Neurosurgical treatment of pediatric brain tumors - results from a single center multidisciplinary setup.

OBJECTIVE: The challenge of pediatric brain tumor surgery is given due to a relative low prevalence but high heterogeneity in age, localization, and pathology. Improvements of long-term overall survival rates were achieved during the past decades stressing the importance of a multidisciplinary decision process guided by a national treatment protocol. We reviewed the entire spectrum of pediatric brain tumor surgeries from the perspective of an interdisciplinary pediatric neuro-oncology center in Germany. METHODS: Every patient who underwent brain tumor surgery from January 2010 to June 2017 in our Pediatric Neurosurgery department was retrospectively included and evaluated regarding the course of treatment. Perioperative data such as tumor localization, timing of surgery, extent of resection, neuropathological diagnosis, transfusion rates, oncologic and radiation therapy, and neurological follow-up including morbidity and mortality were evaluated. RESULTS: Two hundred ninety-three pediatric brain tumor patients were applicable (age: 8.28 ± 5.62 years, 1.22:1.0 m:f). A total of 531 tumor surgical interventions was performed within these patients (457 tumor resections, 74 tumor biopsies; mean interventions per patient 1.8 ± 1.2). Due to a critical neurologic status, 32 operations (6%) were performed on the day of admission. In 65.2% of all cases, tumor were approached supratentorially. Most frequent diagnoses of the cases were glial tumors (47.8%) and embryonal tumors (17.6%). Preoperative planned extent of resection was achieved in 92.7%. Pre- and postoperative neurologic deficits resolved completely in 30.7%, whereas symptom regressed in 28.6% of surgical interventions. New postoperative neurologic deficit was observed in 10.7%, which resolved or improved in 80% of these cases during 30 days. The mortality rate was 1%. CONCLUSION: We outlined the center perspective of a specialized pediatric neuro-oncological center describing the heterogeneous distribution of cases regarding age-related prevalence, tumor localization, and biology, which requires a high multidisciplinary expertise. The study contributes to define challenges in treating pediatric brain tumors and to develop quality indicators for pediatric neuro-oncological surgery. We assume that an adequate volume load of patients within a interdisciplinary infrastructure is warranted to aim for effective treatment and decent quality of life for the majority of long-term surviving pediatric tumor patients.

Imaging Characteristics of CNS Neuroblastoma-FOXR2: A Retrospective and Multi-Institutional Description of 25 Cases.

BACKGROUND AND PURPOSE: The 5th edition of the World Health Organization Classification of CNS tumors defines the CNS neuroblastoma FOXR2 in the group of embryonal tumors. Published clinical outcomes tend to suggest a favorable outcome after resection, craniospinal irradiation, and chemotherapy. This multicenter study aimed to describe imaging features of CNS neuroblastoma-FOXR2, which have been poorly characterized thus far. MATERIALS AND METHODS: On the basis of a previously published cohort of tumors molecularly classified as CNS neuroblastoma-FOXR2, patients with available imaging data were identified. The imaging features on preoperative MR imaging and CT data were recorded by 8 experienced pediatric neuroradiologists in consensus review meetings. RESULTS: Twenty-five patients were evaluated (13 girls; median age, 4.5 years). The tumors were often large (mean, 115 [ SD, 83] mL), showed no (24%) or limited (60%) perilesional edema, demonstrated heterogeneous enhancement, were often calcified and/or hemorrhagic (52%), were always T2WI-hyperintense to GM, and commonly had cystic and/or necrotic components (96%). The mean ADC values were low (687.8 [SD 136.3] × 10-6 mm2/s). The tumors were always supratentorial. Metastases were infrequent (20%) and, when present, were of nodular appearance and leptomeningeal. CONCLUSIONS: In our cohort, CNS neuroblastoma FOXR2 tumors showed imaging features suggesting high-grade malignancy and, at the same time, showed characteristics of less aggressive behavior. There are important differential diagnoses, but the results of this study may assist in considering this diagnosis preoperatively.

Endoscopic third ventriculostomy in children with third ventricular pressure gradient and open ventricular outlets on MRI.

