Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II—Report from the German/Swiss SIOP-LGG 2004 cohort

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.     

Genotoxic and cytotoxic effects of 4-aroyl-1-nitrosohydrazine-carboxamides onO 6-alkylguanine-DNA alkyltransferase-positive and-negative human cell lines

Five different representatives (I–V) of a new class of bifunctional alkylating agents, the 4-aroyl-1-nitrosohydrazinecarboxamides (nitrososemicarbazides), were evaluated for their potential interaction with DNA and for their cytotoxic activity in vitro toO ⁶-alkylguanine-DNA alkyltransferase-positive (Mer⁺) and-negative (Mer^–) human cell lines. The HeLa MR cell line (Mer^–) showed up to 20-fold higher sensitivity at IC₅₀ (dose that inhibits colony formation by 50%) to agents I–V than did the HeLa S3 cell line (Mer⁺) in a colony-formation assay. These data were compared to those obtained by treatment of the two cell lines with carmustine, a currently used antitumor drug. In Mer⁺ cells comparable results to those with carmustine were obtained with compounds III, IV and V; in Mer^– cells compounds I and II showed nearly the same effects as carmustine. Whether compounds I–V produce DNA strand breaks and/or DNA-protein cross-links was investigated using an alkaline filter elution technique. In this assay all compounds produced DNA single-strand breaks; no correlation could be detected between the strand breakage frequency and cytostatic, mutagenic and antitumor activity.Abbreviations Carmustine 1,2-bis-(2-chloroethyl)-1-nitrosourea - lomustine 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea - IC₅₀ dose that inhibits colony formation by 50% - PC polycarbonate - HVLP polyvinylidene fluoride     

Single burr hole endoscopic biopsy with third ventriculostomy��measurements and computer-assisted planning

Objective  

In cases of non-communicating hydrocephalus, a combined endoscopic third ventriculostomy (ETV) and tumor biopsy might be necessary. We suggest a computer-assisted planning procedure to perform ETV and biopsy via a single burr hole.     

Results of posterior cranial vault remodeling for plagiocephaly and brachycephaly by the meander technique

Objective

Several techniques to remodel the posterior calvarium in order to increase intracranial volume (ICV) and to improve cosmetic appearance are reported. This study presents the results of meander technique in patients with brachycephaly and posterior plagiocephaly.

Methods

During December 2011 and July 2013, a total of 12 children (median age: 15 months) underwent posterior cranial vault remodeling by the meander technique (brachycephaly, n?=?6; posterior plagiocephaly, n?=?6). The available pre- and postoperative MRIs were assessed with regard to ICV, cranial index (CI) and asymmetry index (AI) as well as the position of the cerebellar tonsils.

Results

No intra- or postoperative complications were observed. Blood transfusions were necessary in nine of 12 patients. A significant increase of the ICV from 1,178.4?±?134.5 to 1,293.0?±?137.5 cm³ (p?p?p?p?p?p?Conclusion The presented surgical technique is considered to be safe. The technique is capable to significantly increase ICV and improve cosmetic appearance of the remodeled calvarium. Further evidence that posterior cranial vault remodeling influences the position of the cerebellar tonsils is added by the results of the study.     

Effects of early and late intravenous norepinephrine infusion on cerebral perfusion,microcirculation, brain-tissue oxygenation,and edema formation in brain-injured rats

