Citations

Purpose: Treatment sequelae compromising reproductive health are highly prevalent in childhood cancer survivors, and a main determinant of health and quality of life. Follicular reserve determines ovarian function life span; thus, its preservation is important in the care of female survivors. Anti-Müllerian hormone (AMH) is a biomarker to measure functional ovarian reserve. We aimed to evaluate the effect of leuprolide during gonadotoxic therapy on pubertal females' post-treatment functional ovarian reserve using AMH levels. Methods: We conducted a single-center retrospective study including all pubertal females who had undergone gonadotoxic treatments between January 2010 and April 2020, and had an AMH level after completion of therapy. We used multivariable linear regressions to compare AMH-level beta coefficients in patients stratified by gonadotoxic risk, adjusting for leuprolide use. Results: Fifty-two females meeting study eligibility were included, of which 35 received leuprolide. The use of leuprolide was associated with higher post-treatment AMH levels in the lower gonadotoxic risk group (beta 2.74, 95% CI 0.97–4.51; p = 0.004). This association was lost in the higher gonadotoxic risk groups. Conclusions: Leuprolide may have a protective effect on the functional ovarian reserve. However, this is limited by increasing treatment gonadotoxicity. Larger, prospective studies are needed to elucidate the potential benefits of gonadotropin-releasing hormone agonist on preservation of ovarian reserve among children receiving gonadotoxic therapies, as cancer survivors.

AbstractBackground and PurposePrevious studies have proposed multiple parallel channels for waste clearance from the brain, though many gaps remain in our understanding of these systems. In this study, we examined periarterial fluid drainage around intracranial and extracranial segments of the internal carotid arteries (ICAs) from the brain into the cervical lymph nodes using a noninvasive and clinical‐based method.MethodsEighty‐one subjects (45 females, aged 15‐80 years old) with nonlesioned epilepsy underwent high‐resolution 3‐dimensional T2‐weighted fluid‐attenuated inversion recovery (FLAIR) MRI. We utilized a noninvasive and clinical‐based method with a manual semiautomated approach to characterize the periarterial lymphatic system's maximum thickness and signal intensities along the ICAs using high‐resolution 3‐dimensional FLAIR imaging. We conducted group comparisons and correlation analyses to investigate sex‐ and age‐based trends. Results were corrected with Bonferroni's test for multiple comparisons, and we performed power analysis for sample size calculations.ResultsUsing high‐resolution FLAIR images, we show evidence that fluid drainage emerges around the ICA petrous segment and joins lymphatic flow from cranial nerves in the upper neck, with this flow ultimately draining into the cervical lymph nodes bilaterally. Lymphatic signal at the petrous segment level was significantly thinner in females compared to males bilaterally (w = 413, p = .0001 on the right, w = 356, p < .0001 on the left). Lymphatic drainage around the petrous segments of the ICAs bilaterally was thicker with age in males but not in females.ConclusionsWe describe the in vivo high‐resolution imaging characteristics of periarterial fluid drainage along the vessel walls of ICAs. This represents a potentially major channel for brain waste clearance. We also report interesting sex‐ and age‐based trends in these structures within our cohort.

AbstractBackgroundPediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes.ProcedureSurvivors who underwent PRT (n = 38) or XRT (n = 20) participated in a neurocognitive evaluation >1 year post radiotherapy. Group differences in cognitive and social functioning were assessed using analysis of covariance (ANCOVA). Regression analyses examined predictors of peer relations and social skills.ResultsAge at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p > .05). XRT participants were younger at diagnosis (XRT M = 5.0 years, PRT M = 7.6 years) and further out from radiotherapy (XRT M = 8.7 years, PRT M = 4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p = .01) and verbal memory (p < .01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation; χ2(1) = 38.67, p < .001; χ2(1) = 5.63, p < .05. Household poverty predicted peer relation difficulties (t = 2.18, p < .05), and verbal memory approached significance (t = −1.99, p = .05). Tumor diameter predicted social skills (t = −2.07, p < .05).ConclusionsRegardless of radiation modality, survivors are at risk for social challenges. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship, as well as consideration of sociodemographic risk factors.

Background: Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. Procedure: Survivors who underwent PRT (n=38) or XRT (n=20) participated in a neurocognitive evaluation >1 year post-radiotherapy. Group differences in cognitive and social functioning were assessed using ANCOVA. Regression analyses examined predictors of peer relations and social skills. Results: Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p>0.05). However, XRT participants were younger at diagnosis (XRT M=5.0 years, PRT M=7.6 years) and further out from radiotherapy (XRT M=8.7 years, PRT M=4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p=0.01) and verbal memory (p<0.01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation (2(1)=38.67, p<0.001; 2(1)=5.63, p<0.05), and verbal memory approached significance as a unique predictor of peer relations (t=-2.01, p=0.05). Total tumor RT dose significantly predicted social skills (t=-2.23, p<0.05). Conclusions: Regardless of radiation modality, survivors are at risk for social challenges, with one-quarter being socially excluded or undervalued. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship.

