Abstract
Background
Brainstem toxicity after radiation therapy (RT) is a devastating complication and a particular concern with proton radiation (PBT). We investigated the incidence and clinical ...correlates of brainstem injury in pediatric brain tumors treated with PBT.
Methods
All patients <21 years with brain tumors treated with PBT at our institution from 2007–2019, with a brainstem Dmean >30 Gy and/or Dmax >50.4 Gy were included. Symptomatic brainstem injury (SBI) was defined as any new or progressive cranial neuropathy, ataxia, and/or motor weakness with corresponding radiographic abnormality within brainstem.
Results
A total of 595 patients were reviewed and 468 (medulloblastoma = 200, gliomas = 114, ependymoma = 87, ATRT = 43) met our inclusion criteria. Median age at RT was 6.3 years and median prescribed RT dose was 54Gy RBE. Fifteen patients (3.2%) developed SBI, at a median of 4 months after RT. Grades 2, 3, 4, and 5 brainstem injuries were seen in 7, 5, 1, and 2 patients respectively. Asymptomatic radiographic changes were seen in 51 patients (10.9%). SBI was significantly higher in patients with age ≤3 years, female gender, ATRT histology, patients receiving high-dose chemotherapy with stem cell rescue, and those not receiving craniospinal irradiation. Patients with SBI had a significantly higher V50–52. In 2014, our institution started using strict brainstem dose constraints (Dmax ≤57 Gy, Dmean ≤52.4 Gy, and V54≤10%). There was a trend towards decrease in SBI from 4.4% (2007-2013) to 1.5% (2014–2019) (P = .089) without affecting survival.
Conclusion
Our results suggest a low risk of SBI after PBT for pediatric brain tumors, comparable to photon therapy. A lower risk was seen after adopting strict brainstem dose constraints.
Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10(-8), hazard ratio = 4.5) in ...238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents.
The most common pathologic group of childhood brain tumors are low grade gliomas (LGG). LGG comprise a variety of histologies among which pilocytic astrocytoma (WHO grade I) is the most common. ...Complete resection of LGG portends an excellent prognosis, but this intervention is mainly possible only with hemispheric tumors. For more centrally-located tumors, especially in young children, there is a risk for tumor-related morbidity including visual compromise and endocrinopathies. Given the generally excellent survival outcomes in children with LGG, the goal of interventions is usually to control tumor growth to avoid morbidities. Previously, chemotherapy was the only intervention available for young patients in whom radiation therapy would cause significant neuro-cognitive morbidity. However, with the discovery of the MAPK pathway as the only molecular pathway involved in LGG tumorigenesis, novel classes of drugs known as BRAF and MEK inhibitors have shown great promise and raise the possibility of chronic long-term therapy.
BACKGROUND
Sporadic optic pathway/hypothalamic gliomas represent a unique entity within pediatric low‐grade glioma. Despite favorable survival, location makes treatment difficult and local ...progression debilitating. This study is a longitudinal assessment of visual acuity (VA) among children treated within the last 2 decades.
METHODS
Clinical characteristics were ed for patients treated from 2000 to 2018 at Texas Children's Cancer Center in Houston. Ophthalmologic data taken at 3‐ to 6‐month intervals were examined with age‐appropriate VA metrics converted to the LogMAR (logarithm of the minimum angle of resolution) scale. Kaplan‐Meier blindness‐free survival (BFS) curves, calculated as time‐to‐bilateral functional blindness (LogMAR ≥0.8 in both eyes), were calculated for patients receiving early radiation therapy (RT; upfront or as first‐line salvage treatment) or chemotherapy (CT) and evaluated using the log‐rank test.
RESULTS
Thirty‐eight patients with a median follow‐up of 8.5 years (range, 2‐17 years) were identified. Median age at diagnosis was 3 years (interquartile range, <1‐6 years). Early RT was administered in 11 patients (29%). Twenty‐seven patients (71%) were treated primarily with CT, initiated at a median age of 3.5 years (range, <1‐11 years). Eight patients in the CT group did eventually require RT secondary to VA loss and following multiple lines of CT. Median age at RT for all patients was 11 years (range, 3‐17 years). BFS rates were 81% at 5 years and 60% at 8 years for CT and 100% at 5 and 8 years for early RT (P = .017).
CONCLUSIONS
In a contemporary cohort, early RT, defined as initial or first‐line salvage therapy, was found to have superior BFS for appropriately selected patients with sporadic optic pathway/hypothalamic gliomas.
LAY SUMMARY
Children with low‐grade brain tumors of the optic pathway generally have excellent long‐term survival; however, given the location of these tumors, there can commonly be threatened vision if the tumor grows.