OBJECTIVE: Patients with non-communicating hydrocephalus due to aqueductal stenosis are often successfully treated with endoscopic third ventriculocisternostomy (ETV). In hydrocephalus, due to other locations of obstruction of the major CSF pathways, endoscopic treatment may also be a good option. We investigated our cohort of patients treated by ETV with patent ventricular outflow but pressure gradient signs at the third ventricle in a single-center retrospective study. METHODS: We retrospectively reviewed records and imaging studies of 137 patients who underwent an ETV in our department in the time period of June 2010 to March 2018. We included patients who showed the following findings in MRI: 1st: open Sylvian aqueduct, 2nd: open outlets of the 4th ventricle, 3rd: open spinal canal, 4th: intra-/extraventricular pressure gradient seen at the 3rd ventricle and excluded patients with history of CSF infection or hemorrhage. Perioperative clinical state and possible complications or reoperations were recorded. Shunt dependency and changes in ventricular dilatation were measured as frontal and occipital horn ratio (FOHR) before surgery and during follow-up. RESULTS: A total of 21 patients met the defined criteria. During the mean follow-up time of 40.7 ± 30 months (range; 5-102 months), two children had to undergo a re-ETV, and six children (all < 1 year of age) received a VP shunt. ETV shunt-free survival was 100% for children > 1 year of age. The ventricular width measured as FOHR was significantly reduced after ETV 0.5 ± 0.08 (range 0.42-0.69; p < 0.05). FOHR was significantly reduced at last follow-up shunt independent patients (0.47 ± 0.05; range 0.41-0.55; p < 0.001) CONCLUSION: We conclude that ETV seems to be a successful treatment option for patients with MRI signs of intra-/extraventricular pressure gradient at the 3rd ventricle and patent aqueduct and fourth ventricular outlets in children older than 1 year of age. This condition is observed only rarely and warrants further research on a multicenter basis in order to get more solid data of its pathophysiology.

Dynamic cerebellar herniation in Chiari patients during the cardiac cycle evaluated by dynamic magnetic resonance imaging.

PURPOSE: Cerebellar herniation in Chiari patients can be dynamic, following the cerebrospinal fluid pulsatility during the cardiac cycle. We present a voxel intensity distribution method (VIDM) to automatically extract the pulsatility-dependent herniation in time-resolved MRI (CINE MRI) and compare it to the simple linear measurements. The degree of herniation is furthermore compared on CINE and static sequences, and the cerebellar movement is correlated to the presence of hydrocephalus and syringomyelia. METHODS: The cerebellar movement in 27 Chiari patients is analyzed with VIDM and the results were compared to linear measurements on an image viewer (visual inspection, VI) using a paired t test. Second, an ANOVA test is applied to compare the degree of herniation on static 3D MRI and CINE. Finally, the Pearson's correlation coefficient is calculated for the correlation between cerebellar movement and the presence of hydrocephalus and syringomyelia. RESULTS: VIDM showed significant movement in 85% of our patients. Assuming that movement < 1 mm cannot be detected reliably on an image viewer, VI identified movement in 29.6% of the patients (p = 0.002). The herniation was greater on static sequences than on CINE in most cases, but this was not statistically significant. The cerebellar movement was not correlated with hydrocephalus or syringomyelia (Pearson's coefficient < 0.3). CONCLUSIONS: VIDM is a sensitive method to detect tissue movement on CINE MRI and could be used for Chiari patients, but also for the evaluation of cyst membranes, ventriculostomies, etc. The cerebellar movement appears not to correlate with hydrocephalus and syringomyelia in Chiari patients.

Chemical synthesis of membrane proteins: a model study on the influenza virus B proton channel.

In the present study we have developed and optimized a robust strategy for the synthesis of highly hydrophobic peptides, especially membrane proteins, exemplarily using the influenza B M2 proton channel (BM2(1-51)). This strategy is based on the native chemical ligation of two fragments, where the thioester fragment is formed from an oxo-ester peptide, which is synthesized using Fmoc-SPPS, and features an in situ cleavable solubilizing tag (ADO, ADO2 or ADO-Lys5). The nearly quantitative production of the ligation product was followed by an optimized work up protocol, resulting in almost quantitative desulfurization and Acm-group cleavage. Circular dichroism analysis in a POPC lipid membrane revealed that the synthetic BM2(1-51) construct adopts a helical structure similar to that of the previously characterized BM2(1-33).

