Role of intraoperative ultrasound and MRI to aid grade of resection of pediatric low-grade gliomas: accumulated experience from 4 centers.

PURPOSE: Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children and achieving complete resection (CR) in pLGG is the most important prognostic factor. There are multiple intraoperative tools to optimize the extent of resection (EOR). This article investigates and discusses the role of intraoperative ultrasound (iUS) and intraoperative magnetic resonance imaging (iMRI) in the surgical treatment of pLGG. METHODS: The tumor registries at Tuebingen, Rome and Pretoria were searched for pLGG with the use of iUS and data on EOR. The tumor registries at Liverpool and Tuebingen were searched for pLGG with the use of iMRI where preoperative CR was the surgical intent. Different iUS and iMRI machines were used in the 4 centers. RESULTS: We included 111 operations which used iUS and 182 operations using iMRI. Both modalities facilitated intended CR in hemispheric supra- and infratentorial location in almost all cases. In more deep-seated tumor location like supratentorial midline tumors, iMRI has advantages over iUS to visualize residual tumor. Functional limitations limiting CR arising from eloquent involved or neighboring brain tissue apply to both modalities in the same way. In the long-term follow-up, both iUS and iMRI show that achieving a complete resection on intraoperative imaging significantly lowers recurrence of disease (chi-square test, p < 0.01). CONCLUSION: iUS and iMRI have specific pros and cons, but both have been proven to improve achieving CR in pLGG. Due to advances in image quality, cost- and time-efficiency, and efforts to improve the user interface, iUS has emerged as the most accessible surgical adjunct to date to aid and guide tumor resection. Since the EOR has the most important effect on long-term outcome and disease control of pLGG in most locations, we strongly recommend taking all possible efforts to use iUS in any surgery, independent of intended resection extent and iMRI if locally available.

Ultrasound-guided initial diagnosis and follow-up of pediatric idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension in children often presents with non-specific symptoms found in conditions such as hydrocephalus. For definite diagnosis, invasive intracranial pressure measurement is usually required. Ultrasound (US) of the optic nerve sheath diameter provides a non-invasive method to assess intracranial pressure. Transtemporal US allows imaging of the third ventricle and thus assessment for hydrocephalus. OBJECTIVE: To investigate whether the combination of US optic nerve sheath and third ventricle diameter can be used as a screening tool in pediatric idiopathic intracranial hypertension to indicate elevated intracranial pressure and exclude hydrocephalus as an underlying pathology. Further, to analyze whether both parameters can be used to monitor treatment outcome. MATERIALS AND METHODS: We prospectively included 36 children with idiopathic intracranial hypertension and 32 controls. Using a 12-Mhz linear transducer and a 1-4-Mhz phased-array transducer, respectively, optic nerve sheath and third ventricle diameters were determined initially and during the course of treatment. RESULTS: In patients, the mean optic nerve sheath diameter was significantly larger (6.45±0.65 mm, controls: 4.96±0.32 mm) and the mean third ventricle diameter (1.69±0.65 mm, controls: 2.99±1.31 mm) was significantly smaller compared to the control group, P<0.001. Optimal cut-off values were 5.55 mm for the optic nerve sheath and 1.83 mm for the third ventricle diameter. CONCLUSIONS: The combined use of US optic nerve sheath and third ventricle diameter is an ideal non-invasive screening tool in pediatric idiopathic intracranial hypertension to indicate elevated intracranial pressure while ruling out hydrocephalus. Treatment can effectively be monitored by repeated US, which also reliably indicates relapse.

Influence of sex and disease etiology on the development of papilledema and optic nerve sheath extension in the setting of intracranial pressure elevation in children.

