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.

High reliability of scrotal ultrasonography in the management of childhood primary testicular neoplasms.

BACKGROUND: The role for testis-sparing surgery in the treatment of primary intratesticular lesions in childhood is growing. The reliability of scrotal ultrasonograpy (US) in the management of these lesions is still controversial. PATIENTS: Between 1991 and 2007, 383 children and adolescents presented with testicular abnormalities. Ultrasound results and records of patients with primary testicular neoplasms were analyzed. RESULTS: 12 of 383 patients (3.1%) had a histologically proven primary intratesticular neoplasm. Scrotal US was highly sensitive for the detection of these lesions. Patients' mean age at initial US was 6 years (9 prepubertal, 3 juvenile patients). The most frequent symptom was a painless unilateral scrotal mass (75%). Tumor markers or testosterone were elevated in 6/12 boys. Histology was intratesticular germ cell in 7, sexcord stromal tumor in 4 and capillary hemangioma in 1 patient. US correctly distinguished between benign and malignant lesions in all cases. When combined with clinical symptoms, US predicted 75% of histologies. After including hormone and tumor marker levels, a correct preoperative diagnosis was made for all boys with germ cell, and for 75% of boys with sexcord stromal tumor. CONCLUSION: Scrotal US is highly sensitive for the detection of childhood primary intratesticular tumors and, when combined with clinical data, highly reliable for differential diagnosis. It may help clinicians to decide when to opt for testis-sparing surgery.

Small-fiber neuropathy and pain sensitization in survivors of pediatric acute lymphoblastic leukemia.

BACKGROUND: Chemotherapy-induced Peripheral Neuropathy (CIPN) of large-fibers affects up to 20% of survivors of pediatric acute lymphoblastic leukemia (ALL). We aimed to describe small-fiber toxicity and pain sensitization in this group. METHODS: In a cross-sectional, bicentric study we assessed 46 survivors of pediatric ALL (Mean age: 5.7 ± 3.5 years at diagnosis, median 2.5 years after therapy; males: 28). INCLUSION CRITERIA: ≥6 years of age, ≥3 months after last administration of Vincristine, and cumulative dose of Vincristine 12 mg/m2. We used a reduced version of the Pediatric-modified Total Neuropathy Score (Ped-mTNS) as bedside test and Quantitative Sensory Testing (QST) for assessment of small- and large-fiber neuropathy as well as pain sensitization. We employed Nerve Conduction Studies (NCS) as the most accurate tool for detecting large-fiber neuropathy. RESULTS: Fifteen survivors (33%) had abnormal rPed-mTNS values (≥4 points) and 5 survivors (11%) reported pain. In QST, the survivor group showed significant (p < 0.001) inferior large-fiber function and pain sensitization when compared to healthy matched peers. We identified deficits of vibration in 33 (72%) and tactile hypoesthesia in 29 (63%), hyperalgesia to blunt pressure in 19 (41%), increased mechanical pain sensitivity in 12 (26%) and allodynia in 16 (35%) of 46 survivors. Only 7 survivors (15%) had pathologic NCS. CONCLUSION: QST is a sensitive tool that revealed signs of large-fiber neuropathy in two thirds, small-fiber neuropathy and pain sensitization in one third of survivors. Prospective studies using QST in pediatric oncology may help to elucidate the pathophysiology of small-fiber neuropathy and pain sensitization as well as their relevance for quality of survival.

Valproic acid inhibits proliferation and changes expression of CD44 and CD56 of malignant glioma cells in vitro.

Recently we were able to show that valproic acid (VPA) induces growth-arrest and differentiation of human neuroblastoma cells. Hence we investigated in vitro the antitumoral effects of VPA on malignant gliomas by determining cell proliferation and expression of CD56 and CD44 of human T98G, A172, 85HG66, 86HG39 and rat C6 cell lines. VPA at concentrations ranging from 0.1 to 1 mM strongly inhibited proliferation of A172, 86HG39, 85HG66 and C6 cells in a dose-dependent manner, whereas T98G cell growth remained unchanged. All human glioma cells were highly positive for CD44, whereas CD56 was differently expressed. After 7 days of incubation with 1mM VPA CD56 expression was markedly increased in T98G, A172 and 85HG66 cells, whereas CD44 expression was decreased in all human cell lines. These data suggest that VPA has antitumoral effects on malignant glioma cells. Therefore we consider VPA as a potent therapeutic agent for treatment of these tumors.

