Evaluating the potential role of determinants of health on encephalocele patient outcomes - a combined retrospective study and systematic review.

INTRODUCTION: To evaluate the outcomes and demographics of encephalocele patients who were born and received treatment in our neonatal ICU and conduct a PRISMA literature review. METHODS: An Institutional Review Board (IRB)-approved retrospective cohort study was undertaken to investigate the results of treating encephalocele patients at Jackson Memorial Hospital (JMH) from 1998 to 2022. The study focused on assessing outcomes and the impact of maternal socioeconomic factors, such as religion, age, and education, along with the timing of diagnosis, in connection with a systematic review. RESULTS: A total of 20 encephalocele patients were identified (13 females and 7 males), with 15 having available medical records for review. Most of these cases involved occipital encephaloceles (73.3%). Maternal ages at the time of delivery ranged from 15 to 42 years, with a mean age of 27.3 years. The average gestational age at birth was 37 weeks. Ten cases had a prenatal diagnosis documented, occurring between 12 and 24.5 weeks of gestation. Three of the surviving patients had records of prenatal counseling that included discussions about termination. No infections were reported. Among the 15 cases, 11 patients (73.3%) were alive at the last follow-up, with a mean age at follow-up of 4.12 years, ranging from 6 weeks to 15 years post-birth. Hydrocephalus was noted in 26.7%. Only 1 mother had completed high school. Most mothers were either on Medicaid (9 patients) or uninsured (3 patients), with only 3 having commercial insurance. Religious affiliations varied among the mothers, with 14 out of 15 identifying with a particular religion. The systematic review identified 22 articles from various countries, with 11 articles meeting the inclusion criteria for qualitative analysis. These articles revealed potential maternal risk factors for encephaloceles, including low-nutrient diets, inadequate folic acid intake, young maternal age, advanced maternal age, low socioeconomic status, and limited educational attainment. CONCLUSIONS: In the twenty-first century, there is a positive trend in the survival rates of children born with encephalocele. However, maternal factors such as low socioeconomic status and limited educational attainment remain prominent, affecting their ability to access timely prenatal care and impacting follow-up medical care for these children.

A quantitative analysis of craniopharyngioma cyst expansion during and after radiation therapy and surgical implications.

OBJECTIVE When complete resection of craniopharyngioma is not achievable or the sequelae are prohibitive, limited surgery and radiation therapy have demonstrated excellent local disease control while minimizing treatment-related sequelae. When residual tissue exists, there is a propensity for further cyst development and expansion during and after radiation therapy. This can result in obstructive hydrocephalus, visual changes, and/or clinical decline. The authors present a quantitative analysis of cyst expansion during and after radiotherapy and examine how it affected subsequent management. METHODS The authors performed an institutional review board-approved retrospective study of patients with histologically confirmed craniopharyngioma treated between 2000 and 2015 with surgery and intensity-modulated radiation therapy (IMRT) at a single institution. Volumetric measurements of cyst contours were generated by radiation oncology treatment planning software postoperatively, during IMRT, and up to 12 months after IMRT. Patient, tumor, and treatment-related variables were collected until the last known follow-up and were analyzed. RESULTS Twenty-seven patients underwent surgery and IMRT. The median total radiation dose was 54 Gy. Of the 27 patients, 11 patients (40.7%) demonstrated cyst expansions within 1 year of IMRT. Of note, all tumors with cyst expansion were radiographically Puget Grade 2. Maximal cyst expansion peaked at 4.27 months following radiation therapy, with a median volume growth of 4.1 cm3 (mean 9.61 cm3) above the postoperative cyst volume. Eight patients experienced spontaneous cyst regression without therapeutic intervention. Three patients experienced MRI-confirmed cyst enlargement during IMRT, all of whom required adaptive planning to ensure adequate coverage of the entire tumor volume. Two of these 3 patients required ventriculoperitoneal shunt placement and additional intervention. One underwent additional resection, and the other had placement of an intracystic catheter for aspiration and delivery of intracystic interferon within 12 months of completing IMRT. All 3 patients now have stable disease. CONCLUSIONS Craniopharyngioma cyst expansion occurred in approximately 40% of the patients during or after radiotherapy. In the majority of patients, cyst expansion was a self-limiting process and did not confer a worse outcome. During radiotherapy, cyst expansion may be apparent on image-guided radiation therapy. Adaptive IMRT planning may be required to ensure that the intended IMRT dose covers the entire tumor and cyst volume. The sequelae of cyst expansion include progressive hydrocephalus, which may be treated with a shunt. For patients with solitary cyst expansion, cyst aspiration and/or intracystic interferon may result in disease control.

