High prevalence of anterior pituitary deficiencies after cranial radiation therapy for skull base meningiomas

Background Cranial irradiation represents one of the first line treatment proposed in skull base meningiomas. While cranial irradiation is associated with a high risk of secondary hypopituitarism, few studies focused on the specific location of skull base meningiomas. Methods Fifty-two adults receiving photon-beam therapy for skull base meningiomas between 2003 and 2014 in our Institution were included. Anterior pituitary (ACTH, FSH, GH, LH, TSH and prolactin) as well as corresponding peripheral hormones (8 am-Cortisol, IGF-1, fT3, fT4, 17βestradiol or testosterone) were biologically screened before radiotherapy (baseline), then yearly until March 2019. The pituitary gland (PG) was delineated on CT and the mean dose delivered to it was calculated. Results Mean age at diagnosis was 56 +/− 14 years. Median follow-up was 7 years. Up to 60% of patients developed at least ≥2 pituitary deficiencies, 10 years after radiotherapy. Gonadotroph, thyrotroph, corticotroph and somatotroph deficiencies occurred in 37, 28, 18 and 15% of patients, respectively. Hyperprolactinemia was found in 13% of patients. None patient had only one pituitary deficiency. In the multivariate analysis, a delivered dose to the PG ≥ 50 Gy or a meningioma size ≥40 mm significantly increased the risk of developing hypopituitarism. Conclusions Over a long-term follow-up, cranial radiation therapy used in skull base meningiomas led to a high prevalence of hypopituitarism, further pronounced in case of tumor ≥4 cm. These results advocate for an annual and prolonged follow-up of the pituitary functions in patients with irradiated skull base meningiomas.

NCOG-41. HISTOLOGICAL ANALYSIS OF SLEEP AND CIRCADIAN BRAIN CIRCUITRY IN CRANIAL RADIATION-INDUCED HYPERSOMNOLENCE (C-RIH) MOUSE MODEL

BACKGROUND Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving cranial radiation-induced hypersomnolence (C-RIH) remain unclear but we hypothesize this may result from damage to neural circuits controlling sleep behavior. We developed a mouse model of C-RIH to explore the impact of radiation on the brain: examining region-specific differences in acute DNA damage response and neuroanatomic structure. METHODS Mice received whole brain radiation then behaviors were monitored using PhenoTyper® cages to determine optimal dose and long-term effects. To test short-term neurologic effects, brains were collected 1hr post-radiation then stained for γH2AX, a signal for DNA damage. Long-term effects were quantified 1-month post-treatment using neuroimaging to determine brain volume and T1 mapping changes in regions associated with sleep, circadian rhythms, and cognition. RESULTS Mice displayed decreased general activity and increased daytime sleep in a dose-dependent and sustained manner. Histologic staining demonstrated that DNA damage following radiation varies across the brain, with homeostatic sleep regions and cognitive regions expressing higher levels of γH2AX than the circadian suprachiasmatic nucleus. These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes using both trypan blue (F(1,18)=235.937, p< 0.001) and clonogenic assays (F(1,24)=40.796, < 0.001). Brain volumes were significantly smaller in irradiated than sham animals in the hippocampus (t(4)=3.833, p=0.019) and the pontine central grey (t(4)=3.504, p=0.025). T1 maps also showed significant changes in relaxation times in many cognitive regions but not sleep or circadian areas. CONCLUSIONS These findings suggest that the homeostatic sleep region and cognitive circuits are vulnerable to radiation and may be relevant to the development of treatment plans in patients. We plan to introduce intracranial tumor to the model to evaluate the impact of timing of treatment and C-RIH on survival.