OBJECTIVES: Reduction of cerebral perfusion during the early phase after traumatic brain injury is followed by a later phase of normal to increased perfusion. Thus, pharmacologically elevating mean arterial blood pressure with the aim of improving cerebral perfusion may exert different time-dependent effects on cortical perfusion, microcirculation, tissue oxygenation and brain edema formation after traumatic brain injury. DESIGN: Randomized, placebo-controlled trial. SETTING: Experimental laboratory at a university hospital. SUBJECTS: A total of 37 male Sprague-Dawley rats subjected to a focal cortical contusion. INTERVENTIONS: At 4 or 24 hrs after focal traumatic brain injury, mean arterial blood pressure was increased to 120 mm Hg for 90 mins by infusing norepinephrine. In rats receiving physiologic saline, mean arterial blood pressure remained unchanged. In the first series, pericontusional cortical perfusion was measured using the laser Doppler flowmetry scanning technique before injury and before, during, and after the infusion period. In a second series, intracranial and cerebral perfusion pressure and intraparenchymal perfusion and tissue oxygen measured within the contused and pericontusional cortex were recorded continuously before, during, and after norepinephrine infusion. Changes in cortical microcirculation were investigated by orthogonal polarization spectral imaging. At the end of each experiment, hemispheric swelling and water content were determined gravimetrically. MEASUREMENTS AND MAIN RESULTS: At 4 and 24 hrs after traumatic brain injury, intravenous norepinephrine significantly increased pericontusional cortical perfusion, which was also reflected by an increase in diameters and flow velocities of pericontusional arterioles and venules. Cerebral perfusion pressure and intraparenchymal perfusion and tissue oxygen were significantly increased during norepinephrine infusion at 4 and 24 hrs. Hemispheric swelling and water content showed no difference between the groups. CONCLUSIONS: After cortical impact injury, early and late intravenous norepinephrine infusion pressure-dependently increased cerebral perfusion and tissue oxygenation without aggravating or reducing brain edema formation. Future studies are warranted to determine long-term changes of short and prolonged norepinephrine-induced increases in mean arterial blood pressure and cerebral perfusion pressure.     

Shunt survival rates by using the adjustable differential pressure valve combined with a gravitational unit (proGAV) in pediatric neurosurgery

Object

Overdrainage is a chronic complication in shunted pediatric patients with hydrocephalus. The use of adjustability of differential pressure (DP) valves in combination with antisiphoning devices may help to overcome this sequela and may diminish the rate of possible shunt failures. The purpose of this retrospective study is to report our experience on shunt survival and infection rate with an adjustable DP valve with integrated gravitational unit in pediatric hydrocephalus.

Methods

The proGAV consists of an adjustable differential pressure (DP) valve and a gravitational unit. During the time period of July 2004 and December 2009, a total of 237 adjustable gravitational valves were used in 203 children (age, 6.5?±?6.54; 0–27 years). In the follow-up period, valve and shunt failures as well as rate of infection were recorded.

Results

Within the average follow-up time of 21.9?±?10.3 months (range, 6–72 months), the valve survival rate was 83.8 %. The overall shunt survival rate including all necessary revisions was 64.3 %. Looking at the group of infants (<1 year of age) within the cohort, the valve survival rate was 77.3 % and the shunt survival rate was 60.9 %. The overall infection rate was 4.6 %.

Conclusion

In a concept of avoiding chronic overdrainage by using the proGAV in hydrocephalic children, we observed a good rate of valve and shunt survival. Compared to previous reported series, we experienced the proGAV as a reliable tool for the treatment of pediatric hydrocephalus.     

Endoscopic neurosurgery in preterm and term newborn infants—a feasibility report

Objective

Neuroendoscopic procedures became essential in neurosurgical treatment of disturbed cerebrospinal fluid dynamics. While a vast number of papers report on the neuroendoscopic experience for adults and children, no series so far reported on techniques and indications for neonate infants. We present our experience for the feasibility of neuroendoscopic procedures in preterm and term newborn infants.

Methods

All preterm and term infants who underwent an endoscopic neurosurgical intervention prior to the 28th day after the previously estimated date of delivery were identified by retrospective review. Surgical procedures and techniques, complications, and further follow-up data are reported.

Results

During the study period, 14 infants (median age at surgery, 36+²/7 weeks of gestation) underwent 20 endoscopic procedures. The performed procedures included endoscopic septostomy (n?=?3), endoscopic shunt placement for multiloculated hydrocephalus (n?=?4), endoscopic transaqueductal stenting for isolated fourth ventricle (n?=?3), and endoscopic lavage for ventriculitis (n?=?4) or for intraventricular hemorrhage (n?=?6). No severe complications were seen, while two patients necessitating unexpected interventions during further follow-up (10 %).

