Hypofractionated re-irradiation for diffuse intrinsic pontine glioma.

BACKGROUND: Re-irradiation (reRT) increases survival in locally recurrent diffuse intrinsic pontine glioma (DIPG). There is no standard dose and fractionation for reRT, but conventional fractionation (CF) is typically used. We report our institutional experience of reRT for DIPG, which includes hypofractionation (HF). METHODS: We reviewed pediatric patients treated with brainstem reRT for DIPG at our institution from 2012 to 2022. Patients were grouped by HF or CF. Outcomes included steroid use, and overall survival (OS) was measured from both diagnosis and start of reRT. RESULTS: Of 22 patients who received reRT for DIPG, two did not complete their course due to clinical decline. Of the 20 who completed reRT, the dose was 20-30 Gy in 2-Gy fractions (n = 6) and 30-36 Gy in 3-Gy fractions (n = 14). Median age was 5 years (range: 3-14), median interval since initial RT was 8 months (range: 3-20), and 12 received concurrent bevacizumab. Median OS from diagnosis was 18 months [95% confidence interval: 17-24]. Median OS from start of reRT for HF versus CF was 8.2 and 7.5 months, respectively (p = .20). Thirteen (93%) in the HF group and three (75%) in the CF group tapered pre-treatment steroid dose down or off within 2 months after reRT due to clinical improvement. There was no significant difference in steroid taper between HF and CF (p = .4). No patients developed radionecrosis. CONCLUSION: reRT with HF achieved survival duration comparable to published outcomes and effectively palliated symptoms. Future investigation of this regimen in the context of new systemic therapies and upfront HF is warranted.

Management of Total Frontal Bone Loss After Surgery for Craniosynostosis: The Modified Visor Bone Flap With Brain Cage.

Complications after craniosynostosis surgery occur in 11% to 36% of cases and may be precipitated by poor soft tissue coverage and concomitant exposure of non-sterile regions; sequelae may result in infection, osteomyelitis, and bone loss requiring complex reconstruction. In the pediatric population, autologous cranioplasty remains the gold standard due to growth potential and a more favorable complication profile than synthetic cranioplasty. Virtual surgery planning (VSP) and computer-assisted design (CAD)/computer-assisted manufacturing (CAM) technology can be utilized to create innovative, patient-specific autologous solutions, similar to the approach with synthetic cranioplasty. A novel surgical approach using VSP was used for an 18-month-old female with near total bifrontal bone loss. Surface area measurements were used to determine the amount of bone available to replace the infected frontal bone. VSP was utilized to determine the most efficient construct configuration possible to achieve maximal coverage via calculation of cranial bone surface area measurements. Surgical reconstruction of the defect was planned as a Modified Visor Bone Flap with Posterior Brain Cage. A construct was fashioned from available cranial bone struts to obtain widespread coverage. 3D Recon images from before and after surgery demonstrate almost complete re-ossification of the cranial vault with significant resulting clinical improvement. Reconstruction of total frontal bone loss is possible by utilizing this technique. VSP can improve the safety and efficiency of complex autologous cranial bone reconstructions. We propose a treatment algorithm to address the problem of near total frontal bone loss in young children for whom alloplastic implants are not suitable.

Diffuse Midline Gliomas: Challenges and New Strategies in a Changing Clinical Landscape.

Diffuse intrinsic pontine glioma (DIPG) was first described by Harvey Cushing, the father of modern neurosurgery, a century ago. Since then, the classification of this tumor changed significantly, as it is now part of the broader family of diffuse midline gliomas (DMGs), a heterogeneous group of tumors of midline structures encompassing the entire rostro-caudal space, from the thalamus to the spinal cord. DMGs are characterized by various epigenetic events that lead to chromatin remodeling similarities, as two decades of studies made possible by increased tissue availability showed. This new understanding of tumor (epi)biology is now driving novel clinical trials that rely on targeted agents, with finally real hopes for a change in an otherwise unforgiving prognosis. This biological discovery is being paralleled with equally exciting work in therapeutic drug delivery. Invasive and noninvasive platforms have been central to early phase clinical trials with a promising safety track record and anecdotal benefits in outcome.

Laser interstitial thermal therapy as a radiation-sparing approach for central nervous system tumors in children with cancer predisposition syndromes: report of a child with Li-Fraumeni syndrome. Illustrative case.

