Radiation-Induced Large Vessel Cerebral Vasculopathy in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy

Purpose The purpose of this research is to evaluate the incidence, time to development, imaging patterns, risk factors, and clinical significance of large vessel cerebral vasculopathy in pediatric patients with brain tumors treated with proton radiotherapy. Materials and Methods A retrospective study was performed on 75 consecutive pediatric patients with primary brain tumors treated with proton radiotherapy. Radiation-induced large vessel cerebral vasculopathy (RLVCV) was defined as intracranial large vessel arterial stenosis or occlusion confirmed on MRA, CTA, and/or catheter angiography within an anatomic region with previous exposure to proton beam therapy and not present prior to radiotherapy. Clinical records were used to determine the incidence, timing, radiation dose to the large vessels, and clinical significance associated with the development of large vessel vasculopathy in these patients. Results RLVCV was present in 5/75 (6.7%) of patients and included tumor pathologies of craniopharyngioma (2), ATRT (1), medulloblastoma (1), and anaplastic astrocytoma (1). Median time from completion of radiotherapy to development was 1.5 years (mean 3.0 years; range 1.0-7.5 years). Neither mean age at time of radiotherapy (5.1 years) nor mean radiotherapy dose to the large vessels (54.5 Gy) were statistically significant risk factors. Four of the five patients with RLVCV presented with acute stroke, and demonstrated MRI evidence of acute infarcts in the expected vascular distributions. Angiography studies demonstrated collateral vessel formation in only two of the patients with RLVCV. No patients demonstrated acute hemorrhage or aneurysm. Two patients were treated with pial synangiomatosis surgery. Conclusion RLVCV can occur in pediatric patients with brain tumors treated with proton radiotherapy. Further studies are necessary to determine potential risk factors for large vessel vasculopathy with proton radiotherapy in comparison with conventional photon radiotherapy

Comparison of multi-shot and single shot echo-planar diffusion tensor techniques for the optic pathway in patients with neurofibromatosis type 1

Purpose Diffusion tensor imaging (DTI) may be helpful in assessing optic pathway integrity as a marker for treatment in neurofibromatosis type 1 (NF1) patients with optic gliomas (OG). However, susceptibility artifacts are common in typical single-shot echo planar imaging (ssDTI). A readout-segmented multi-shot EPI technique (rsDTI) was utilized to minimize susceptibility distortions of the skull base and improve quantitative metrics. Methods Healthy controls, children with NF1 without OG, and NF1 with OG ± visual symptoms were included. All subjects were scanned with both rsDTI and ssDTI sequences sequentially. Diffusion metrics and deterministic fiber tracking were calculated. Tract count, volume, and length were also compared by a two-factor mixed ANOVA. Results Five healthy controls, 7 NF1 children without OG, and 12 NF1 children with OG were imaged. Six OG patients had visual symptoms. Four subjects had no detectable optic pathway fibers on ssDTI due to susceptibility, for which rsDTI was able to delineate. Tract count (p < 0.001), tract volume (p < 0.001), and FA (P < 0.001) were significantly higher for rsDTI versus ssDTI for all subjects. MD (p < 0.001) and RD (p < 0.001) were significantly lower for rsDTI vs ssDTI. Finally, MD, AD, and RD had a significantly lower difference in NF1 children with visual symptoms compared to NF1 children without visual symptoms only on ssDTI scans. Conclusion DTI with readout-segmented multi-shot EPI technique can better visualize the optic pathway and allow more confident measurements of anisotropy in NF1 patients. This is shown by a significant increase in FA, tract count, and volume with rsDTI versus ssDTI

Novel Homozygous Deletion in STRADA Gene Associated With Polyhydramnios, Megalencephaly, and Epilepsy in 2 Siblings: Implications for Diagnosis and Treatment

Mutations in the STE20-related kinase adaptor α (STRADA) gene have been reported to cause an autosomal recessive neurodevelopmental disorder characterized by infantile-onset epilepsy, developmental delay, and craniofacial dysmorphisms. To date, there have been 17 reported individuals diagnosed with STRADA mutations, 16 of which are from a single Old Order Mennonite cohort and share a deletion of exons 9-13. The remaining individual is of consanguineous Indian descent and has a homozygous single–base pair duplication. We report a novel STRADA gene deletion of exons 7-9 in 2 sisters from nonconsanguineous parents, as well as an improvement in seizure control in 1 sibling following treatment with sirolimus, an m-Tor inhibitor of potential benefit to patients with this genetic mutation

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of &lt; 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age &lt; 3 or &gt; 10 years (11% v 3% and 33% v 23%, respectively; P &lt; .001) and with longer symptom duration ( P &lt; .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement

Comparison of multi-shot and single shot echo-planar diffusion tensor techniques for the optic pathway in patients with neurofibromatosis type 1