Radiation therapy for pediatric craniopharyngioma.

OBJECT: The treatment of craniopharyngioma is highly controversial. Continued advances in limited surgery and radiation therapy have maintained excellent local disease control while minimizing treatment-related sequelae. Further analyses of outcomes are necessary to characterize the long-term effects of radiation therapy. METHODS: An extensive literature review was performed for all studies including radiation therapy, with or without surgery, for pediatric craniopharyngioma. RESULTS: The authors identified 32 papers describing radiation therapy for treatment of pediatric craniopharyngioma, with disease control ranging from 44 to 100%. Modern studies report at least 90% disease control with 5-year follow-up. Fifteen studies reported outcomes, demonstrating that more than two-thirds of patients treated with surgery and radiation therapy have favorable outcomes, and this rate is more than 85% in the modern era. CONCLUSIONS: Conservative surgery and radiation therapy results in long-term disease control in pediatric patients with craniopharyngioma that is comparable to results obtained with radical surgery alone. However, children with craniopharyngioma remain vulnerable to late treatment failures and side effects from radiation therapy, including endocrinopathies, vasculopathies, and secondary tumors, which may be detrimental to the quality of life. Long-term follow-up beyond 5-10 years is necessary to assess tumor control relative to functional outcomes.

Myc and Loss of p53 Cooperate to Drive Formation of Choroid Plexus Carcinoma.

Choroid plexus carcinoma (CPC) is a rare brain tumor that occurs most commonly in very young children and has a dismal prognosis despite intensive therapy. Improved outcomes for patients with CPC depend on a deeper understanding of the mechanisms underlying the disease. Here we developed transgenic models of CPCs by activating the Myc oncogene and deleting the Trp53 tumor suppressor gene in murine neural stem cells or progenitors. Murine CPC resembled their human counterparts at a histologic level, and like the hypodiploid subset of human CPC, exhibited multiple whole-chromosome losses, particularly of chromosomes 8, 12, and 19. Analysis of murine and human CPC gene expression profiles and copy number changes revealed altered expression of genes involved in cell cycle, DNA damage response, and cilium function. High-throughput drug screening identified small molecule inhibitors that decreased the viability of CPC. These models will be valuable tools for understanding the biology of choroid plexus tumors and for testing novel approaches to therapy. SIGNIFICANCE: This study describes new mouse models of choroid plexus carcinoma and uses them to investigate the biology and therapeutic responsiveness of this highly malignant pediatric brain tumor.

Presentation and outcomes in surgically and conservatively managed pediatric Rathke cleft cysts.

OBJECTIVE Rathke cleft cysts (RCCs) are sellar lesions that are commonly encountered in adults but infrequently diagnosed in the pediatric population. As a result, the optimal management of pediatric RCCs remains a subject of controversy. Only 2 prior surgical series have been published on pediatric RCCs and no study has compared the presentation and outcomes of surgically versus conservatively managed cases. The authors therefore performed a comparative analysis of pediatric cases of RCC in which patients were treated with surgery or managed in a conservative manner. METHODS All cases involving pediatric patients diagnosed with an RCC at the University of Virginia between 2000 and 2016 were included in this study. Patient medical records, operative notes, and neuroimaging findings were reviewed. Patients who developed visual field deficits, radiographic evidence of chiasmal compression, or medically refractory headaches were considered candidates for surgical intervention. All patients who were selected for surgery underwent an endoscopic endonasal approach with cyst fenestration. RESULTS A total of 24 pediatric patients were diagnosed with an RCC over a 16-year period. Seven patients ultimately underwent transsphenoidal cyst fenestration, and 17 were managed conservatively. The patients' age at diagnosis, cyst size, and pituitary function at the time of RCC diagnosis were similar in the conservatively and surgically managed cohorts. At diagnosis, 19 of 24 patients endorsed headaches that led to neuroimaging. All patients in the surgical cohort endorsed severe headaches at diagnosis compared with 71% in the conservative group. For the 7 patients treated with surgery, complete cyst evacuation was achieved in 86% of cases. Transient postoperative endocrinopathy occurred in 4 (57%) of 7 surgically treated individuals and resolved in all cases. In the conservative cohort, 1 patient developed a delayed pituitary-related endocrinopathy. Headache resolution occurred in 5 (71%) of the 7 patients who underwent surgery and 7 (58%) of the 12 who were treated without surgery. Cyst recurrence was documented in 1 individual in the surgical cohort who underwent a subtotal cyst fenestration that ultimately required re-intervention. In the conservative cohort, spontaneous cyst shrinkage occurred in 35% of patients with a median time to regression of 23.5 months. CONCLUSIONS Pediatric RCCs are benign sellar lesions that often present with headaches. While cyst fenestration mitigates headaches in most patients, the majority of conservatively managed pediatric patients with RCCs will have spontaneous headache resolution. Furthermore, spontaneous RCC regression occurs in a substantial number of individuals. Thus, in the absence of optic compression, visual field deficit, or diagnostic uncertainty, many pediatric cases of RCC can be managed conservatively.

