Adeno-associated virus vector hydrogel formulations for brain cancer gene therapy applications.

Gelatin-based formulations are utilized in neurosurgical procedures, with Medisponge® serving as an illustration of a secure and biocompatible hemostatic formulation. Noteworthy are combined hemostatic products that integrate pharmacological agents with gelatin. Gelatin matrices, which host biologically active substances, provide a platform for a variety of molecules. Biopolymers function as carriers for chemicals and genes, a facet particularly pertinent in brain cancer therapy, as gene therapy complement conventional approaches. The registration of Zolgensma underscores the efficacy of rAAV vectors in therapeutic gene delivery to the CNS. rAAVs, renowned for their safety, stability, and neuron-targeting capabilities, predominate in CNS gene therapy studies. The effectiveness of rAAV vector therapy varies based on the serotype and administration route. Local gene therapy employing hydrogel (e.g., post-tumor resection) enables the circumvention of the blood-brain barrier and restricts formulation diffusion. This study formulates gelatin rAAV gene formulations and evaluates vector transduction potential. Transduction efficiency was assessed using ex vivo mouse brains and in vitro cancer cell lines. In vitro, the transduction of rAAV vectors in gelatin matrices was quantified through qPCR, measuring the itr and Gfp expression. rAAVDJ and rAAV2 demonstrated superior transduction in ex vivo and in vitro models. Among the cell lines tested (Hs683, B16-F10, NIH:OVCAR-3), gelatin matrix F1 exhibited selective transduction, particularly with Hs683 human glioma cells, surpassing the performance Medisponge®. This research highlights the exploration of local brain cancer therapy, emphasizing the potential of gelatin as an rAAV vector carrier for gene therapy. The functional transduction activity of gelatin rAAV formulations is demonstrated.

Single Center Experience in Cerebrospinal Fluid Dynamics Testing.

Normal pressure hydrocephalus is more complex than a simple disturbance of the cerebrospinal fluid (CSF) circulation. Nevertheless, an assessment of CSF dynamics is key to making decisions about shunt insertion, shunt malfunction, and for further management if a patient fails to improve. We summarize our 25 years of single center experience in CSF dynamics assessment using pressure measurement and analysis. 4473 computerized infusion tests have been performed. We have shown that CSF infusion studies are safe, with incidence of infection at less than 1%. Raised resistance to CSF outflow positively correlates (p < 0.014) with improvement after shunting and is associated with disturbance of cerebral blood flow and its autoregulation (p < 0.02). CSF infusion studies are valuable in assessing possible shunt malfunction in vivo and for avoiding unnecessary revisions. Infusion tests are safe and provide useful information for clinical decision-making for the management of patients suffering from hydrocephalus.

Cephalic index in the evaluation of surgical treatment of children with sagittal synostosis. Preliminary report.

AIM OF THE STUDY: To analyze changes of the cephalic index (CI) values in patients with sagittal synostosis operated on in the Department of Surgery of Children and Adolescents of the Institute of Mother and Child in Warsaw. MATERIAL AND METHODS: The study group consisted of 14 consecutive cases (11 boys and 3 girls). In 8 patients younger than 3 months of age (1st subgroup) the modified reversed-pi technique (craniotomy in the shape of the reversed Greek π letter) was utilized. In 6 older infants and in patients with severe head deformity - the radical cranial vault reconstructions were performed (2nd subgroup). The statistical analysis of the preoperative (preop) and postoperative (postop) cephalic index (CI) values was done. RESULTS: For the entire study group the preop CI values ranged from 61 to 77 (mean 68.14, median 68.5) and postop CIs from 73 to 89 (mean 77.64, median 76). In the 1st subgroup the preop CIs ranged from 63 to 77 (mean 69.625, median 69) whereas the postop CIs from 69 to 89 (mean 78.125, median 76.5). In the 2nd subgroup the preop CI values ranged from 61 to 72 (mean 66.1667, median 66) and postop from 73 to 81 (mean 77, median 77). All the differences were statistically significant. CONCLUSION: The values of cephalic index increased after both types of procedures. It signifies the correction of dolichocephaly in both subgroups of the patients. However, because of the small number of operated children, further studies are necessary.

Motor cortex stimulation in the treatment of neuropathic pain.

BACKGROUND AND PURPOSE: Despite the rapid development of neuropharmacotherapy, medical treatment of neuropathic pain (NP) still constitutes a significant socioeconomic problem. The authors herein present a group of patients treated with motor cortex stimulation (MCS) for NP of various types and aetiologies. MATERIAL AND METHODS: Our cohort included 12 female and 11 male NP patients aged 53 ± 16 treated with MCS. Eleven patients were diagnosed with neuropathic facial pain (NFP), 8 with hemi-body neuropathic pain (HNP), and 4 with deafferentation pain (DP). Prior to surgery, 16 out of 23 patients were treated with repetitive transcranial magnetic stimulation (rTMS), with a positive response in 10 cases. Pain intensity in our group was evaluated with the visual analogue scale (VAS) one month before and three months after MCS implantation. RESULTS: Improvement on the VAS was reported in the whole group of patients (p < 0.001). The best results were reported in the NFP group (p < 0.001) while the worst ones were noted in the DP group (p = 0.04). Anamnesis duration positively correlated with outcome. Infection forced the authors to permanently remove the system in one case. There were no other complications in the group. CONCLUSIONS: Minimally invasive, safe neuromodulative treatment with MCS permits neuropathic pain control with good efficacy. The type of neuropathic pain might be a prognostic factor.