Although radiation is generally deferred in children on the basis of legitimate concerns regarding the effects on the developing brain, it may represent a vision‐preserving therapy for well‐selected older patients.
The treatment paradigm for pediatric optic pathway glioma has mostly shifted from using radiation therapy (RT) as the definitive therapy to favor postponement of RT for secondary and tertiary lines of systemic therapy. Despite excellent patient survival rates, long‐term vision outcomes with chemotherapy are poor. Well‐selected older patients who receive early RT as upfront or first‐line salvage therapy retain meaningful long‐term visual acuity.
BACKGROUND
The authors analyzed the incidence and types of second malignant neoplasms (SMNs) in patients treated for medulloblastoma.
METHODS
The authors compared the incidence of SMNs after ...radiotherapy (RT) for medulloblastoma in patients treated in 1973‐2014 with the incidence in the general population with the multiple primary–standardized incidence ratio function of Surveillance, Epidemiology, and End Results 9. Observed‐to‐expected incidence (O/E) ratios and 95% confidence intervals (CIs) were reported for the entire cohort and by disease site according to age at diagnosis, treatment era, and receipt of chemotherapy. P values < .05 were considered statistically significant.
RESULTS
Of the 1294 patients with medulloblastoma who received RT, 68 developed 75 SMNs. The O/E ratio for SMNs among all patients was 4.49 (95% CI, 3.53‐5.62; P < .05). The site at highest risk was the central nervous system (CNS; O/E, 40.62; 95% CI, 25.46‐61.51), which was followed by the endocrine system (O/E, 15.95; 95% CI, 9.12‐25.91), bone (O/E, 14.45; 95% CI, 1.75‐52.21), soft tissues (O/E, 9.01; 95% CI, 1.09‐32.56), the digestive system (O/E, 5.03; 95% CI, 2.51‐9.00), and the lymphatic/hematopoietic system (O/E, 3.37; 95% CI, 1.35‐6.94). The O/E ratio was higher for patients given chemotherapy and RT (O/E, 5.52; 95% CI, 3.75‐7.83) than for those given RT only (O/E, 3.96; 95% CI, 2.88‐5.32).
CONCLUSIONS
Patients with medulloblastoma are at elevated risk for SMNs in comparison with the general population. Variations in O/E for SMNs by organ systems were found for treatment modality, age at diagnosis, and time of diagnosis. The most common site, the CNS, was involved more often in younger patients and those given chemotherapy with RT.
This analysis of the Surveillance, Epidemiology, and End Results database shows increases in observed‐to‐expected incidence ratios of secondary malignant neoplasms among more than 1000 patients receiving radiotherapy for medulloblastoma. The highest such ratio is found for the central nervous system, and the ratios also vary according to the receipt of chemotherapy, age at diagnosis, treatment era, and sex.
Introduction
Diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) represents a unique category of nephroblastomatosis. Treatment has ranged from observation to multiple regimens of ...chemotherapy. Wilms tumors (WTs) develop in 100% of untreated patients and between 32 and 52% of treated patients. Renal preservation rates have not been previously reported. An aim of the Children’s Oncology Group (COG) study AREN0534 was to prospectively evaluate the efficacy of chemotherapy in preserving renal units and preventing WT development in children with DHPLN.
Methods
Patients were enrolled through the COG protocol AREN03B2 with central radiological review. DHPLN was defined as the cortical surface of the kidney being composed of hyperplastic rests, with the entire nephrogenic zone involved, and with a thick rind capping all of one or both kidneys. Treatment was with vincristine and dactinomycin (regimen EE4A), with cross-sectional imaging at weeks 6 and 12. If the patient’s disease was stable or decreasing, treatment was continued for 19 weeks. Renal preservation, WT development rates at 1 year, and overall survival (OS) are reported.
Results
Nine patients were enrolled (five females and four males), with a median age at enrollment of 10.22 months (range 2.92–29.11). One patient who was enrolled was deemed unevaluable because they did not meet the radiological criteria for DHPLN, resulting in eight evaluable patients. These eight patients had DHPLN confirmed via radiological criteria (all bilateral). Initial chemotherapy was EE4A for all eight patients, with seven of eight patients starting chemotherapy without tissue diagnosis.One patient who had an upfront partial nephrectomy was found to have DHPLN in the specimen and was subsequently treated with EE4A. All patients remained alive, with a median follow-up of 6.6 years (range 4.5–9.1). No patients were anephric; 14 of 16 kidneys were functioning (87.5%). Six of eight patients (75%) did not have WT on therapy, but two of these patients relapsed within 6 months of stopping therapy; both had favorable histology WT. One patient who was diagnosed with WT on therapy relapsed at 12 months (one of eight 12.5%) and developed anaplastic histology.