Defining the molecular features of radiation-induced glioma: a systematic review and meta-analysis

Background Cranial radiation therapy is essential in treating many pediatric cancers, especially brain tumors, however its use comes with the risk of developing second malignancies. Cranial radiation-induced gliomas (RIGs) are aggressive high-grade tumors with a dismal prognosis, for which no standard therapy exists. A definitive molecular signature for RIGs has not yet been established. We sought to address this gap by performing a systematic review and meta-analysis of the molecular features of cranial RIGs. Methods A systematic review of the literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English language articles and case reports referring to radiation-induced high-grade gliomas located in the human brain that included molecular analyses were identified, evaluated and data extracted for collation. Results Of 1727 records identified, 31 were eligible, containing 102 unique RIGs with molecular data. The most frequent genetic alterations in RIGs included PDGFRA or TP53 mutations, PDGFRA or CDK4 amplifications, and CDKN2A deletion, along with 1q gain, 1p loss and 13q loss. Of note, mutations in ACVR1, EGFR, H3F3A, HIST1H3B, HIST1H3C, IDH2, SMARCB1 or the TERT promoter were not observed. A comparative analysis revealed that RIGs are molecularly distinct from most other astrocytomas and gliomas and instead align most closely with the pedGBM_RTK1 subgroup of pediatric glioblastoma. Conclusions This comprehensive analysis highlights the major molecular features of RIGs, demonstrates their molecular distinction from many other astrocytomas and gliomas, and reveals potential genetic drivers and therapeutic targets for this currently fatal disease.

Financial hardship in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).

10026 Background: The impact of childhood and adolescent cancer on the long-term financial outcomes of survivors is poorly understood. We compared financial hardship between survivors and siblings enrolled in the CCSS and identified survivors at elevated risk. Methods: Survivors treated for cancer at age < 21 years in 1970-1999 and siblings responded to a survey (23 binary-response questions) at age ≥26 years administered in 2017-2019. Principal component analysis with promax rotation extracted 3 factors with eigenvalues > 1 and KR-20 reliability coefficients > 0.7, retaining items with factor loadings > 0.4. These factors were behavioral hardship (8 items, e.g., forgone needed medical care), material hardship/financial sacrifices (8 items, e.g., problems paying medical bills) and psychological hardship (3 items, e.g., worry about having enough money to pay rent/mortgage). Factor scores were calculated by adding the item responses and dividing by their standard deviation. Multiple linear regression examined the association of sociodemographic and cancer treatment variables with factor scores. Results: Among 3349 survivors (49% male; median age [range] 40.2 [26.0-67.4] years) and 976 siblings (42% male, median age 46.5 [ 26.1-69.2] years), survivors were more likely to report being sent to debt collection (29.5 vs 21.4%), problems paying medical bills (20.0 vs 11.9%), foregoing needed medical care (13.3 vs 7.7%) and worry/stress about paying their mortgage (32.8 vs 23.2%) or having enough money to buy nutritious meals (25.0 vs 16.2%), all P < 0.001. Survivors reported greater hardship than siblings on all 3 factors: behavioral hardship (standardized mean score 0.51 vs 0.36), material hardship/financial sacrifices (0.63 vs 0.44), psychological hardship (0.69 vs 0.44), all P < 0.001. Behavioral hardship was increased by female gender (regression coefficient [ꞵ] 0.17, 95% CI 0.10-0.25), < high school (ꞵ 0.45, CI 0.12-0.79) or < college (ꞵ 0.18, CI 0.09-0.26) education, no (ꞵ 1.14, CI 0.93-1.35) or public (ꞵ 0.23, CI 0.10-0.35) health insurance, being divorced/separated (ꞵ 0.28, CI 0.10-0.46) and ≥250mg/m2 anthracycline chemotherapy (ꞵ 0.09, CI 0.00-0.19). The same variables were significantly associated with the other two hardship factors, but total body irradiation and cranial radiation also contributed to the risk of material hardship/financial sacrifices, and ≥8g/m2 cyclophosphamide equivalent dose and cranial radiation contributed to psychological hardship. Conclusions: Survivors of childhood and adolescent cancer are at elevated risk for financial hardship as compared to sibling controls. Those at highest risk can be defined using a combination of sociodemographic and treatment variables. This information can be used to inform targeted intervention strategies to reduce the risk of poor financial outcomes in this vulnerable population.