Statistical analysis of the intracranial procedures in Poland in 2008-2009.

BACKGROUND AND PURPOSE: Quantitative and qualitative analysis of neurosurgical procedures provides important data for assessment of the development and trends in the field of neurosurgery. The authors present statistical data on intracranial procedures (IPs) performed in Poland in 2008-2009. MATERIAL AND METHODS: Data on IPs come from reports of the National Health Fund, grouped according to the system of Diagnosis-Related Groups, group A - nervous system diseases. Data concerning the year 2009 include all IPs performed in Poland. Data from the second half of 2008 to 2009 (18 months) come from 35 neurosurgical centers in Poland, divided by provinces. We analyzed the number of IPs, the cost of procedures, duration of hospitalization and deaths. RESULTS: 20 849 IPs were performed in Poland in 2009. The most common procedure was A12 (6807; 32.65%), and the rarest was A04 (96; 0.46%). The annual cost of all IPs was 228 599 956 PLN. Average cost of the procedure ranged from 1578 PLN (A14) to 47 940 PLN (A03). Duration of the hospitalization ranged between 3 days (A14) and 12 days (A12). The highest percentage of deaths was reported for A01 (n = 1050, 19.06%). Reports from 35 neurosurgical centers in the second half of 2008 and 2009 showed the highest number of IPs per 100 000 population in Kujawsko-Pomorskie (93) and the lowest in Wielkopolskie (27) and Podkarpackie (27). The highest number of IPs (1669) was performed in neurosurgical center M1 (Malopolskie), and the lowest (99) in W1 (Wielkopolskie). CONCLUSIONS: A significant disparity in the number of IPs performed in different centers in Poland was observed.

Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients.

The NBN (NBS1) gene belongs to a group of double-strand break repair genes. Mutations in any of these genes cause genome instability syndromes and contribute to carcinogenesis. NBN gene mutations cause increased tumor risk in Nijmegen breakage syndrome (NBS) homozygotes as well as in NBN heterozygotes. NBS patients develop different types of malignancies; among solid tumors, medulloblastoma (MB), an embryonal tumor of the cerebellum, has been reported most frequently. The majority of medulloblastomas occur sporadically, some of them manifest within familial cancer syndromes. Several signaling pathways are known to be engaged in hereditary and sporadic MB. The aim of our study was to identify mutations in selected exons of the NBN gene and to determine the frequency of the most common NBN gene mutations in pediatric patients with different types of medulloblastoma. We screened a total of 104 patients with MB and identified 7 heterozygous carriers (6.7%) of two different germ-line mutations of NBN gene; all of them had classic MB. Our results indicate that heterozygous carriers of the germ-line NBN gene mutations (c.511A>G and c.657_661del5) may exhibit increased susceptibility to developing MB. The risk of medulloblastoma is estimated to be 3.0 (for c.511A>G) and 4.86 (for c.657_661del5) times higher than in the general Polish population (p<0.05). These results suggest that heterozygous NBN germ-line mutations may contribute to the etiology of medulloblastoma.

Usefulness of magnetic resonance imaging with SWI sequence (susceptibility-weighted imaging) in diagnosing cerebral hemosiderosis - case report.

BACKGROUND: The purpose of this study was to determine whether the SWI sequence may improve the MRI evaluation of hemosiderin deposits in the brain. CASE REPORT: We report a case of a 7-year-old girl after a total resection of a large tumor mass (ependymoma G II) located in the left hemisphere. Late complication of surgery was hemosiderosis of the brain diagnosed with SWI sequence. CONCLUSIONS: SWI sequence is very sensitive in diagnosing hemosiderin deposits. It allowed us to recognize cerebral hemosiderosis in this case. We suggest to include this sequence in routine MRI examinations of the brain, especially in cases of potential and suspected intracranial bleeding.

Long-term functional outcome of surgical treatment of juvenile pilocytic astrocytoma of the cerebellum in children.

PURPOSE: Increasing incidence of pediatric brain tumors and improving survival rates encouraged us to assess long-term functional outcome of patients with cerebellar juvenile pilocytic astrocytoma (JPA). MATERIALS AND METHODS: Our study encompassed 105 children treated since 1980-2005 and consisted in analysis of mailed, custom-designed questionnaires. RESULTS: Mean follow-up time was 8.3 years. Sixty out of 104 patients presented permanent neurological deficits and 47/104 presented significant behavioral disorders. Eighty-nine children continued their education at primary, secondary or high school level. Most patients and their parents were satisfied with treatment outcome. Patients' and parents' notes were usually concordant. CONCLUSIONS: Long-term functional treatment outcome of cerebellar JPA is relatively favorable, in spite of permanent neurological deficits and emotional disorders in over half of the patients. Vermian tumors are associated with worse long-term functional outcome. Neurological deficits and emotional disorders do not preclude further education and independent functioning.