Introduction: Dilatation of the optic nerve sheath diameter and swelling of the optic disc are known phenomena associated with intracranial pressure elevation. Research question: Do sex and disease etiology have an impact on the development of optic disc elevation and optic nerve sheath extension in children in the setting of ICP elevation? Fundoscopic papilledema and point-of-care-ultrasound techniques-optic nerve sheath diameter (US-ONSD) and optic disc elevation (US-ODE) - were compared in this regard. Material and methods: 72 children were included in this prospective study; 50 with proven pathology (e.g. pseudotumor cerebri, tumor), 22 with pathology excluded. Bilateral US-ONSD and US-ODE were quantified by US using a 12-MHz-linear-array-transducer. This was compared with fundoscopic optic disc findings and in 28 patients with invasive ICP values, stratified for sex and etiology. Results: In patients with proven disease, significant more girls (69%) had fundoscopic papilledema compared with boys (37%, p < 0.05). Girls had also larger US-ODE values (0.86 ± 0.36 mm vs. 0.65 ± 0.40 mm in boys). 80% of tumor patients had initial papilledema (100% girls, 79% boys), compared with 50% in pseudotumor cerebri (PTC) (83% girls, 30% boys). US-ONSD had no sex- and no etiology-specificity. Discussion and conclusion: Presence of papilledema appears to be influenced by sex and etiology, whereas US-ONSD is not. Girls seem more likely to develop papilledema under similar conditions. Male sex and PTC appear as risk factors for being undetected by fundoscopic findings. US-ONSD and US-ODE seem useful tools to identify pathologies with potentially increased ICP requiring treatment in children regardless of sex and etiology.

Transorbital point-of-care ultrasound versus fundoscopic papilledema to support treatment indication for potentially elevated intracranial pressure in children.

PURPOSE: To compare transorbital point-of-care ultrasound techniques -optic nerve sheath diameter (US-ONSD) and optic disc elevation (US-ODE)- with fundoscopic papilledema to detect potentially raised intracranial pressure (ICP) with treatment indication in children. METHODS: In a prospective study, 72 symptomatic children were included, 50 with later proven disease associated with raised ICP (e.g. pseudotumour cerebri, brain tumour, hydrocephalus) and 22 with pathology excluded. Bilateral US-ONSD and US-ODE were quantified by US using a 12-MHz-linear-array transducer. This was compared to fundoscopic optic disc findings (existence of papilledema) and, in 28 cases, invasively measured ICP values. RESULTS: The sensitivity and specificity of a cut-off value of US-ONSD (5.73 mm) to detect treatment indication for diseases associated with increased ICP was 92% and 86.4%, respectively, compared to US-ODE (0.43 mm) with sensitivity: 72%, specificity: 77.3%. Fundoscopic papilledema had a sensitivity of 46% and a specificity of 100% in this context. Repeatability and observer-reliability of US-ODE examination was eminent (Cronbach's α = 0.978-0.989). Papilledema was detected fundoscopically only when US-ODE was > 0.67 mm; a US-ODE > 0.43 mm had a positive predictive value of 90% for potentially increased ICP. CONCLUSION: In our cohort, transorbital point-of-care US-ONSD and US-ODE detected potentially elevated ICP requiring treatment in children more reliably than fundoscopy. US-ONSD and US-ODE indicated the decrease in ICP after treatment earlier and more reliably than fundoscopy. The established cut-off values for US-ONSD and US-ODE and a newly developed US-based grading of ODE can be used as an ideal first-line screening tool to detect or exclude conditions with potentially elevated ICP in children.

Intracranial Pressure, Autoregulation, and Cerebral Perfusion in Infants With Nonsyndromic Craniosynostosis at the Time of Surgical Correction.

BACKGROUND AND OBJECTIVE: Although an increased intracranial pressure (ICP) is a known problem in children with syndromic craniosynostosis, it remains unclear whether elevated ICP and impaired cerebral perfusion exist in nonsyndromic synostosis and should be defined as targets of primary treatment. This study aimed to investigate ICP, cerebral autoregulation (CAR), and brain perfusion in infants with nonsyndromic craniosynostosis at first surgical intervention. METHODS: Forty-three infants were prospectively included. The patients underwent perioperative measurement of mean arterial blood pressure, ICP, and brain perfusion before and after cranial vault decompression. Physiological parameters with possible influences on ICP and autoregulation/brain perfusion were standardized for age. CAR was assessed by the pressure reactivity index (PRx), calculated using the mean arterial blood pressure and ICP. RESULTS: Biparietal decompression was performed in 29 infants with sagittal synostosis (mean age, 6.1 ± 1.3 months). Fronto-orbital advancement was performed in 10 and 4 infants with metopic and unilateral coronal synostosis, respectively (mean age, 11.6 ± 2.1 months). An elevated ICP (>15 mm Hg) was found in 20 of 26 sagittal (mean, 21.7 ± 4.4 mm Hg), 2 of 8 metopic (mean, 17.1 ± 0.4 mm Hg), and 2 of 4 unilateral coronal synostosis cases (mean, 18.9 ± 2.5 mm Hg). Initial ICP was higher in sagittal synostosis than in metopic/coronal synostosis (P = .002). The postdecompression ICP was significantly reduced in sagittal synostosis cases (P < .001). The relative cerebral blood flow and blood flow velocity significantly increased after decompression. Impaired CAR was found in infants with a mean ICP >12 mm Hg (PRx, 0.26 ± 0.32), as compared with those with a mean ICP ≤ 12 mm Hg (PRx, -0.37 ± 0.07, P = .001). CONCLUSION: Contrary to common belief, an elevated ICP and significantly impaired CAR can exist early in single suture synostosis, particularly sagittal synostosis. Because an influence of raised ICP on long-term cognitive development is known in other diseases, we suggest that preventing increased ICP during the phase of maximal brain development may be a goal for decompressive surgery, at least for sagittal synostosis cases.