Use of Chronic Prescription Medications and Prevalence of Polypharmacy in Survivors of Childhood Cancer

BackgroundAs survivors of childhood cancer age, development of cancer treatment-related chronic health conditions often occur. This study aimed to describe the pattern of chronic prescription medication use and identify factors associated with polypharmacy among survivors of childhood cancer.MethodsThis was a retrospective study conducted at the pediatric oncology long-term follow-up clinic in Hong Kong. Eligible subjects included survivors who were (1) diagnosed with cancer before 18 years old, (2) were at least 3 years post-cancer diagnosis and had completed treatment for at least 30 days, and (3) receiving long-term follow-up care at the study site between 2015 and 2018. Dispensing records of eligible survivors were reviewed to identify medications taken daily for ≥30 days or used on an “as needed” basis for ≥6 months cumulatively within the past 12-month period. Polypharmacy was defined as the concurrent use of ≥5 chronic medications. Multivariable log-binomial modeling was conducted to identify treatment and clinical factors associated with medication use pattern and polypharmacy.ResultsThis study included 625 survivors (mean current age = 17.9 years, standard deviation [SD] = 7.2 years) who were 9.2 [5.2] years post-treatment. Approximately one-third (n = 219, 35.0%) of survivors were prescribed at least one chronic medication. Frequently prescribed medication classes include systemic antihistamines (26.5%), sex hormones (19.2%), and thyroid replacement therapy (16.0%). Overall prevalence of polypharmacy was 5.3% (n = 33). A higher rate of polypharmacy was found in survivors of CNS tumors (13.6%) than in survivors of hematological malignancies (4.3%) and other solid tumors (5.3%) (P = .0051). Higher medication burden was also observed in survivors who had undergone cranial radiation (RR = 6.31; 95% CI = 2.75–14.49) or hematopoietic stem-cell transplantation (HSCT) (RR = 3.53; 95% CI = 1.59–7.83).ConclusionAlthough polypharmacy was observed in a minority of included survivors of childhood cancer, chronic medication use was common. Special attention should be paid to survivors of CNS tumors and survivors who have undergone HSCT or cranial radiation. These individuals should be monitored closely for drug–drug interactions and adverse health outcomes that may result from multiple chronic medications, particularly during hospitalization in an acute care setting.

High Prevalence of Anterior Pituitary Deficiencies after Cranial Radiation Therapy for Skull Base Meningiomas.

Background: Cranial irradiation represents the first-line treatment proposed in skull base meningiomas. While cranial irradiation is associated with a high risk of secondary hypopituitarism, few studies focused on the specific location of skull base meningiomas. Methods: 52 adults receiving photon-beam therapy for skull base meningiomas between 1978 and 2014 in our Institution were included. Anterior pituitary (ACTH, FSH, GH, LH, TSH and prolactin) as well as corresponding peripheral hormones (8am-Cortisol, IGF-1, fT3, fT4, 17βestradiol or testosterone) were biologically screened before radiotherapy (baseline), then yearly until March 2019. The pituitary gland (PG) was delineated on CT and the mean dose delivered to it was calculated.Results: Mean age at diagnosis was 56 +/-14 years. Median follow-up was 7 years. Up to 60% of patients developed at least ≥ 2 pituitary deficiencies, 10 years after radiotherapy. Gonadotroph, thyrotroph, corticotroph and somatotroph deficiencies occurred in 37%, 28%, 18% and 15% of patients, respectively. Hyperprolactinemia was found in 13 % of patients. None patient had only one pituitary deficiency. In the multivariate analysis, a delivered dose to the PG ≥ 50 Gy or a meningioma size ≥ 40 mm significantly increased the risk of developing hypopituitarism. Conclusions: Over a long-term follow-up, cranial radiation therapy used in skull base meningiomas led to a high prevalence of hypopituitarism, further pronounced in case of tumor ≥ 4cm. These results advocate for an annual and prolonged follow-up of the pituitary functions in patients with irradiated skull base meningiomas.