BACKGROUNDBoth intensity‐modulated radiotherapy (RT) and passively scattered proton therapy have a risk of secondary malignant neoplasm (SMN) in children. To determine the influence of RT modality on the incidence of SMN after craniospinal irradiation (CSI), the authors compared the incidence of SMN in children who had medulloblastoma treated with either photon CSI plus an intensity‐modulated RT boost (group I) or passively scattered proton CSI plus a boost (group II).METHODSFrom 1996 to 2014, 115 children with medulloblastoma (group I, n = 63; group II, n = 52) received CSI followed by a boost to the tumor bed. Most patients had standard‐risk disease (63.5%). The median follow‐up was 12.8 years for group I and 8.7 years for group II.RESULTSThe 5‐year and 10‐year overall survival (OS) rates were 88.8% and 85.1%, respectively, for standard‐risk patients and 63.1% and 57.3%, respectively, for high‐risk patients, with no OS difference by RT modality (P = .81). Six SMNs were identified (4 in group I, 2 in group II). The 5‐year and 10‐year SMN incidence rates were 1.0% and 6.9%, respectively (0.0% and 8.0%, respectively, in group I; 2.2% and 4.9%, respectively, in group II; P = .74). Two SMNs occurred in the clinical target volume in the brain, 2 occurred in the exit dose region from the photon spinal field, 1 occurred in the entrance path of a proton beam, and 1 occurred outside the radiation field. There were no reported cases of secondary leukemia.CONCLUSIONSThis analysis demonstrates no difference in OS or SMN incidence between patients in groups I and II 10 years after RT.LAY SUMMARY One hundred fifteen children with medulloblastoma received radiotherapy (RT) with either photon craniospinal irradiation (CSI) and an intensity‐modulated RT boost (group I; n = 63) or passively scattered proton CSI and a boost (group II;, n = 52). The majority of children had standard‐risk disease (63.5%). The 5‐year and 10‐year overall survival rates were 88.8% and 85.1% for standard‐risk patients, respectively, and 63.1% and 57.3% for high‐risk patients, respectively, with no difference in overall survival by RT group (P = .81). The 5‐year and 10‐year second malignant neoplasm incidence rates were 1.0% and 6.9%, respectively, with no difference in second malignant neoplasm incidence according to RT group (P = .74).

Abstract Background Proton radiotherapy (PRT) may be associated with less neurocognitive risk than photon RT (XRT) for pediatric brain tumor survivors. We compared neurocognitive and academic outcomes in long‐term survivors treated with XRT versus PRT. Methods Survivors underwent neurocognitive evaluation >1 year after craniospinal (CSI) or focal PRT or XRT. Groups were compared using separate one‐way analyses of covariance for the CSI and focal groups. Results PRT ( n = 58) and XRT ( n = 30) subgroups were similar on gender (66% male), age at RT (median = 6.5 years), age at follow‐up (median = 14.6 years), and government assistance status (32%). PRT and XRT focal groups differed on follow‐up interval, shunt history, and total RT dose (all p < .05), whereas PRT and XRT CSI groups differed on follow‐up interval, baseline neurocognitive performance score, boost volume, and CSI dose (all p < .05). The PRT focal group outperformed the XRT focal group on inhibition/switching ( p = .04). The PRT CSI group outperformed the XRT CSI group on inattention/impulsivity (both p < .05). Several clinical variables (i.e., RT dose, boost field, baseline performance) predicted neurocognitive outcomes (all p < .05). The PRT focal group performed comparably to population means on most neurocognitive measures, while both CSI groups performed below expectation on multiple measures. The XRT CSI group was most impaired. All groups fell below expectation on processing speed, fine motor, and academic fluency (most p < .01). Conclusions Findings suggest generally favorable neurocognitive and academic long‐term outcomes following focal PRT. Impairment was greatest following CSI regardless of modality. Dosimetry and baseline characteristics are important determinants of outcome alone or in combination with modality.

Abstract Background: Endocrine deficiencies are common following craniospinal irradiation (CSI) in children with brain tumors, but empirical data comparing outcomes following proton (PRT) and photon radiation therapy (XRT) are limited. Methods: This retrospective chart review compared the incidence of hypothyroidism, growth hormone deficiency (GHD), and adrenal insufficiency (AI) in patients with medulloblastoma treated with XRT and PRT between 1997 and 2016. All patients received CSI and had routine endocrine screening labs to evaluate for thyroid dysfunction, GHD, and AI. We used proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) comparing the development of hypothyroidism, AI, and GHD between radiation modalities, adjusting for age at diagnosis, sex, race/ethnicity, and CSI dose.Results: We identified 118 patients with medulloblastoma who were followed for a median of 5.6 years from the end of radiotherapy. Thirty-five (31%) patients developed hypothyroidism, 71 (66%) GHD, and 20 (18%) AI. Compared to PRT, XRT was associated with a higher incidence of primary (28% vs. 6%; HR=4.61, 95% CI 1.2-17.7, p=0.03) and central hypothyroidism (33% vs. 9%; HR 2.35 (0.8-6.8, p=0.12). GHD and AI incidence rates were similar between the groups. Conclusions: Primary and central hypothyroidism occur less often after PRT CSI, compared to XRT CSI. This suggests that the thyroid and pituitary glands receive less radiation after spine and posterior fossa boost RT, respectively, using PRT.