Effect of antisiphon devices on ventriculoperitoneal shunt drainage dynamics in growing children.

OBJECTIVE: Infants and small children face changing boundary conditions when treated with a ventriculoperitoneal shunt (VPS) for hydrocephalus. There are no systematic data describing shunt drainage behavior and changes over time in a growing child. Using a child-adapted patient simulator, the authors investigated the drainage behaviors of fixed differential pressure (DP) valves and adjustable valves with devices for preventing overdrainage in children of different ages. METHODS: Three miniNAV DP valves with a 10-cm H2O medium-pressure setting (MN10) and three adjustable proGAV2.0 valves with a 25-cm H2O gravitational unit (GU) at low 5-cm H2O opening pressure (PG5) and medium 10-cm H2O opening pressure (PG10) settings were each investigated with a hardware-in-the-loop test bed. This test bed consisted of a posture motion mechanism and two pressure compartments that mimicked intracranial and abdominal pressures and was used to test the VPS under realistic in vitro conditions. Body orientation and length were physically set according to the child's age. The software simulated the physiological situations of children aged 1, 5, and 10 years. All valves were tested according to these specifications, with 5 runs for 1 hour each in the horizontal, vertical, and horizontal positions. Intracranial pressure (ICP) and VPS flow were measured, and the respective cerebrospinal fluid volume changes and ICP set value were computed. RESULTS: The drainage parameters increased with age in all valves in the vertical position, with that of MN10 being pronounced in the 1-year-old simulation. The GU values in PG5 and PG10 substantially reduced drainage compared with MN10. PG10 prevented drainage in the 1-year-old and 5-year-old setups, but there was some drainage at physiological ICP in the 10-year-old setup. In contrast, MN10 produced the largest decreases in ICP across all ages and positions, and overdrainage resulted in insufficient ICP recovery in the subsequent horizontal position. ICP levels were mostly constant with PG10 at all ages. CONCLUSIONS: This study shows that unprotected DP valves may lead to overdrainage in infants, whereas low-pressure GU valves can prevent overdrainage through 5 years and medium-pressure GU valves admit physiological ICP through at least 10 years. Therefore, devices for preventing overdrainage should be included in the first implanted shunt, and opening pressure should be adjusted as the child grows.

Non-Invasive Quantitative Approximation of Intracranial Pressure in Pediatric Idiopathic Intracranial Hypertension Based on Point-of-Care Ultrasound of the Optic Nerve Sheath Diameter.

BACKGROUND: To investigate whether ultrasound-based optic nerve sheath diameter (US-ONSD) is a reliable measure to follow up children with idiopathic intracranial hypertension (IIH). In addition, to analyze the inter- and intra-individual relationships between US-ONSD and intracranial pressure (ICP), and to investigate whether an individualized mathematical regression equation obtained from two paired US-ONSD/ICP values can be used to approximate ICP from US-ONSD values. METHODS: 159 US examinations and 53 invasive ICP measures via lumbar puncture (LP) were performed in 28 children with IIH. US-ONSD was measured using a 12 Mhz linear transducer and compared to ICP values. In 15 children, a minimum of 2 paired US-ONSD/ICP determinations were performed, and repeated-measures correlation (rmcorr) and intra-individual correlations were analyzed. RESULTS: The cohort correlation between US-ONSD and ICP was moderate (r = 0.504, p < 0.01). Rmcorr (r = 0.91, p < 0.01) and intra-individual correlations (r = 0.956-1) of US-ONSD and ICP were excellent. A mathematical regression equation can be calculated from two paired US-ONSD/ICP values and applied to the individual patient to approximate ICP from US-ONSD. CONCLUSIONS: Related to excellent intra-individual correlations between US-ONSD and ICP, an individualized regression formula, created from two pairs of US-ONSD/ICP values, may be used to directly approximate ICP based on US-ONSD values. Hence, US-ONSD may become a non-invasive and reliable measure to control treatment efficacy in pediatric IIH.