Novel GOPC(FIG)-ROS1 fusion in a pediatric high-grade glioma survivor.

Pediatric high-grade glioma is a rare tumor characterized by high mortality. The authors report the first case of a high-grade glioma associated with a GOPC(FIG)-ROS1 fusion in a pediatric patient. The patient underwent gross-total resection at the age of 4 years, followed by adjuvant high-dose chemotherapy and autologous hematopoietic stem cell rescue. At 30 months after transplantation, she remains disease free.

Spatial heterogeneity in medulloblastoma.

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma.

PURPOSE: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. METHODS AND MATERIALS: Pediatric patients with CNS embryonal tumors (n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose-volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. RESULTS: When the dose distribution was partitioned into 2 levels, both had a significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. CONCLUSIONS: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts.

Phase II trial of conformal radiation therapy for pediatric patients with craniopharyngioma and correlation of surgical factors and radiation dosimetry with change in cognitive function.

OBJECT: A Phase II trial of conformal radiation therapy (CRT) for craniopharyngioma was conducted to determine whether the irradiated volume could be safely reduced to decrease effects on cognitive function. METHODS: Between July 1997 and January 2003, 28 pediatric patients (median age 7.3 +/- 4.12 years) received CRT in whom doses (54-55.8 Gy) were administered to the gross tumor volume (solid and cystic components) surrounded by a 1-cm clinical target volume margin. Patients were evaluated serially with neuropsychometric testing. Statistical analyses were performed to determine the effect of clinical factors and radiation dosimetry on intelligence quotient (IQ). The median follow-up period was 36.6 months (range 24.4-80 months). The estimated 3-year progression-free survival rate was 90.3 +/- 7.3%. Three patients experienced local disease progression. Cognitive outcome for patients was adversely affected by the following factors: age younger than 7.4 years (p = 0.001), an interval between symptoms and diagnosis of more than 73 days (p = 0.06), more extensive surgery (p = 0.014), multiple surgical procedures (p = 0.002), diabetes insipidus (p = 0.02), hydrocephalus at diagnosis (p = 0.009), a cerebrospinal fluid shunt (p = 0.005), shunt revisions (p = 0.01), Ommaya reservoir laterality (p = 0.005), and cyst aspirations (p = 0.02). The percentage of total brain, supratentorial brain, or left temporal lobe volumes receiving a dose in excess of 45 Gy had a significant impact on longitudinal IQ. CONCLUSIONS: The use of CRT with a 1-cm margin for clinical target volume results in tumor control equivalent to that achieved using conventionally planned radiation therapy. Surgical morbidity and a volume-receiving dose more than 45 Gy are factors affecting longitudinal IQ after CRT in patients treated for craniopharyngioma.

Reevaluating the weekend effect on patients with hydrocephalus undergoing operative shunt intervention.

OBJECT Recently published data have suggested an increase in adverse outcomes in pediatric patients after insertion or revision of a ventricular CSF diversion shunt after a same-day weekend procedure. The authors undertook an evaluation of the impact of weekend admission and time to shunting on surgery-related quality outcomes in pediatric patients who underwent ventricular shunt insertion or revision. METHODS Pediatric patients with hydrocephalus who underwent ventriculoperitoneal, ventriculoatrial, or ventriculopleural shunt placement were selected from the 2000-2010 Nationwide Inpatient Sample and Kids' Inpatient Database. Multivariate regression analyses (adjusted for patient, hospital, case severity, and time to shunting) were used to determine the differences in inpatient mortality and routine discharge rates among patients admitted on a weekday versus those among patients admitted on a weekend. RESULTS There were 99,472 pediatric patients with shunted hydrocephalus, 16% of whom were admitted on a weekend. After adjustment for disease severity, time to procedure, and admission acuity, weekend admission was not associated with an increase in the inpatient mortality rate (p = 0.46) or a change in the percentage of routine discharges (p = 0.98) after ventricular shunt procedures. In addition, associations were unchanged after an evaluation of patients who underwent shunt revision surgery. High-volume centers were incidentally noted in multivariate analysis to have increased rates of routine discharge (OR 1.04 [95% CI 1.01-1.07]; p = 0.02). CONCLUSIONS Contrary to those of previous studies, the authors' data suggest that weekend admission is not associated with poorer outcomes for ventricular shunt insertion or revision. Increased rates of routine discharge were noted at high-volume centers.