Abstract Purpose177Lu-PSMA is a promising therapy for patients with metastatic castration resistant prostate cancer patients (mCRPC). To our knowledge, no study has compared the pharmacokinetic profiles of 177Lu-PSMA therapy delivered intra-arterially. We aimed to compare the feasibility and safety of selective intra-arterial (IA) administration vs conventional intravenous (IV) administration of 177Lu-PSMA in mCRPC. MethodsIn this within-patient pilot study, four patients (median age, 62.5; range, 53-72) with mCRPC who were referred to our clinic between January 2018 and September 2019 for treatment with 177Lu-PSMA. Patients were treated in two visits; in each visit receiving half of the total empiric therapeutic dose of 200 mCi, IV at the first visit and IA at the second visit. They were followed upto 8 weeks using routine parameters such as hematological status, renal function, and serum PSA levels. For each patient, organ biodistribution in lesions, kidneys, liver, bone marrow, prostate, and whole body was calculated for both administration routes according to the Medical Internal Radiation Dose (MIRD) schema. Mean absorbed doses (MAD) across all patients were compared between both administration routes. ResultsThe MAD of all metastatic lesions was significantly higher by IA vs IV administration (1.59 vs 1.20 MGy/MBq; p=0.024). The prostate gland had a lower MAD between IA and IV administrations, but the difference was not significant (0.27 vs 0.36 MGy/MBq; p=0.22). Patients tolerated IA administration very well without unexpected side effects. ConclusionThese preliminary results of an ongoing study showed that IA 177Lu-PSMA therapy is feasible and safe to treat metastatic lesions, potentially having a higher delivery efficacy compared to IV administration.This study is approved by Cerrahpasa Medical Faculty ethics committee on March 5, 2019 and retrospectively registered with file no: 83045809-604.01.02.

Abstract PURPOSE By reducing dose to normal brain tissue, proton radiotherapy (PRT) may lessen neurocognitive risk traditionally associated with photon radiotherapy (XRT). We examined change in neurocognitive scores over time in pediatric medulloblastoma patients treated with PRT versus XRT. METHODS Neurocognitive scores from 79 patients (37 PRT, 42 XRT) were examined. Patients were treated between 2007–2018 on the same treatment protocols that differed only by craniospinal modality (PRT versus XRT). Change in scores over time since diagnosis were compared between groups. RESULTS Groups were similar on most demographic/clinical variables: sex (67.1% male), age at diagnosis (mean 8.6 years), CSI dose (median 23.4 Gy), length of follow-up (mean 4.3 years), and parental education (mean 14.3 years). Boost dose (p&lt;0.001) and margin (p=0.001) differed between groups. Adjusting for covariates, the PRT group exhibited superior outcomes in global IQ, perceptual reasoning, and working memory versus the XRT group (all p&lt;0.05). The XRT group exhibited significant decline in global IQ, working memory, and processing speed (all p&lt;0.05). The PRT group exhibited stable scores in all domains except processing speed (p=0.003). Posterior fossa syndrome imparted risk independent of modality. CONCLUSION This is the first study comparing neurocognitive trajectories between pediatric patients treated for medulloblastoma with PRT versus XRT on comparable, contemporary protocols. PRT was associated with more favorable neurocognitive outcomes in most domains compared to XRT, although processing speed emerged as vulnerable in both groups. This is the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

Background. Early diagnosis of cerebral venous sinus thrombosis (CVST) associated with reproductive health-related risk factors (RHRF) including pregnancy, puerperium, and oral contraceptive (OC) use can prevent severe neurological sequelae; thus, the symptoms must be documented in detail for each group. Methods. Out of 1144 patients with CVST, a total of 777 women were enrolled from a multicenter for the study of cerebral venous sinus thrombosis (VENOST). Demographic, biochemical, clinical, and radiological aspects were compared for 324 cases with RHRF and 453 cases without RHRF. Results. The mean age of the RHRF (-) group (43.2 ± 13 years) was significantly higher than of the RHRF (+) group (34±9 years). A previous history of deep venous thrombosis (3%), isolated cavernous sinus involvement (1%), cranial neuropathy (13%), comorbid malignancy (7%), and its disability scores after 12 months (9%) were significantly higher in the RHRF (-) group. The RHRF (+) group consisted of 44% cases of puerperium, 33% cases of OC users and 23% of pregnant women. The mean age was found to be higher in OC users (38±9 years). A previous history of deep venous thrombosis was slightly higher in the pregnancy subgroup (4%). Epileptic seizures were more common in the puerperium group (44%). Conclusion. The results of our study indicate that the risk of CSVT increases parallel to age, OC use, and puerperium period. In addition, when considering the frequency of findings and symptoms, epileptic seizures in the puerperium subgroup of the RHRF (+) group and malignancies in the RHRF (-) group may accompany the CSVT. In daily practice, predicting these risks for the CSVT and early recognition of the symptoms will provide significant benefits to patients.