Surgical Management of Pre-Chiasmatic Intraorbital Optic Nerve Gliomas in Children after Loss of Visual Function-Resection from Bulbus to Chiasm.

Optic pathway gliomas in children carry significant morbidity and therapeutic challenges. For the subgroup of pre-chiasmatic gliomas, intraorbital and intradural resection is a curative option after blindness. We present a two-center cohort using different surgical approaches. A retrospective analysis was performed, including 10 children. Mean age at surgery was 6.8 years. Interval between diagnosis and surgery was 1-74 (mean 24 ± 5.5, median 10) months. Indications for surgery were exophthalmos, pain, tumor progression, or a combination. Eight patients underwent an extradural trans-orbital-roof approach to resect the intra-orbital tumor, including the optic canal part plus intradural pre-chiasmatic resection. Gross total resection was achieved in 7/8, and none had a recurrence. One residual behind the bulbus showed progression, treated by chemotherapy. In two patients, a combined supra-orbital mini-craniotomy plus orbital frame osteotomy was used for intraorbital tumor resection + intradural pre-chiasmatic dissection. In these two patients, remnants of the optic nerve within the optic canal remained stable. No patient had a chiasmatic functional affection nor permanent oculomotor deficits. In selected patients, a surgical resection from bulb to chiasm ± removal of optic canal tumor was safe without long-term sequela and with an excellent cosmetic result. Surgery normalizes exophthalmos and provides an effective tumor control.

Risk Stratification for Immediate Postoperative Hearing Loss by Preoperative BAER (Brainstem Auditory Evoked Response) and Audiometry in NF2-Associated Vestibular Schwannomas.

Both brainstem auditory evoked potentials (BAEP) and audiometry play a crucial role in neuro-oncological treatment decisions in Neurofibromatosis Type 2 associated (NF2) vestibular schwannoma (VS) as hearing preservation is the major goal. In this study, we investigated the risk of immediate postoperative hearing deterioration (>15 dB and/or 15% loss in pure-tone average [PTA]/ speech discrimination score [SDS] in a cohort of 100 operated VS (ears) in 72 NF2 patients by retrospective analysis of pre- and postoperative hearing data (PTA, SDS, American Association of Otolaryngology-Head and Neck Surgery [AAO-HNS], and brainstem auditory evoked potential [BAEP] class) taking into account relevant influencing factors, particularly preoperative audiometry and BAEP status and the extent of resection. Immediately after surgery, the hearing was preserved in 73% of ears and approximately ~60% of ears kept their hearing classes. Preoperative BAEP (p = 0.015) and resection amount (p = 0.048) significantly influenced postoperative hearing outcome. The prediction model for postoperative hearing deterioration/loss between preoperative BAEP and AAO-HNS class showed increased risk by increasing BAEP class. Twenty-one tumors/ears were identified with large BAEP and AAO-HNS class discrepancies (≥2 points) and were associated with a high (48-100%) risk of deafness after surgery in ears with preoperative available hearing. Overall, the results were heterogeneous but the better both BAEP and audiometry class before surgery, the higher the chance of hearing maintenance afterwards. Large resection amounts (e.g., 100% risk in near-total resections) exhibit a significant (p < 0.05) higher risk compared to smaller amounts (e.g., 10/20% in laser-coagulated/partially resected tumors). Our results emphasized the indispensable role of both hearing monitoring in form of audiometry and neurophysiology (BAEP) in the pre-and perioperative monitoring of NF2-associated VS. Both BAEP and audiometry are good prognostic markers for the postoperative hearing outcome. The extent of resection should be strictly guided by and adjusted to the intraoperative neurophysiological monitoring.

Age at Onset and Presenting Symptoms of Neurofibromatosis Type 2 as Prognostic Factors for Clinical Course of Vestibular Schwannomas.