BACKGROUND: Ionizing radiation and alkylating chemotherapies increase secondary malignancy risk in patients with cancer predisposition syndromes (CPSs), such as Li-Fraumeni syndrome. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has not been associated with mutagenic risks. We describe the case of a child with LFS and a history of treated choroid plexus carcinoma (CPC) who developed a second primary glial tumor that was safely treated with magnetic resonance imaging (MRI)-guided LITT. OBSERVATIONS: A 4-year-old male with left parietal World Health Organization grade III CPC associated with a TP53 germline mutation was evaluated. The patient underwent neoadjuvant platinum-based chemotherapy before near-total resection, followed by 131I-8H9 immunotherapy and 30 fractions of 54-Gy proton radiotherapy. He remained without evidence of disease for 2 years before developing a slow-growing mass adjacent to the left frontal ventricular horn. Stereotactic biopsy revealed a glial neoplasm. Given the nonsuperficial location and focality of the lesion, MRI-guided LITT was performed for ablative therapy. There were no complications, and 2 years of surveillance revealed continued retraction of the ablated tumor focus and no subsequent disease. LESSONS: Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

The Role of Virtual Surgical Planning in Surgery for Complex Craniosynostosis.

Background: Virtual surgical planning (VSP) decreases reliance on intraoperative subjective assessment of aesthetic and functional outcomes in craniofacial surgery. Here, we describe our experience of using VSP for complex craniosynostosis surgery to inform preoperative decision making and optimize postoperative outcomes. Methods: Chart review was performed for children treated with craniosynostosis at our institution from 2015 to 2021. Eight VSP maneuvers were defined and assigned to each patient when applicable: (1) complex cranioplasty: combined autologous and synthetic; (2) autologous cranioplasty; (3) synthetic cranioplasty; (4) vector analysis and distractor placement; (5) complex osteotomies; (6) multilayered intraoperative plans; (7) volume analysis; and (8) communication with parents. Outcomes between VSP and non-VSP cohorts were compared. Results: Of 166 total cases, 32 were considered complex, defined by multisutural craniosynostosis, syndromic craniosynostosis, or revision status. Of these complex cases, 20 underwent VSP and 12 did not. There was no difference in mean operative time between the VSP and non-VSP groups (541 versus 532 min, P = 0.82) or in unexpected return to operating room (10.5% versus 8.3%, P = 0.84). VSP was most often used to communicate the surgical plan with parents (90%) and plan complex osteotomies (85%). Conclusions: In this cohort, VSP was most often used to communicate the surgical plan with families and plan complex osteotomies. Our results indicate that VSP may improve intraoperative efficiency and safety for complex craniosynostosis surgery. This tool can be considered a useful adjunct to plan and guide intraoperative decisions in complex cases, reducing variability and guiding parental expectations.

Theranostic Intratumoral Convection-Enhanced Delivery of 124I-Omburtamab in Patients with Diffuse Intrinsic Pontine Glioma: Pharmacokinetics and Lesion Dosimetry.

Diffuse intrinsic pontine glioma (DIPG) is a rare childhood malignancy with poor prognosis. There are no effective treatment options other than external beam therapy. We conducted a pilot, first-in-human study using 124I-omburtamab imaging and theranostics as a therapeutic approach using a localized convection-enhanced delivery (CED) technique for administering radiolabeled antibody. We report the detailed pharmacokinetics and dosimetry results of intratumoral delivery of 124I-omburtamab. Methods: Forty-five DIPG patients who received 9.0-370.7 MBq of 124I-omburtamab intratumorally via CED underwent serial brain and whole-body PET/CT imaging at 3-5 time points after injection within 4, 24-48, 72-96, 120-144, and 168-240 h from the end of infusion. Serial blood samples were obtained for kinetic analysis. Whole-body, blood, lesion, and normal-tissue activities were measured, kinetic parameters (uptake and clearance half-life times) estimated, and radiation-absorbed doses calculated using the OLINDA software program. Results: All patients showed prominent activity within the lesion that was retained over several days and was detectable up to the last time point of imaging, with a mean 124I residence time in the lesion of 24.9 h and dose equivalent of 353 ± 181 mSv/MBq. Whole-body doses were low, with a dose equivalent of 0.69 ± 0.28 mSv/MBq. Systemic distribution and activities in normal organs and blood were low. Radiation dose to blood was very low, with a mean value of 0.27 ± 0.21 mGy/MBq. Whole-body clearance was monoexponential with a mean biologic half-life of 62.7 h and an effective half-life of 37.9 h. Blood clearance was biexponential, with a mean biologic half-life of 22.2 h for the rapid α phase and 155 h for the slower ß phase. Conclusion: Intratumoral CED of 124I-omburtamab is a novel theranostics approach in DIPG. It allows for delivery of high radiation doses to the DIPG lesions, with high lesion activities and low systemic activities and high tumor-to-normal-tissue ratios and achieving a wide safety margin. Imaging of the actual therapeutic administration of 124I-omburtamab allows for direct estimation of the therapeutic lesion and normal-tissue-absorbed doses.