Utility of diffusion tensor imaging studies linked to neuronavigation and other modalities in repeat hemispherotomy for intractable epilepsy.

OBJECT Hemispherectomy for unilateral, medically refractory epilepsy is associated with excellent long-term seizure control. However, for patients with recurrent seizures following disconnection, workup and investigation can be challenging, and surgical options may be limited. Few studies have examined the role of repeat hemispherotomy in these patients. The authors hypothesized that residual fiber connections between the hemispheres could be the underlying cause of recurrent epilepsy in these patients. Diffusion tensor imaging (DTI) was used to test this hypothesis, and to target residual connections at reoperation using neuronavigation. METHODS The authors identified 8 patients with recurrent seizures following hemispherectomy who underwent surgery between 1995 and 2012. Prolonged video electroencephalography recordings documented persistent seizures arising from the affected hemisphere. In all patients, DTI demonstrated residual white matter association fibers connecting the hemispheres. A repeat craniotomy and neuronavigation-guided targeted disconnection of these residual fibers was performed. Engel class was used to determine outcome after surgery at a minimum of 2 years of follow-up. RESULTS Two patients underwent initial hemidecortication and 6 had periinsular hemispherotomy as their first procedures at a median age of 9.7 months. Initial pathologies included hemimegalencephaly (n = 4), multilobar cortical dysplasia (n = 3), and Rasmussen's encephalitis (n = 1). The mean duration of seizure freedom for the group after the initial procedure was 32.5 months (range 6-77 months). In all patients, DTI showed limited but definite residual connections between the 2 hemispheres, primarily across the rostrum/genu of the corpus callosum. The median age at reoperation was 6.8 years (range 1.3-14 years). The average time taken for reoperation was 3 hours (range 1.8-4.3 hours), with a mean blood loss of 150 ml (range 50-250 ml). One patient required a blood transfusion. Five patients are seizure free, and the remaining 3 patients are Engel Class II, with a minimum follow-up of 24 months for the group. CONCLUSIONS Repeat hemispherotomy is an option for consideration in patients with recurrent intractable epilepsy following failed surgery for catastrophic epilepsy. In conjunction with other modalities to establish seizure onset zones, advanced MRI and DTI sequences may be of value in identifying patients with residual connectivity between the affected and unaffected hemispheres. Targeted disconnection of these residual areas of connectivity using neuronavigation may result in improved seizure outcomes, with minimal and acceptable morbidity.

Radiation dosimetry predicts IQ after conformal radiation therapy in pediatric patients with localized ependymoma.

PURPOSE: To assess the effects of radiation dose-volume distribution on the trajectory of IQ development after conformal radiation therapy (CRT) in pediatric patients with ependymoma. METHODS AND MATERIALS: The study included 88 patients (median age, 2.8 years +/- 4.5 years) with localized ependymoma who received CRT (54-59.4 Gy) that used a 1-cm margin on the postoperative tumor bed. Patients were evaluated with tests that included IQ measures at baseline (before CRT) and at 6, 12, 24, 36, 48, and 60 months. Differential dose-volume histograms (DVH) were derived for total-brain, supratentorial-brain, and right and left temporal-lobe volumes. The data were partitioned into three dose intervals and integrated to create variables that represent the fractional volume that received dose over the specified intervals (e.g., V(0-20 Gy), V(20-40 Gy), V(40-65 Gy)) and modeled with clinical variables to develop a regression equation to estimate IQ after CRT. RESULTS: A total of 327 IQ tests were performed in 66 patients with infratentorial tumors and 20 with supratentorial tumors. The median follow-up was 29.4 months. For all patients, IQ was best estimated by age (years) at CRT; percent volume of the supratentorial brain that received doses between 0 and 20 Gy, 20 and 40 Gy, and 40 and 65 Gy; and time (months) after CRT. Age contributed significantly to the intercept (p > 0.0001), and the dose-volume coefficients were statistically significant (V(0-20 Gy), p = 0.01; V(20-40 Gy), p < 0.001; V(40-65 Gy), p = 0.04). A similar model was developed exclusively for patients with infratentorial tumors but not supratentorial tumors. CONCLUSION: Radiation dosimetry can be used to predict IQ after CRT in patients with localized ependymoma. The specificity of models may be enhanced by grouping according to tumor location.