The presenting symptoms of the tumor suppressor gene syndrome neurofibromatosis type 2 (NF2) are often non-specific and unrelated to the disease hallmark bilateral vestibular schwannomas (VS). However, age at onset and presenting symptoms may have predictive values for the clinical course of VS. In this retrospective single-center study, we addressed this issue by reviewing 106 patients with 194 VS. Presenting symptoms attributable to VS commonly occur in 87% of adults and 31% of children. Age at onset significantly correlates with tumor volumes at presentation (p = 0.034). In addition, age at onset significantly correlates with pure-tone average (p = 0.0001), speech discrimination scores (p = 0.001), age at beginning of hearing loss (p = 0.0001), age at deafness (p = 0.0001), and age at first surgery (p = 0.0001). Patients presenting with VS related symptoms had significantly (p < 0.05) worse hearing values at presentation and after surgery. These patients also exhibited higher growth rates and tumor volumes compared to patients with non-VS related presenting symptoms, but this difference did not reach the significance level of p < 0.05. Due to the late appearance of these symptoms, the time of beginning hearing loss, surgery and deafness is significantly delayed (p < 0.05) compared to patients not presenting with VS. In summary, age at onset and type of presenting symptom provide excellent prognostic parameters for predicting VS- and hearing-related clinical course.

Presenting symptoms in children with neurofibromatosis type 2.

PURPOSE: The hallmark of neurofibromatosis type 2 (NF2) is the presence of bilateral vestibular schwannomas (VS) which however have not yet developed or grown to large size in children and young adolescents. Therefore, early diagnosis in pediatric patients without family history of NF2 has to be made by signs and symptoms not related to VS which will be reviewed in this study. METHODS: A total of 70 children diagnosed for NF2 at an age of < 18 years were identified from our patient cohort. Age and symptoms, signs and pathology at symptom onset, age at NF2 diagnosis and symptoms leading to diagnosis as well as genetic findings were retrospectively reviewed. RESULTS: The average age at symptom/sign onset was 8 ± 6 (range 0-17) years and 11 ± 5 (range 1-17) years at time of diagnosis. Fifteen children had a positive family history and were diagnosed upon additional clinical symptoms. The most frequent first presenting symptom/signs were ophthalmological abnormalities (49%), followed by cutaneous features (40%), non-VS-related neurological deficits (33%), and symptoms attributable to VS (21%). VS were not only the most common symptomatic neoplasm but also the most frequent pathological evidence for the diagnosis (72%). In 42 patients with available genetic testing results, pathogenic mutations were most frequently identified (n = 27). CONCLUSION: The presenting symptoms in NF2 children appear "unspecific" or less specific for classical NF2 compared with adult NF2 patients, posing a challenge particularly for cases without family history. In children, ophthalmological and cutaneous features should raise clinical suspicion for NF2 and referral to an NF2 specialized center is recommended.

Managing NF2-associated vestibular schwannomas in children and young adults: review of an institutional series regarding effects of surgery and bevacizumab on growth rates, tumor volume, and hearing quality.

We reviewed our experience in managing of NF2-associated vestibular schwannoma (VS) in children and young adults regarding the effect of surgery and postoperative bevacizumab treatment. A total of 579 volumetric and hearing data sets were analyzed. The effect of surgery on tumor volume and growth rate was investigated in 46 tumors and on hearing function in 39 tumors. Long-term hearing follow-up behavior was compared with 20 non-operated ears in additional 15 patients. Sixteen operated VS were treated with bevacizumab. Mutation analysis of the NF2 gene was performed in 25 patients. Surgery significantly slowed down VS growth rate. Factors associated with a higher growth rate were increasing patient age, tumor volume, and constitutional truncating mutations. Immediately after surgery, functional hearing was maintained in 82% of ears. Deterioration of hearing was associated with initial hearing quality, larger tumor volumes, and larger resection amounts. Average hearing scores were initially better in the group of non-operated VS. Over time, hearing scores in both groups worsened with a similar dynamic. During bevacizumab treatment of residual tumors, four different patterns of growth were observed. Decompression of the internal auditory canal with various degrees of tumor resection decreases the postoperative tumor growth rates. Carefully tailored BAEP-guided surgery does not cause additional hearing deterioration. Secondary bevacizumab treatment showed heterogenous effects both regarding tumor size and hearing preservation. It seems that postoperative tumor residuals, that grow slower, behave differently to bevacizumab than reported for not-operated faster growing VS.