Microcirculatory dysfunction and tissue oxygenation in critical illness.

Severe sepsis is defined by organ failure, often of the kidneys, heart, and brain. It has been proposed that inadequate delivery of oxygen, or insufficient extraction of oxygen in tissue, may explain organ failure. Despite adequate maintenance of systemic oxygen delivery in septic patients, their morbidity and mortality remain high. The assumption that tissue oxygenation can be preserved by maintaining its blood supply follows from physiological models that only apply to tissue with uniformly perfused capillaries. In sepsis, the microcirculation is profoundly disturbed, and the blood supply of individual organs may therefore no longer reflect their access to oxygen. We review how capillary flow patterns affect oxygen extraction efficacy in tissue, and how the regulation of tissue blood flow must be adjusted to meet the metabolic needs of the tissue as capillary flows become disturbed as observed in critical illness. Using the brain, heart, and kidney as examples, we discuss whether disturbed capillary flow patterns might explain the apparent mismatch between organ blood flow and organ function in sepsis. Finally, we discuss diagnostic means of detecting capillary flow disturbance in animal models and in critically ill patients, and address therapeutic strategies that might improve tissue oxygenation by modifying capillary flow patterns.

Mean Diffusional Kurtosis in Patients with Glioma: Initial Results with a Fast Imaging Method in a Clinical Setting.

BACKGROUND AND PURPOSE: Diffusional kurtosis imaging is an MR imaging technique that provides microstructural information in biologic systems. Its application in clinical studies, however, is hampered by long acquisition and postprocessing times. We evaluated a new and fast (2 minutes 46 seconds) diffusional kurtosis imaging method with regard to glioma grading, compared it with conventional diffusional kurtosis imaging, and compared the diagnostic accuracy of fast mean kurtosis (MK') to that of the widely used mean diffusivity. MATERIALS AND METHODS: MK' and mean diffusivity were measured in the contrast-enhancing tumor core, the perifocal hyperintensity (indicated on T2 FLAIR images), and the contralateral normal-appearing white and gray matter of 34 patients (22 with high-grade and 12 with low-grade gliomas). MK' and mean diffusivity in the different tumor grades were compared by using a Wilcoxon rank sum test. Receiver operating characteristic curves and the areas under the curve were calculated to determine the diagnostic accuracy of MK' and mean diffusivity. RESULTS: MK' in the tumor core, but not mean diffusivity, differentiated high-grade from low-grade gliomas, and MK' differentiated glioblastomas from the remaining gliomas with high accuracy (area under the curveMK' = 0.842; PMK' < .001). MK' and mean diffusivity identified glioblastomas in the group of high-grade gliomas with similar significance and accuracy (area under the curveMK' = 0.886; area under the curvemean diffusivity = 0.876; PMK' = .003; Pmean diffusivity = .004). The mean MK' in all tissue types was comparable to that obtained by conventional diffusional kurtosis imaging. CONCLUSIONS: The diffusional kurtosis imaging approach used here is considerably faster than conventional diffusional kurtosis imaging methods but yields comparable results. It can be accommodated in clinical protocols and enables exploration of the role of MK' as a biomarker in determining glioma subtypes or response evaluation.

Prophylactic cranial irradiation in patients with small cell lung cancer. A retrospective study of recurrence, survival and morbidity.