Acute effects of irradiation on cognition: changes in attention on a computerized continuous performance test during radiotherapy in pediatric patients with localized primary brain tumors.

PURPOSE: To assess sustained attention, impulsivity, and reaction time during radiotherapy (RT) for pediatric patients with localized primary brain tumors. METHODS AND MATERIALS: Thirty-nine patients (median age 12.3 years, range 5.9-22.9) with primary brain tumors were evaluated prospectively using the computerized Conners' continuous performance test (CPT) before and during conformal RT (CRT). The data were modeled to assess the longitudinal changes in the CPT scores and the effects of clinical variables on these changes during the first 50 days after the initiation of CRT. RESULTS: The CPT scores exhibited an increasing trend for errors of omission (inattentiveness), decreasing trend for errors of commission (impulsivity), and slower reaction times. However, none of the changes were statistically significant. The overall index, which is an algorithm-based weighted sum of the CPT scores, remained within the range of normal throughout treatment. Older patients (age >12 years) were more attentive (p < 0.0005), less impulsive (p < 0.07), and had faster reaction times (p < 0.001) at baseline than the younger patients. The reaction time was significantly reduced during treatment for the older patients and lengthened significantly for the younger patients (p < 0.04). Patients with a shunted hydrocephalus (p < 0.02), seizure history (p < 0.0006), and residual tumor (p < 0.02) were significantly more impulsive. Nonshunted patients (p < 0.0001), those with more extensive resection (p < 0.0001), and patients with ependymoma (p < 0.006) had slower initial reaction times. CONCLUSION: Children with brain tumors have problems with sustained attention and reaction time resulting from the tumor and therapeutic interventions before RT. The reaction time slowed during treatment for patients <12 years old. RT, as administered in the trial from which these data were derived, has limited acute effects on changes in the CPT scores measuring attention, impulsiveness, and reaction time.

Craniopharyngioma: the St. Jude Children's Research Hospital experience 1984-2001.

PURPOSE: To review our institution's experience in the treatment of craniopharyngioma and assess the merits of initial therapy with limited surgery and irradiation. METHODS AND MATERIALS: The data of 30 patients (median age 8.6 years) with a diagnosis of craniopharyngioma between April 1984 and September 1997 were reviewed. Their course of treatment, neurologic, endocrine, and cognitive function, and quality of life at last follow-up were compared. RESULTS: Fifteen patients were initially treated with surgery (8 required irradiation after relapse) and 15 with limited surgery and irradiation (2 required additional treatment for tumor progression). Only 1 patient died of tumor progression. The surgery group lost a mean of 9.8 points in full-scale IQ, and the combined-modality group lost only 1.25 points (p <0.063). Patients in the surgery group who had relapses (n = 9) lost a mean of 13.1 points (p <0.067). A loss of 10 points was considered clinically significant. The surgery group also had more frequent neurologic, ophthalmic, and endocrine complications. The mean Health Utility Index (a functional quality-of-life index) was higher for the combined-modality group (0.85) than for the surgery group (0.71; p <0.063, one-sided t test). CONCLUSIONS: The acute neurologic, cognitive, and endocrine effects of surgery often affect long-term function and quality of life. Our experience suggests that limited surgery and radiotherapy cause lesser or comparable sequelae. Diabetes insipidus was the only endocrine deficiency that differed substantially in frequency between the two groups. Newer radiation planning and delivery techniques may make a combined-modality approach a good initial option for most patients.

Surgical management of large scalp infantile hemangiomas.

BACKGROUND: Infantile Hemangiomas (IH) are the most common benign tumor of infancy, occurring in over 10% of newborns. While most IHs involute and never require intervention, some scalp IHs may cause severe cosmetic deformity and threaten tissue integrity that requires surgical excision. CASE DESCRIPTION: We present our experience with two infants who presented with large scalp IH. After vascular imaging, the patients underwent surgical resection of the IH and primary wound closure with excellent cosmetic outcome. We detail the surgical management of these cases and review the relevant literature. CONCLUSION: In some cases the IHs leave behind fibro-fatty residuum causing contour deformity. Surgery is often required for very large lesions causing extensive anatomical and/or functional disruption. The goal of surgical intervention is to restore normal anatomic contour and shape while minimizing the size of the permanent scar.