Minimal Effect of Bevacizumab Treatment on Residual Vestibular Schwannomas after Partial Resection in Young Neurofibromatosis Type 2 Patients.

Hearing-preserving partial resection of neurofibromatosis type 2 (NF2) associated vestibular schwannomas (VS) is a preferred treatment strategy, particularly for children and adolescents. However, the residual tumors do grow and lead at some point to continued hearing deterioration. An adjuvant bevacizumab treatment may provide an option for slowing down this process. In this retrospective study, we reviewed tumor volume and hearing data of 16 operated VS in nine patients younger than 30 years over a period of 63 to 142 months. All these patients had one or more bevacizumab treatment periods and most of them had a non-treatment period after surgery. Four different patterns of growth were observed for the residual tumors: (1) growth in the non-treatment periods, which slowed down in the treatment periods; (2) growth slowed down in one but not in another on-period; (3) unaffected growth; (4) no or minimal growth regardless of the treatment. Neither radiological regression of tumor volume nor hearing improvement were observed in the treatment periods. Accelerated hearing deterioration was observed in several non-treatment periods, but also in some treatment periods. No straightforward correlation can be drawn between tumor growth and hearing scores. Tumor growth and worsening of hearing between two measurement points were slightly less in the treatment periods; however, the differences were not significant, because variations were large. In conclusion, our comprehensive follow-up on 16 VS in nine NF2 patients did show heterogenous effects of bevacizumab on small residual vestibular schwannomas after surgery both regarding tumor size and hearing preservation. Thus, smaller and slower growing tumor residuals seem to behave differently to bevacizumab than reported for not-operated faster growing VS.

Impact of Surgery on Long-Term Results of Hearing in Neurofibromatosis Type-2 Associated Vestibular Schwannomas.

Hearing preservation is a major goal in the treatment of neurofibromatosis type 2 (NF2) associated vestibular schwannoma (VS), particularly in children and adolescents. In this study, we retrospectively reviewed hearing and volumetry data sets of 39 operated tumors (ears) in 23 patients under the age of 25 and in a follow-up period of 21 to 167 months. Hearing data over a compatible period on 20 other tumors, which did not receive surgery due to their less aggressive nature, were included for comparison. Surgery was carried out via a retrosigmoid approach with the brainstem auditory evoked potential (BAEP) guide. Immediately after surgery, functional hearing was maintained in 82% of ears. Average hearing scores were better in the non-surgery ears. However, the hearing scores in both groups worsened gradually with a similar dynamic during the 42-month postoperative follow-up period. No accelerated impairment of hearing was evident for the operated cases. Rather, the gap between the two hearing deterioration lines tended to close at the end of the follow-up period. Our result suggested that the BAEP-guided surgery did not cause additional hearing deterioration in the long-term and seemed to slow down hearing deterioration of those tumors that were initially more aggressive.

Management of NF2-associated vestibular schwannomas in children and young adults: influence of surgery and clinical factors on tumor volume and growth rate.

OBJECTIVE: The authors' aim was to evaluate the tumor volume and growth rate of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas (VSs) and the clinical factors or type of mutations before and after surgery in children and adults younger than 25 years at the time of diagnosis. METHODS: A total of 579 volumetric measurements were performed in 46 operated tumors in 28 NF2 patients, using thin-slice (< 3 mm) T1-weighted contrast-enhanced MRI. The follow-up period ranged from 21 to 167 months (mean 75 months). Growth rate was calculated using a multilinear regression model. Mutation analysis of the NF2 gene was performed in 25 patients. RESULTS: Surgery significantly (p = 0.013) slowed the VS growth rate from 0.69 ± 1.30 cm3/yr to 0.23 ± 0.42 cm3/yr. Factors significantly associated with a higher growth rate of VSs were increasing patient age (p < 0.0005), tumor volume (p = 0.006), tumor size (p = 0.001), and constitutional truncating mutations in the NF2 gene (p = 0.018). VS growth rates tended to be higher in patients with spinal ependymomas and in right-sided tumors and lower in the presence of peripheral schwannomas; however, no statistical significance was achieved. CONCLUSIONS: Decompression of the internal auditory canal with various degrees of tumor resection decreases the postoperative tumor growth rate in children and young adults with NF2-associated VS. Patients with potential risk factors for accelerated growth (e.g., large volume, truncating mutations) and with increasing age should be monitored more closely before and after surgery.