Purpose Diffusion tensor imaging (DTI) may be helpful in assessing optic pathway integrity as a marker for treatment in neurofibromatosis type 1 (NF1) patients with optic gliomas (OG). However, susceptibility artifacts are common in typical single-shot echo planar imaging (ssDTI). A readout-segmented multi-shot EPI technique (rsDTI) was utilized to minimize susceptibility distortions of the skull base and improve quantitative metrics. Methods Healthy controls, children with NF1 without OG, and NF1 with OG ± visual symptoms were included. All subjects were scanned with both rsDTI and ssDTI sequences sequentially. Diffusion metrics and deterministic fiber tracking were calculated. Tract count, volume, and length were also compared by a two-factor mixed ANOVA. Results Five healthy controls, 7 NF1 children without OG, and 12 NF1 children with OG were imaged. Six OG patients had visual symptoms. Four subjects had no detectable optic pathway fibers on ssDTI due to susceptibility, for which rsDTI was able to delineate. Tract count (p < 0.001), tract volume (p < 0.001), and FA (P < 0.001) were significantly higher for rsDTI versus ssDTI for all subjects. MD (p < 0.001) and RD (p < 0.001) were significantly lower for rsDTI vs ssDTI. Finally, MD, AD, and RD had a significantly lower difference in NF1 children with visual symptoms compared to NF1 children without visual symptoms only on ssDTI scans. Conclusion DTI with readout-segmented multi-shot EPI technique can better visualize the optic pathway and allow more confident measurements of anisotropy in NF1 patients. This is shown by a significant increase in FA, tract count, and volume with rsDTI versus ssDTI

Radiation Induced Cerebral Microbleeds in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy

Purpose Proton beam radiotherapy (PBT) has been increasingly utilized to treat pediatric brain tumors, however, limited information exists regarding radiation induced cerebral microbleeds (CMBs) among these patients. The purpose was to evaluate the incidence, risk factors, and imaging appearance of CMBs in pediatric patients with brain tumors treated with PBT. Methods A retrospective study was performed on 100 pediatric patients with primary brain tumors treated with PBT. CMBs were diagnosed by examining serial MRIs including susceptibility-weighted imaging. Radiation therapy plans were analyzed to determine doses to individual CMBs. Clinical records were used to determine risk factors associated with the development of CMBs in these patients. Results The mean age at time of PBT was 8.1 years. The median follow-up duration was 57 months. The median time to development of CMBs was 8 months (mean 11 months; range 3-28 months). The percentage of patients with CMBs was 43%, 66%, 80%, 81%, 83%, and 81% at 1-year, 2-years, 3-years, 4-year, 5-years, and greater than 5 years from completion of proton radiotherapy. The majority (87%) of CMBs were found in areas of brain exposed to ≥ 30 Gy. Risk factors included maximum radiotherapy dose (P=0.001), percentage and volume of brain exposed to ≥ 30 Gy (P=0.0004; P=0.0005), and patient age at time of PBT (P=0.0004). Chemotherapy was not a significant risk factor (P=0.35). No CMBs required surgical intervention. Conclusion CMBs develop in a high percentage of pediatric patients with brain tumors treated with proton radiotherapy within the first few years following treatment. Significant risk factors for development of CMBs include younger age at time of PBT, higher maximum radiotherapy dose, and higher percentage and volume of brain exposed to ≥ 30 Gy. These findings demonstrate similarities with CMBs that develop in pediatric brain tumor patients treated with photon radiotherapy

Radiation Induced Cerebral Microbleeds in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy

Purpose Proton beam radiotherapy (PBT) has been increasingly utilized to treat pediatric brain tumors, however, limited information exists regarding radiation induced cerebral microbleeds (CMBs) among these patients. The purpose was to evaluate the incidence, risk factors, and imaging appearance of CMBs in pediatric patients with brain tumors treated with PBT. Methods A retrospective study was performed on 100 pediatric patients with primary brain tumors treated with PBT. CMBs were diagnosed by examining serial MRIs including susceptibility-weighted imaging. Radiation therapy plans were analyzed to determine doses to individual CMBs. Clinical records were used to determine risk factors associated with the development of CMBs in these patients. Results The mean age at time of PBT was 8.1 years. The median follow-up duration was 57 months. The median time to development of CMBs was 8 months (mean 11 months; range 3-28 months). The percentage of patients with CMBs was 43%, 66%, 80%, 81%, 83%, and 81% at 1-year, 2-years, 3-years, 4-year, 5-years, and greater than 5 years from completion of proton radiotherapy. The majority (87%) of CMBs were found in areas of brain exposed to ≥ 30 Gy. Risk factors included maximum radiotherapy dose (P=0.001), percentage and volume of brain exposed to ≥ 30 Gy (P=0.0004; P=0.0005), and patient age at time of PBT (P=0.0004). Chemotherapy was not a significant risk factor (P=0.35). No CMBs required surgical intervention. Conclusion CMBs develop in a high percentage of pediatric patients with brain tumors treated with proton radiotherapy within the first few years following treatment. Significant risk factors for development of CMBs include younger age at time of PBT, higher maximum radiotherapy dose, and higher percentage and volume of brain exposed to ≥ 30 Gy. These findings demonstrate similarities with CMBs that develop in pediatric brain tumor patients treated with photon radiotherapy

First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811

Treatment options for patients with HER2-positive advanced gastric cancer are limited, and the prognosis for these patients is poor. Pembrolizumab has demonstrated promising antitumor activity in patients with advanced gastric or gastroesophageal junction adenocarcinoma as monotherapy, in combination with chemotherapy and in combination with trastuzumab. Combining pembrolizumab with trastuzumab and chemotherapy may therefore provide a benefit for patients with advanced HER2-positive gastric cancer. Here we aimed to describe the design of and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-811 study, which will evaluate the efficacy and safety of pembrolizumab or placebo in combination with trastuzumab and chemotherapy as first-line treatment for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. Clinical trial registration: NCT03615326 (ClinicalTrials.gov)