Late isolated central nervous system relapse in childhood B-cell acute lymphoblastic leukemia treated with intensified systemic therapy and delayed reduced-dose cranial radiation: A report from the Children’s Oncology Group study AALL02P2

Background: Patients with late, occurring ≥18 months post-diagnosis, isolated central nervous relapse (iCNS-R) of B-acute lymphoblastic leukemia (ALL) have excellent outcomes with chemotherapy plus cranial radiotherapy, with 5-yr overall survival (OS) approaching 80% in POG 9412. Subsequent relapse and radiation-related morbidity remain the causes of treatment failure and long-term sequelae. COG AALL02P2 aimed to maintain outcomes in patients with late iCNS-R using intensified chemotherapy and a decrease in cranial irradiation from 1800 to 1200 cGy. Procedures: COG AALL02P2 enrolled 118 eligible patients with B-ALL and early iCNS-R who received intensified systemic therapy, triple intrathecal chemotherapy and 1200 cGy cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until104 weeks post-diagnosis. Results: The 3-yr event-free and overall survival (EFS) and OS were 64.3±4.5% and 79.6±3.8%, with 46.1% (18/39) of relapses including the CNS. Of the 112 patients who completed therapy, 78 received protocol-specified radiation. Study enrollment was closed after interim monitoring analysis showed inferior EFS compared to POG 9412. Patients with initial NCI standard risk classification fared better than high risk patients. Conclusions: COG AALL02P2 showed inferior EFS but similar OS compared to POG 9412. Limitations included a small sample size, more intensive prior therapies, and a significant number of patients (34/118, 29%) who did not receive protocol-directed radiation due to early relapse prior to 1 year or did not otherwise follow the treatment plan. New approaches are needed to improve outcome for these patients and determine the optimal timing and dose of cranial radiation in the treatment of iCNS-R.

Stereotactic radiosurgery for treatment of radiation-induced meningiomas: a multiinstitutional study

OBJECTIVERadiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs.METHODSFrom 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS.RESULTSFifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4–195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3–45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028–65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS.CONCLUSIONSSRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

Clinical Presentation and Stroke Incidence Differ by Moyamoya Etiology

Introduction: Moyamoya arteriopathy, which can be idiopathic or associated with sickle cell disease, neurofibromatosis, Down syndrome, or cranial radiation therapy, is a progressive cerebral arteriopathy associated with high rates of incident and recurrent stroke. Little is known about how these subgroups differ with respect to clinical presentation, radiographic findings, stroke risk, and functional outcomes. Methods: Using ICD codes, we identified children ages 28 days to 18 years treated for moyamoya arteriopathy at our tertiary care center between 2003 and 2019. Demographic, clinical, and radiographic data were extracted from the medical record. The Pediatric Stroke Recurrence and Recovery Questionnaire was administered to consenting participants. Results: Sixty-nine patients met inclusion criteria (33 idiopathic, 18 sickle cell disease, 11 neurofibromatosis, 6 Down syndrome, 1 cranial radiation therapy). Median follow-up time was 7.7 years; 24 patients had at least 5 years of follow-up data. Frequency of stroke at presentation differed by subgroup ( P < .001). Of patients with at least 2 years of follow-up, 33 (55%) experienced stroke. The proportion of patients experiencing stroke differed by subgroup (50% of idiopathic cases, 72% of sickle cell disease, 11% of neurofibromatosis, and 100% of Down syndrome, P = .003). The frequency of bilateral versus unilateral disease ( P = .001) and stroke-free survival following presentation ( P = .01) also differed by subgroup. Conclusions: In this single-center cohort, moyamoya subgroups differed with respect to clinical and radiographic characteristics, with neurofibromatosis-associated moyamoya syndrome having a milder phenotype and Down syndrome–associated moyamoya portending a more aggressive course. These findings need confirmation in a larger, multi-center cohort with longer duration of follow-up.