Low mutational load in pediatric medulloblastoma still translates into neoantigens as targets for specific T-cell immunotherapy.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in childhood and adolescence. Although some patients present with distinct genetic alterations, such as mutated TP53 or MYC amplification, pediatric medulloblastoma is a tumor entity with minimal mutational load and low immunogenicity. METHODS: We identified tumor-specific mutations using next-generation sequencing of medulloblastoma DNA and RNA derived from primary tumor samples from pediatric patients. Tumor-specific mutations were confirmed using deep sequencing and in silico analyses predicted high binding affinity of the neoantigen-derived peptides to the patients' human leukocyte antigen molecules. Tumor-specific peptides were synthesized and used to induce a de novo T-cell response characterized by interferon gamma and tumor necrosis factor alpha release of CD8+ cytotoxic T cells in vitro. RESULTS: Despite low mutational tumor burden, at least two immunogenic tumor-specific peptides were identified in each patient. T cells showed a balanced CD4/CD8 ratio and mostly effector memory phenotype. Induction of a CD8-specific T-cell response was achieved for the neoepitopes derived from Histidine Ammonia-Lyase (HAL), Neuraminidase 2 (NEU2), Proprotein Convertase Subtilisin (PCSK9), Programmed Cell Death 10 (PDCD10), Supervillin (SVIL) and tRNA Splicing Endonuclease Subunit 54 (TSEN54) variants. CONCLUSION: Detection of patient-specific, tumor-derived neoantigens confirms that even in tumors with low mutational load a molecular design of targets for specific T-cell immunotherapy is possible. The identified neoantigens may guide future approaches of adoptive T-cell transfer, transgenic T-cell receptor transfer or tumor vaccination.

The Postopera tive Quality of Life in Children and Adolescents with Craniopharyngioma.

BACKGROUND: Craniopharyngioma is a tumor of low histological malignancy resulting from an anomaly of embryonic development. Affected children and adolescents are being studied with respect to their quality of life, progression-free survival, and overall survival in the framework of the ongoing KRANIOPHARYNGEOM 2007 project. METHODS: This prospective, multicenter project consists of a randomized trial with an adaptive design combined with a purely observational study. The randomized, unblinded trial includes patients whose tumors have been incompletely resected and is intended to compare the outcomes of immediate postoperative radiotherapy versus radiotherapy on progression. Its primary endpoint is quality of life as assessed subjectively by the patients them- selves with the "Pediatric Quality of Life" questionnaire (PEDQOL). In exploratory analyses, linear mixed models were used to study the effect of further factors on quality of life. RESULTS: An interim intention-to-treat analysis of the randomized trial revealed only minor differences between the treatment arms with respect to quality of life (n = 24). The exploratory analyses (n = 131) showed that preoperative involvement of, or operative damage to, the anterior and posterior regions of the hypothalamus was associated with a lower quality of life. Complete resection was followed by a lower quality of life than incomplete resection. Radiotherapy, a common treatment for tumors that progress after incomplete resection, was also associated with a lower quality of life. CONCLUSION: Hypothalamus-sparing treatment approaches are recommended to optimize the quality of life of children and adolescents with cranio- pharyngioma. The available evidence does not support any recommendation as to when radiotherapy should be performed after incomplete resection so that the best quality of life can be achieved.

Comprehensive anatomical and functional imaging in patients with type I neurofibromatosis using simultaneous FDG-PET/MRI.