Different effects of valproic acid on proliferation and migration of malignant glioma cells in vitro.

Valproic acid (VPA) has been considered as a possible treatment agent for malignant gliomas. In order to characterise the possibilities of VPA, we investigated the effects on cell migration and proliferation. Human cell lines T98G, A172, 85HG66 and 86HG39 were treated with VPA or left untreated, afterwards Boyden chamber assay was used for measuring vertical migration. In a second assay cells were stimulated to create spheroids and spheroid migration was measured. Proliferation was assessed using a cell counter. VPA decreased proliferation of 86HG39 > A172 > 85HG66 cells, whereas T98G remained uninfluenced. The influence of VPA on migration was different; whereas VPA dose-dependently stimulated migration of 86HG39 cells, migration of T98G and 85HG66 decreased, whereas A172 cells remained uninfluenced. Only 86HG39 and A172 cells created spheroids. In both cell lines Boyden-chamber-findings were confirmed by analysing the influence of VPA on spheroid migration. These non-uniform data demonstrate that the benefit of VPA in glioma treatment is not clear and needs further investigation.

Increased efficacy of aphidicolin killing of human neuroblastoma cells in vitro by encapsulation in liposomes.

Aphidicolin is a tetracyclic diterpene antibiotic which kills human neuroblastoma cells (NB) in vitro while it has no significant effect on the viability of different human cell types including normal embryonal cells. In the present study, we tested whether aphidicolin encapsulated in liposomes kills NB cells with the efficacy superior to that of unencapsulated aphidicolin. The drug was entrapped in vesicles composed of phosphatidylcholine, phosphatidylserine and cholesterol in a molar ratio of 83:5:12. The treatment with encapsulated aphidicolin at a concentration of 200 nmol for 5 days killed all cells of three human NB cell lines. In contrast, at least 30% of the cells survived 5 days of treatment with 200 nmol unencapsulated aphidicolin. The results showed that aphidicolin killing of human NB cells may be increased by encapsulation in liposomes.

Structure of mouse DNA (cytosine-5-)-methyltransferase.

DNA (cytosine-5-)-methyltransferase was purified as a single polypeptide (190 kDa by SDS-PAGE) from mouse P815 mastocytoma cells. This enzyme transfers methyl groups to unmethylated as well as to hemimethylated DNA sites with a strong preference for the hemimethylated substrate. A structural analysis of the isolated enzyme by electron microscopical techniques was undertaken. On the basis of the results obtained, we propose a model for the enzyme structure. This model describes the enzyme as a hemi-elliptical globular structure with dimensions of 5.4-6.7 nm for the height h and 10.3-10.8 nm for the diameter d, respectively; this globular structure bears a small appendix at the flat side. A molecular mass of 235-250 kDa is calculated from the measured dimensions. Limited trypsin digestion of the enzyme led to a 160-kDa fragment which preserved the gross morphology of the original material. The possible structure function relationships are discussed.

Congenital microgastria, growth hormone deficiency and diabetes insipidus.

UNLABELLED: Microgastria is a rare malformation of the stomach always associated with variable patterns of malformations of the lung, heart, aortic arch, skeleton, and central nervous system. Many cases present with asplenia and hepatic symmetry as well as intestinal malrotation. We report a first case of a 4.5-year-old girl with congenital microgastria in association with growth hormone deficiency, diabetes insipidus, brachyoesophagus, hernia of the diaphragm, gastro-oesophageal reflux, intestinal malrotation, enlarged symmetrical liver, asplenia, as well as mental and statomotor retardation. CONCLUSION: Congenital microgastria is always associated with malformations of other organs. Patients at any age presenting one of the symptoms: failure to thrive, vomiting, asplenia, midline defects and parts of the VACTERL association should be carefully examined to exclude microgastria.

[Diagnosis and outcome of neurotropic enterovirus infections in childhood]. / Diagnostik und klinischer Verlauf neurotroper Enterovirusinfektionen im Kindesalter.