Conclusions

Despite the fragility of preterm and term newborn infants, neuroendoscopic procedures may play an important role in the treatment of disturbed cerebrospinal fluid (CSF) dynamics also in this patient population. The neuroendoscopic approach may be curative in conditions like isolated lateral ventricle, may facilitate simplified and effective CSF diversion in multiloculated hydrocephalus or isolated fourth ventricle, and may be beneficial in the course of ventriculitis and intraventricular hemorrhage. Further studies must verify our experience with a bigger cohort of patients and on a multicenter basis.     

Calvarial dermoids and epidermoids in infants and children: sonographic spectrum and follow-up

Objective  Dermoids and epidermoids are defined as ectodermal inclusion cysts. The aim of this study was to evaluate the spontaneous natural behavior and the ultrasonographic appearance of calvarial dermoids and epidermoids. Materials and methods  The ultrasonographic image datasets of 100 consecutive children up to 4 years of age (52 females, 48 males; age range at first examination 1 week to 40 months, mean age 8.3 ± 6.9 months) presenting with a firm palpable calvarial mass (103 lesions) were studied retrospectively. All ultrasound (US) examinations were performed using a 7- to 10-MHz linear transducer including B-mode and color Doppler sonography. US follow-up studies (up to 47 months) could be achieved in 30 patients with 33 lesions. Results  At first presentation, all 103 lesions demonstrated very similar US features: a round or oval configuration (diameter 3–18 mm), hypoechogenic, and homogeneous internal structures with a marked hyperechogenic superficial capsule, which were localized adjacent to or expanded into the osseous external calvarial table. No conspicuous flow signs on color Doppler were seen. In 33 lesions with US follow-up investigations, 49% showed variable signs of regression: reduction of size, increase of internal echogenicity, and decrease of demarcation. Eight lesions (24%) remained unchanged. A slight progression up to a maximum diameter of 17 mm but without any increase in osseous destruction was observed in the remainder (27%). There was no lesion with a complete destruction of the underlying bone and no intracranial extension in any of the cases. Conclusions  Calvarial dermoids and epidermoids in infants and children show a benign natural behavior with spontaneous regression in a large number of cases. On US, they demonstrate uniform pathognomonic features enabling the correct diagnosis in any of those lesions. Thus, additional, mainly radiation burdening and sometimes misleading imaging techniques should be restricted. Surgical treatment protocols should be handled conservatively and lesions should be primarily followed-up clinically and by US. Thomas Riebel and Siegfried David contributed equally to this study.     

High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group

BackgroundKnowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce.MethodsWe analyzed clinical datasets of 128 pediatric patients with spinal LGG followed within the prospective multicenter trials HIT-LGG 1996 (n = 36), SIOP-LGG 2004 (n = 56), and the subsequent LGG-Interim registry (n = 36).ResultsSpinal LGG, predominantly pilocytic astrocytomas (76%), harbored KIAA1549-BRAF fusion in 14/35 patients (40%) and FGFR1-TACC1 fusion in 3/26 patients (12%), as well as BRAFV600E mutation in 2/66 patients (3%). 10-year overall survival (OS) and event-free survival (EFS) was 93% ± 2% and 38% ± 5%, respectively. Disseminated disease (n = 16) was associated with inferior OS and EFS, while age ≥11 years and total resection were favorable factors for EFS. We observed 117 patients following total (n = 24) or subtotal/partial resection (n = 74), biopsy (n = 16), or radiologic diagnosis only (n = 3). Eleven patients were treated first with chemotherapy (n = 9) or irradiation (n = 2). Up to 20.8 years after diagnosis/initial intervention, 73/128 patients experienced one (n = 43) or up to six (n = 30) radiological/clinical disease progressions. Tumor resections were repeated in 36 patients (range, 2-6) and 47 patients required nonsurgical treatment (chemotherapy, n = 20; radiotherapy, n = 10; multiple treatment lines, n = 17). Long-term disease control for a median of 6.5 (range, 0.02-20) years was achieved in 73/77 patients following one (n = 57) or repeated (n = 16) resections, and in 35/47 patients after nonsurgical treatment.ConclusionsThe majority of patients experienced disease progression, even after years. Multiple interventions were required for more than a third, yet multimodal treatment enabled long-term disease control. Molecular testing may reveal therapeutic targets.