BACKGROUND: Prophylactic cerebral irradiation (PCI) is a standard treatment for all small cell lung cancer (SCLC) patients with response to chemotherapy. The aims of this study were: to evaluate patients undergoing PCI with regard to cerebral recurrence rate, site of recurrence, and overall survival (OS) and to investigate the influence of steroid dose on acute toxicity. MATERIALS AND METHODS: From 2007 to 2010 a total of 118 consecutive patients underwent PCI (25 Gray in 10 fractions). In total, 114/118 received full PCI dose, all 118 were included in the study. Data were analyzed retrospectively with regard to disease stage, treatment, date of PCI, steroid dose during PCI, toxicity, time to recurrence, site of recurrence and time of death. The median follow up time was 16.6 months (range 3-54 months). RESULTS: Of the 118 patients undergoing PCI, 74 had limited disease (LD-SCLC) and 44 had extensive disease (ED-SCLC). The median age was 65 years (range 46-80 years). The median overall survival of all patients from the time of diagnosis was 16.0 months (CI 95% 13.0-19.0), in LD-SCLC it was 24.0 months (CI 95% 19.6-28.3), and in ED-SCLC it was 12.0 months (CI 95% 9.6-14.4). Twenty-one patients (17.8%) were diagnosed with cerebral recurrence. Five of these presented with metastatic disease within the limbic system. Of these five patients, four had miliary cerebral disease and one had non-oligometastatic disease. The time from PCI to cerebral recurrence ranged from 4 to 27 months. Prednisolone administration varied from 0 to 100 mg/day. Forty-eight patients were not treated with steroids, 64.6% of these patients reported acute toxicity. Of the 36 patients receiving 50 mg prednisolone, only 22.2% had side effects. The most common symptoms during PCI were nausea and headache. CONCLUSIONS: Twenty-one patients out of 118 developed brain metastases after PCI: five of the twenty-one had metastases located in the limbic system. The study showed that prophylactic steroid use might reduce acute toxicity to PCI. Survival data and recurrence rates are comparable to other clinical studies.

The assessment of cortisol in human hair: associations with sociodemographic variables and potential confounders.

To inform the future use of hair cortisol measurement, we have investigated influences of potential confounding variables (natural hair colour, frequency of hair washes, age, sex, oral contraceptive (OC) use and smoking status) on hair cortisol levels. The main study sample comprised 360 participants (172 women) covering a wide range of ages (1-91 years; mean = 25.95). In addition, to more closely examine influences of natural hair colour and young age on hair cortisol levels, two additional samples comprising 69 participants with natural blond or dark brown hair (hair colour sample) as well as 28 young children and 34 adults (young age sample) were recruited. Results revealed a lack of an effect for natural hair colour, OC use, and smoking status on hair cortisol levels (all p's >0.10). No influence of frequency of hair washes was seen for proximal hair segments (p = 0.335) but for the third hair segment indicating lower cortisol content (p = 0.008). We found elevated hair cortisol levels in young children and older adults (p < 0.001). Finally, men showed higher hair cortisol levels than women (p = 0.002). The present data indicate that hair cortisol measurement provides a useful tool in stress-related psychobiological research when applied with the consideration of possible confounders including age and sex.

Paraplegia due to drop metastases from anaplastic oligodendroglioma.

In this article, we report on a rare case of spinal seeding from a cerebral anaplastic oligodendroglioma presenting with signs of medullar compression. We discuss the prevalence, mechanisms and imaging findings of spinal seeding in various gliomas. A suitable clinical treatment and follow up for these patients is suggested.

Left-right difference in fetal liver oxygenation during hypoxia estimated by BOLD MRI in a fetal sheep model.

OBJECTIVE: The purpose of this study was to measure differences in oxygenation between the left and right sides of the fetal liver during varying oxygenation levels. METHODS: Eight ewes carrying singleton fetuses at gestational age 125 days (term, 145 days) were included in the study. Under anesthesia the ewes were ventilated with gas containing different levels of oxygen, thereby subjecting the fetuses to hyperoxia (mean ± SD maternal arterial partial pressure of oxygen (pO2), 23.2 ± 8.2 kPa) and hypoxia (mean maternal arterial pO2, 7.1 ± 0.5 kPa). Changes in oxygenation within the fetal liver were assessed by blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). RESULTS: During hyperoxia there was no difference between the BOLD signal in the left and right sides of the fetal liver; mean change in BOLD (ΔBOLD)(hyperox), -0.9 ± 3.7%. During hypoxia, however, the decrease in the BOLD signal was more pronounced in the right side as compared with the left side, thereby creating a significant increase in the left-right difference in the BOLD signal; mean ΔBOLD(hypox), 5.2 ± 2.2% (P = 0.002, paired t-test). The left-right difference was directly proportional to the degree of hypoxia (R2 = 0.86, P = 0.007). CONCLUSIONS: To our knowledge, this is the first study demonstrating differences in oxygenation between the left and right sides of the fetal liver during hypoxia, a difference that can be explained by increased ductus venosus shunting. Thus, the BOLD MRI technique is a promising non-invasive tool that might be useful for the future monitoring of the human fetus.