BACKGROUND: Enterovirus infections are among the most common causes of aseptic meningitis. Worldwide there are reports about recurring outbreaks, especially during the summer. They are favoured by conditions of bad hygiene and contaminated water, transmission is predominantly through the faeco-oral route or by droplet infection. The most common species are Coxsackie B and ECHO (Enteric Cytopathogenic Human Orphan) virus. ECHO viruses have a worldwide distribution and usually occur as "summer flu" or aseptic meningitis and meningoencephalitis in toddlers and infants. Type 30 caused an outbreak of aseptic meningitis in the Rhein-Main region in summer 1997. During five months 63 children younger than 16 years were reported. PATIENTS AND METHODS: During this outbreak 18 children with prooved enterovirus infections were treated at the Frankfurt/Main University Children's Hospital. Standardized infectiological diagnostic procedures were performed and risc factors, clinical symptoms, inflammatory marker, neurophysiological findings (electroencephalography, evoked potentials) and outcome were assessed. RESULTS: The affected children were between 3 and 11 years old. Clinical symptoms were cephalgia, nausea, vomiting, meningism and seizures with fever. Virus isolation from faecal and cerebrospinal fluid (CSF) samples and the use of polymerase chain reaction (PCR) was superior to serological methods. Erythrocyte sedimentation rates showed more significant increase than C-reactive protein (CRP) and blood leukocytes. CSF pleocytosis showed high variation. Clinical course as well as prognosis and outcome were favourable. CONCLUSION: Virusisolation in stool and CSF is most promising in the diagnostic of cerebral enterovirus infections. Usually the outcome is favourable, encephalitis can occur as serious complication.

[Nervous system manifestations in HIV infected children]. / Affektionen des Nervensystems bei perinatal HIV-infizierten Kindern.

In 34 perinatally HIV infected children time of manifestation, type and treatability of neurologic disorders were investigated for a period of 7 years (1987-1994). Neurological investigations were done every 6 months; EEG and MRI/CT were examined initially in the asymptomatic stage and were repeated when neurologic Symptoms occurred. Zidovudine therapy was started after onset of symptoms, dosage was raised, when treatment with Zidovudine had already begun (600-720 mg/m2/day). Various neurological manifestations were seen in 4 of 12 patients in stage B (33%) and in 11 of 14 children in AIDS (80%). 7 of the 14 AIDS-patients (50%) developed a subacute progressive course or progressive plateau course and 4 of 14 (30%) a static course of encephalopathy. Pathological changes in EEG were seen in 54% of investigated patients with neurological deficits. Neuroimaging revealed pathological findings in all symptomatic subjects, 6 of 11 patients in AIDS (55%) has a severe general cerebral atrophy and multifocal white matter lesions. Zidovudine had a positive temporary effect from 6 to 12 months in 5 of 11 treated patients (45%). At present a thorough neurological examination is the most sensitive method to detect neurological impairment in HIV infected children. In most cases CT/MRI scan provides information about the course of the encephalopathy. Antiretroviral therapy has a limited benefit, if neurologic symptoms start after the second year of life.

C-MYC expression in medulloblastoma and its prognostic value.

To identify prognostic factors in medulloblastoma, a common malignant brain tumor of childhood, expression of the oncogene c-myc was examined at the mRNA level by in situ hybridization. c-myc mRNA expression was observed in 30 of 72 tumors (42%). The c-myc gene copy number was determined by quantitative PCR from genomic DNA of paraffin-embedded tumors. c-myc gene amplification was present in 5 of 62 cases (8.3%). Therefore, c-myc amplification was obviously not the cause of c-myc mRNA expression in most samples. Kaplan-Meier estimation revealed a significant correlation between c-myc mRNA expression and survival (total mean follow-up 4.6 +/- 3.6 years, log-rank p = 0.02). Multivariate logistic regression analysis including sex, age, histological type, degree of surgical resection and expression of synaptophysin, GFAP and c-myc, was carried out on 54 patients who received both radiotherapy and chemotherapy. The analysis identified expression of c-myc as an independent predictive factor of death from disease.