PURPOSE: To demonstrate the clinical use of FDG-PET/MRI for monitoring enlargement and metabolism of plexiform neurofibromas (PNF) in patients with neurofibromatosis type 1 (NF1), in whom the development of a malignant peripheral nerve sheath tumor (MPNST) is often a life limiting event. METHODS: NF1 patients who underwent a simultaneous FDG-PET/MRI examination in our institution from September 2012 to February 2018 were included. Indication was suspicion of malignant transformation of a PNF to MPNST. A maximum of six peripheral nerve lesions per patient were defined as targets. Standardized uptake values (SUV) and apparent diffusion coefficients (ADC) were measured. The presence of target sign and contrast-medium enhancement was visually recorded. Growth rates were estimated comparing prior or follow-up examinations and correlated with FDG uptake and ADC values. The presence of CNS lesions in cerebral T2 weighted images was recorded. RESULTS: In 28 NF1 patients a total number of 83 peripheral nerve tumors, 75 benign PNFs and eight MPNSTs, were selected as target lesions. The SUVs of MPNSTs were significantly higher than the SUVs of PNF (3.84 ± 3.98 [SUVmean MPNSTs] vs. 1.85 ± 1.03 [SUVmean PNF], P < .01). Similarly, lesion SUVmean-to-liver SUVmean ratios significantly differed between MPNSTs and PNF (3.20 ± 2.70 [MPNSTs] vs. 1.23 ± 0.61 [PNF]; P < .01). For differentiation between still benign PNF and MPNSTs, we defined SUVmax ≥ 2.78 as a significant cut-off value. Growth rate of PNF correlated significantly positively with SUVmean (rs = .41; P = .003). MRI parameters like ADCmean (1.87 ± 0.24 × 10-3 mm2/s [PNF] vs. 1.76 ± 0.11 × 10-3 mm2/s [MPNSTs]; P > .05], contrast medium enhancement (P = .50) and target sign (P = .86) did not differ between groups. CONCLUSION: Simultaneous FDG-PET/MRI is a comprehensive imaging modality for monitoring PNF in NF1 patients. The combined acquisition of both morphologic information in MRI and metabolic information in PET enables the correlation of lesion growth rates with metabolic activity and to define SUV thresholds of significance to identify malignant transformation, which is of utmost clinical significance.

Perioperative Cerebral Oxygenation Metabolism in Neonates with Hypoplastic Left Heart Syndrome or Transposition of the Great Arteries.

Optimizing oxygen delivery to the brain is one of the main goals in children with congenital heart defects after surgery. It has been shown that cerebral oxygen saturation (cSO2) is depressed within the first day after neonatal cardiopulmonary bypass surgery. However, peri-operative cerebral oxygen metabolism has not yet been assessed in previous studies. The aim of this study was to describe the peri-operative changes in cerebral oxygen metabolism in neonates with congenital heart defects following cardiopulmonary bypass surgery. Prospective observational cohort study. PICU of a tertiary referral center. Fourteen neonates with hypoplastic left heart syndrome (HLHS) undergoing Norwood procedure and 14 neonates with transposition of great arteries (TGA) undergoing arterial switch operation (ASO) were enrolled. Pediatric heart surgery. We measured non-invasively regional cSO2 and microperfusion (rcFlow) using tissue spectrometry and laser Doppler flowmetry before and after surgery. Cerebral fractional tissue oxygen extraction (cFTOE), the arterio-cerebral difference in oxygen content (acDO2) and approximated cerebral metabolic rate of oxygen (aCMRO2) were calculated. According to the postsurgical hemodynamics, arterial saturation (aSO2) normalized immediately after surgery in the TGA group, whereas HLHS patients still were cyanotic. cSO2 significantly increased in TGA group over 48 h after ASO (p = 0.004) and was significantly higher compared to HLHS group after Norwood procedure. cFTOE as a risk marker for brain injury was elevated before surgery (TGA group 0.37 ± 0.10, HLHS group 0.42 ± 0.12) and showed a slight decrease after ASO (p = 0.35) but significantly decreased in patients after Norwood procedure (p = 0.02). Preo-peratively, acDO2 was significantly higher in patients with HLHS compared to patients with TGA (7.7 ± 2.5 vs. 5.2 ± 1.6 ml/dl, p = 0.005), but normalized in the posto-perative course. Before surgery, the aCMRO2 was slightly higher in the HLHS group (5.1 ± 1.5 vs. 3.9 ± 2.5 AU, p = 0.14), but significantly decreased after Norwood procedure (- 1.6 AU, p = 0.009). There was no difference in rcFlow between both groups and between the points in time prior and after surgery. Neonates undergoing cardiac surgery suffer from peri-operative changes in hemodynamics and cerebral hypoxemic stress. The cerebral oxygen metabolism seems to be more affected in cyanotic children with functionally univentricular hearts compared to post-operative acyanotic patients. Additional stress factors must be avoided to achieve the best possible neurological outcome.