[Pain perception of adolescents with chronic functional pain : adaptation and psychometric validation of the Pain Perception Scale (SES) by Geissner]. / Schmerzempfindung bei Jugendlichen mit chronischen funktionellen Schmerzen : Adaptation und psychometrische Uberprüfung der Schmerzempfindungsskala (SES) nach Geissner.

BACKGROUND: Pain perception is a central aspect of the multidimensional model of chronic pain. Up to now, validated measurement tools are lacking in the German language for measuring pain perception in adolescents. The aim of this study was to examine and adapt the well-established Pain Perception Scale for Adults by Geissner (SES) for use in adolescents with chronic pain to provide a measure for clinical diagnosis and evaluation of treatment effects. MATERIAL AND METHODS: Principal component, reliability and item analyses were conducted on a sample with 139 adolescents. To test validity, age and sex effects, correlations with pain-related constructs, differences between treatment groups (inpatients vs outpatients) and concordance between adolescents and their parents were analysed. RESULTS: Findings support a two-factor solution with one affective and one sensory factor; three additional sensory items were included in the final version. The scales show good internal consistency. Consistent with hypotheses, we found significant correlations with pain characteristics, emotional and cognitive variables as well as pain-related disability. Inpatients and outpatients show a significant difference in affective pain perception. Concordance between parents and adolescents was high. CONCLUSION: With this questionnaire there is now a validated German assessment tool to measure pain perception in adolescents with chronic pain (Pain Perception Scale for Adolescents, SES-J). Due to its practicability it is suitable for clinical application.

Higher cortisol content in hair among long-term unemployed individuals compared to controls.

Unemployment and financial strain are chronic stressors that have been shown to be associated with an increase in mean salivary and serum cortisol levels. Hair analysis for cortisol content is a new promising tool by which hair segmental analysis may provide a retrospective calendar of cumulative cortisol exposure over time rather than momentary assessments. Participants of this study were 31 unemployed and 28 employed individuals (46 women). Hair segmental analysis was conducted using 3-cm long segments starting with the scalp-near segment. Due to differing hair length, 52 individuals had values for the second segment and n=33 individuals had values for the third segment. Univariate analysis of variance indicated that unemployed individuals had higher cortisol content in the first (p<0.05, eta(2)=0.071) and second (p<0.05, eta(2)=0.085) hair segment (a total of 6 cm long hair representing the preceding 6 months of collection). Consistent with other data from our laboratory, there was a wash-out effect for the third segment (p<0.05 for segment 3 vs. segment 1 and 2). Unemployed individuals indicated increased levels of perceived stress and impairments in subjective well-being compared to employed individuals. These subjective measures of perceived stress and well-being were unrelated to cortisol content in hair. We conclude that hair analysis for cortisol content may be a valid method to detect differences in cumulative cortisol exposure between chronically stressed individuals and healthy controls. Due to a wash-out effect, retrospective ascertainment of cortisol exposure may be limited to the preceding 6 months of specimen collection.

BOLD MRI in sheep fetuses: a non-invasive method for measuring changes in tissue oxygenation.

OBJECTIVE: The purpose of this descriptive study was to correlate changes in the blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal with direct measurements of fetal tissue oxygenation. METHODS: Seven anesthetized ewes carrying singleton fetuses at 125 days' gestation (term 145 days) underwent BOLD MRI, covering the entire fetus in a multislice approach. The fetuses were subjected to normoxic, hypoxic and hyperoxic conditions by changing the O(2)/N(2)O ratio in the maternal ventilated gas supply. The partial pressure of oxygen (pO2) in the fetal liver was measured using an oxygen-sensitive optode. Maternal arterial blood samples were simultaneously withdrawn for blood gas analysis. These measurements were compared with BOLD MRI signals in the fetal liver, kidney, spleen and brain. RESULTS: We demonstrated a consistent increase in the BOLD MRI signal with increasing tissue pO(2). For the fetal liver, spleen and kidney we observed a clear association between changes in maternal arterial blood pO2 and changes in BOLD MRI signal. Interestingly, we found that the BOLD signal of the fetal brain remained unchanged during hypoxic, normoxic and hyperoxic conditions. CONCLUSIONS: This experimental study demonstrated that BOLD MRI is a reliable non-invasive method for measuring changes in tissue oxygenation in fetal sheep. The unchanged signal in the fetal brain during altered maternal oxygen conditions is probably explained by the brain-sparing mechanism.