Conclusions
Chemotherapy for patients with DHPLN was effective in preserving kidney function. Five-year OS is excellent, however the ideal type and duration of chemotherapy to prevent WT development remains elusive.
Traditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these ...drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities.
Gene expression profiles of 46 samples of medulloblastoma were generated using the U133av2 Affymetrix oligonucleotide array and validated using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Genetic abnormalities were confirmed using fluorescence in situ hybridization (FISH) and direct sequencing.
Unsupervised analysis of gene expression profiles partitioned medulloblastomas into five distinct subgroups (subgroups A to E). Gene expression signatures that distinguished these subgroups predicted the presence of key molecular alterations that we subsequently confirmed by gene sequence analysis and FISH. Subgroup-specific abnormalities included mutations in the Wingless (WNT) pathway and deletion of chromosome 6 (subgroup B) and mutations in the Sonic Hedgehog (SHH) pathway (subgroup D). Real-time RT-PCR analysis of gene expression profiles was then used to predict accurately the presence of mutations in the WNT and SHH pathways in a separate group of 31 medulloblastomas.
Genome-wide expression profiles can partition large tumor cohorts into subgroups that are enriched for specific genetic alterations. This approach may assist ultimately in the selection of patients for future clinical trials of molecular targeted therapies.
Cerebellar mutism syndrome (CMS), also known as posterior fossa syndrome, occurs in a subset of children after posterior fossa tumor resection, most commonly medulloblastoma. Patients with this ...syndrome exhibit often transient, although protracted, symptoms of language impairment, emotional lability, cerebellar, and brainstem dysfunction. However, many patients experience persistent neurological deficits and lasting neurocognitive impairment. Historically, research and clinical care were hindered by inconsistent nomenclature, poorly defined diagnostic criteria, and uncertainty surrounding risk factors and etiology. Proposed diagnostic criteria include two major symptoms, language impairment and emotional lability, as proposed by the international Board of the Posterior Fossa Society in their consensus statement as well as other experts in this field. Risk factors most commonly associated with development of CMS include midline tumor location, diagnosis of medulloblastoma and specific tumor subtype, younger age at diagnosis, and preoperative language impairment. A proposed etiology of CMS includes disruption of the cerebellar outflow tracts, the cerebellar nuclei, and their efferent projections through the superior cerebellar peduncle. Treatment for CMS remains supportive. Herein, we present a comprehensive overview of CMS etiology, diagnosis, risk factors, clinical presentation, and clinical management. In addition, we identify essential multidisciplinary research priorities to advance diagnostics, prevention, and intervention efforts for patients with, or at risk for, development of CMS.
The clinical significance of magnetic resonance imaging (MRI) changes after radiation therapy (RT) in children with ependymoma is not well defined. We compared imaging changes following proton beam ...radiation therapy (PBRT) to those after photon-based intensity modulated RT (IMRT).
Seventy-two patients with nonmetastatic intracranial ependymoma who received postoperative RT (37 PBRT, 35 IMRT) were analyzed retrospectively. MRI images were reviewed by 2 neuroradiologists.
Sixteen PBRT patients (43%) developed postradiation MRI changes at 3.8 months (median) with resolution by 6.1 months. Six IMRT patients (17%) developed changes at 5.3 months (median) with 8.3 months to resolution. Mean age at radiation was 4.4 and 6.9 years for PBRT and IMRT, respectively (P = .06). Age at diagnosis (>3 years) and time of radiation (≥3 years) was associated with fewer imaging changes on univariate analysis (odds ratio OR: 0.35, P = .048; OR: 0.36, P = .05). PBRT (compared to IMRT) was associated with more frequent imaging changes, both on univariate (OR: 3.68, P = .019) and multivariate (OR: 3.89, P = .024) analyses. Seven (3 IMRT, 4 PBRT) of 22 patients with changes had symptoms requiring intervention. Most patients were treated with steroids; some PBRT patients also received bevacizumab and hyperbaric oxygen therapy. None of the IMRT patients had lasting deficits, but 2 patients died from recurrent disease. Three PBRT patients had persistent neurological deficits, and 1 child died secondarily to complications from radiation necrosis.
Postradiation MRI changes are more common with PBRT and in patients less than 3 years of age at diagnosis and treatment. It is difficult to predict causes for development of imaging changes that progress to clinical significance. These changes are usually self-limiting, but some require medical intervention, especially those involving the brainstem.
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