal abnormalities in the basal ganglia and minimal, symmetric signal abnormalities involving the deep frontoparietal cerebral white matter, respectively. The role of neuroimaging as part of the clinical evaluation of IPD needs to be considered to assess for white matter changes and cerebral aneurysms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This article addresses questions that radiologists frequently ask when planning, performing, processing, and interpreting MRI perfusion studies in CNS imaging.
Perfusion MRI is a promising tool in ...assessing stroke, brain tumors, and neurodegenerative diseases. Most of the impediments that have limited the use of per-fusion MRI can be overcome to allow integration of these methods into modern neuroimaging protocols.
To evaluate patient outcomes after sacroplasty (percutaneous sacral augmentation) with guidance using CT compared to fluoroscopy with augmented reality overlay using fluoroscopic cone-beam CT and ...FDA-approved software (CBCT-AF).
Retrospective IRB-approved study of all patients undergoing sacroplasty between 3/2019–9/2020 was performed. Procedural details were collected including whether the procedure was performed with CT-fluoroscopic guidance versus cone beam CT with vector navigation and real-time neuroforaminal contour overlay. Clinical details collected included Visual Analogue Scale (VAS) pain scores within 6-months post intervention. Images were analyzed on PACS to measure exact volumes of implanted cement.
Twelve patients underwent sacroplasty using either CT (n = 13 hemisacra) or CBCT-AF (n = 10 hemisacra). No clinically significant complications occurred. Comparing CT versus CBCT-AF guidance there was no significant difference in radiation dose (CBCT-AF trended toward lower dose, p = 0.20), total anesthesia time (p = 0.71), or infused cement volume (p = 0.21). VAS pain scores decreased an average of 6.14 and 5.25 points for the CT and CBCT-AF groups respectively (p = 0.46, no significant difference between groups).
Sacroplasty improved back pain in all patients, while CBCT-AF safely provided similar outcomes with trends toward lower radiation dose and cement volume compared to CT-fluoroscopy.
•Cone beam CT is used on-label and compared to CT-fluroscopic guidance during percutaneous cement augmentation of sacral fractures.•This analysis included 10 hemisacra augmented using CBCT-AF, and 13 using CT.•Sacroplasty was safe and improved pain in all patients (CBCT-AF and CT groups).•CBCT-AF trended toward lower radiation dose.•CT trended toward higher cement volume implanted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To measure the ablation zone temperature and nontarget tissue temperature during radiofrequency (RF) ablation in bone containing metal instrumentation versus no metal instrumentation (control group).
...Ex vivo experiments were performed on 15 swine vertebrae (control, n = 5; titanium screw, n = 5; stainless steel screw, n = 5). Screws and RF ablation probe were inserted identically under fluoroscopy. During RF ablation (3 W, 5 minutes), temperature was measured 10 mm from RF ablation centerpoint and in muscle contacting the screw. Magnetic resonance (MR) imaging, gross pathologic, and histopathologic analyses were performed on 1 specimen from each group.
Ablation zone temperatures at 2.5 and 5 minutes increased by 12.2 °C ± 2.6 °C and 21.5 °C ± 2.1 °C (control); 11.0 °C ± 4.1 °C and 20.0 °C ± 2.9 °C (juxta-titanium screw), and 10.0 °C ± 3.4 °C and 17.2 °C ± 3.5 °C (juxta-stainless steel) screw; differences among groups did not reach significance by analysis of variance (P = .87). Mixed-effects linear regression revealed a statistically significant increase in temperature over time in all 3 groups (4.2 °C/min ± 0.4 °C/min, P < .001). Compared with the control, there was no significant difference in the temperature change over time for titanium (-0.3 °C/min ± 0.5 °C/min, P = .53) or steel groups (-0.4 °C/min ± 0.5 °C/min, P = .38). The mean screw temperature at the final time point did not show a statistically significant change compared with baseline in either the titanium group (-1.2 °C ± 2.3 °C, P = .50) or steel group (2.6 °C ± 2.9 °C, P = .11). MR imaging and pathologic analyses revealed homogeneous ablation without sparing of the peri-hardware zones.
Adjacent metallic instrumentation did not affect the rate of or absolute increase in temperature in the ablation zone, did not create peri-metallic ablation inhomogeneities, and did not result in significant nontarget heating of muscle tissue in contact with the metal instrumentation.
Patient-centric care has garnered the attention of the radiology community. The authors describe a patient-centric approach to iodinated contrast administration designed to optimize the diagnostic ...yield of contrast-enhanced CT while minimizing patient iodine load and exposure to ionizing radiation, thereby enhancing patient safety while providing reasonable diagnostic efficacy. Patient-centric CT hardware settings and contrast media administration are important considerations for clinical CT quality and safety.
Background
Neonates and young children require efficacious magnetic resonance imaging (MRI) examinations but are potentially more susceptible to the short- and long-term adverse effects of ...gadolinium-based contrast agents due to the immaturity of their body functions.
Objective
To evaluate the acute safety and diagnostic efficacy of gadoteridol (ProHance) for contrast-enhanced MRI of the central nervous system (CNS) in children ≤2 years of age.
Materials and methods
One hundred twenty-five children ≤2 years old (including 57 children <6 months old) who underwent contrast-enhanced MRI of the CNS with gadoteridol at 0.1 mmol/kg body weight were retrospectively enrolled at five imaging centers. Safety data were assessed for acute/subacute adverse events in the 48 h following gadoteridol administration and, when available, vital signs, electrocardiogram (ECG) and clinical laboratory values obtained from blood samples taken from 48 h before until 48 h following the MRI exam. The efficacy of gadoteridol-enhanced MRI compared to unenhanced MRI for disease diagnosis was evaluated prospectively by three blinded, unaffiliated readers.
Results
Thirteen changes of laboratory values (11 mild, 1 moderate, 1 unspecified) were reported as adverse events in 7 (5.6%) patients. A relationship to gadoteridol was deemed possible though doubtful for two of these adverse events in two patients (1.6%). There were no clinical adverse events, no serious adverse events and no clinically meaningful changes in vital signs or ECG recordings. Accurate differentiation of tumor from non-neoplastic disease, and exact matching of specific MRI-determined diagnoses with on-site final diagnoses, was achieved in significantly more patients by each reader following the evaluation of combined pre- and post-contrast images compared to pre-contrast images alone (84.6–88.0% vs. 70.9–76.9%;
P
≤0.006 and 67.5–79.5% vs. 47.0–66.7%;
P
≤0.011, respectively).
Conclusion
Gadoteridol at 0.1 mmol/kg body weight is safe, well tolerated and effective for contrast-enhanced MRI of the CNS in children ≤2 years of age.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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