[Attitudes on euthanasia and medical advance directives]. / Einstellungen zur Sterbehilfe und zu Patientenverfügungen -- Ergebnisse einer Befragung von 727 Arzten.

BACKGROUND: With regard to medical decisions and measures at the end of life, the values and attitudes of those concerned are crucial. However, they have hardly been taken into account so far in German empirical studies on euthanasia and medical advance directives. METHOD: Between October 2003 and May 2004, a mail survey of a representative group of internists, anaesthetists and general practitioners from Bavaria, Westphalia-Lippe and Thuringia was conducted. RESULTS: Of 1,557 mailed questionnaires 727 were returned (rate of returns: 46 %). The survey showed, high of appreciation for medical advance directives and, at the same, time scepticism regarding surrogate decision-making by legal guardians and authorized representatives. Furthermore, the survey revealed a considerable amount of uncertainty in the physicians about the application of certain measures at the end of life to the different forms of euthanasia. In practice, many physicians do not comprehend the juridical differentiation between (illegal) active and (legal) passive or indirect euthanasia. CONCLUSIONS: In training and further education more scope should be given to the reflection of medical decisions at the end of life. At the same time, the usual, partly counterintuitive legal definitions should be brought more into line with medical decision making, while taking into account developments in English speaking areas. A transdisciplinary discourse is indispensable for the development of medical ethical and legal justifications suitable as guidance for action.

Acute myeloid and T-cell acute lymphoblastic leukaemia with aberrant antigen expression exhibit similar TCRdelta gene rearrangements.

TCR delta gene recombination patterns were analysed by Southern blot, polymerase chain reaction and nucleotide sequencing in acute myeloid leukaemias, with coexpression of lymphoid antigens (Ly+ AML, n=10) as well as in early T-cell acute lymphoblastic leukaemias with (My+ T-ALL, n=10) and without coexpression of myeloid antigens (My(-) T-ALL, n=9). These 29 acute leukaemias exhibiting TCR delta gene rearrangements were selected from 66 Ly+ AML, 14 My+ T-ALL and 12 My(-) T-ALL cases. Similar recombination patterns, namely D delta 2J delta1 and V delta 1J delta1 gene rearrangements, were observed in Ly+ AML and My+T-ALL. In contrast to V delta2 D delta3 rearrangements in B-cell precursor ALL, these rearrangements require activation of a T-cell-specific TCR delta enhancer. Comparison of My+ T-ALL and Ly+ AML with My(-) T-ALL exhibited a higher incidence of incomplete D delta 2J delta1 rearrangements in My+ T-ALL and Ly+ AML. Since a D delta 2J delta1 rearrangement is an early event in TCR delta recombination, these leukaemias seem to be arrested at an earlier stage of differentiation. Similar patterns of TCR delta rearrangements in My+ T-ALL and Ly+ AML suggest existence of a common myeloid/T-lymphoid progenitor cell. Although weak or missing expression of terminal deoxynucleotidyl transferase (T delta T) was found in 7/10 Ly+ AML cases, no difference was observed in numbers of N-nucleotides inserted in junctional regions when comparing with 3/10 cases exhibiting TdT expression. Since TdT activity is necessary for N-nucleotide addition, this finding suggests down-regulation of T delta T expression after rearrangement took place in these Ly+ AML cases.

[Comparative studies with mesoptometer and nyktometer ]. / Vergleichende Untersuchungen mit Mesoptometer und Nyktometer.

Mesoptometer Model I (Oculus) and Nyktometer (Rodenstock) were compared monocularly in 328 eyes. The individual measurements varied widely, more so for mesopic vision with dazzle than for mesopic vision without dazzle. When the results were classified in accordance with the normal limits proposed by the German Ophthalmological Society there was good correlation between the two instruments. The results fell into the same category in about 85% of the cases.