Tethered cord syndrome in children - impact of surgical treatment on functional neurological and urological outcome.

BACKGROUND AND PURPOSE: Tethered cord syndrome (TCS) consists of solid adhesion of the distal spinal cord to adjacent structures, resulting in repetitive spinal cord traction during truncal movements. The condition is usually a sequel of lumbosacral dysraphism, spinal cord injury or surgical procedure. Clinical signs of TCS include sphincter disturbances, lumbosacral pain, sensorimotor deficits and orthopaedic deformity. The aim of this study was to assess long-term results of surgical treatment of TCS in children and to define any prognostic factors associated with long- -term outcome. MATERIAL AND METHODS: Between 1980 and 2005, we treated 59 children with TCS. The group included 22 boys and 37 girls (mean age at surgery: 7.7 years). In total, 75 surgical procedures were performed. Mean follow-up time was 4.4 years. RESULTS: Meaningful clinical improvement was obtained in 19 children (32.2%) and was more pronounced in lower extremities than in sphincters. Degree of untethering was the only factor significantly influencing outcome. Neither age at surgery nor severity of spinal cord traction had any prognostic value. Significant correlations were found between severity of pre-existing myelopathy and development of neurogenic bladder, independently of treatment instituted. There was no permanent morbidity and perioperative mortality was nil. CONCLUSIONS: Late results of surgical treatment of TCS in children are generally unsatisfactory - worthwhile improvement was obtained in about 1/3 of patients only. Improvement was more pronounced in lower extremities than in sphincters. The sole factor contributing to good functional outcome was complete untethering of the cord. The decision whether to operate on a child with TCS must be based on coherent clinical, radiological and urological premises; surgery should be performed before irreversible deficits appear.

Multiple shunt system revisions in patients with hydrocephalus - causes, effects, regularities and prognostic factors.

BACKGROUND AND PURPOSE: Hydrocephalus in its various forms constitutes one of the major problems in neurosurgery. All neurosurgeons struggle with shunt malfunctions and their complications. Clinical experience suggests that there may exist a definite constellation of clinical features associated with higher risk of shunt malfunction. The aim of this study was to elucidate this issue based on our clinical experience. MATERIAL AND METHODS: Retrospective analysis of the clinical database was used to assess shunt procedures performed between 1980 and 2005 in 1860 children and adolescents with active hydrocephalus as the main or associated problem at admission. Overall, 2197 procedures were performed and the analysis included only patients who were treated surgically at least 3 times (n=106). Patients' age ranged from one day to 22 years. RESULTS: Recurrent shunt malfunctions were mostly associated with non-modifiable parameters (e.g. age <1 year, porencephaly, benign tectal mass and slit ventricle syndrome). Modifiable parameters (e.g. type of shunt or surgical technique) had no significant influence on treatment outcome. CONCLUSIONS: 1. The proportion of patients who require multiple (> or = 3) shunt revisions is small. 2. Higher risk of shunt malfunction and its subsequent revisions is associated with age below 1 year at first shunt insertion and aetiology of hydrocephalus resulting in severe shunt dependence. 3. Time interval between consecutive shunt revisions does not exceed 1 year in most cases.

Palliative procedures in the management of brain tumours in children. Change of therapeutic strategy over the last 25 years--an institutional experience Department of Neurosurgery of the Children's Memorial Health Institute in Warsaw.

BACKGROUND AND PURPOSE: The growing incidence of paediatric brain tumours and improved treatment outcome result in longer survival time. In this context, the issue of palliative treatment is becoming increasingly important. THE AIM of this paper is to assess the role of palliative procedures in the treatment of paediatric brain tumours and to analyze changes in therapeutic strategy concerning palliative procedures that have taken place within the last 25 years in one institution. MATERIAL AND METHODS: During the last 25 years (between 1980 and 2005), at the Department of Neurosurgery of the Children's Memorial Health Institute we have treated a total of 3279 children with the principal diagnosis of "CNS tumour", who underwent 611 palliative procedures. In 36 cases we performed a combined therapeutic-diagnostic procedure. This is a retrospective study, based on a review of medical records and search of our clinical database. RESULTS: There were significant differences in the frequency of palliative procedures depending on particular tumour location. There was also a significant linear increase of both the numbers and proportion of palliative procedures in consecutive years. Morbidity associated with palliative procedures was 1.8% and there was 1 perioperative death. CONCLUSIONS: 1. There are significant differences in the frequency of palliative procedures performed in the treatment of paediatric brain tumours depending on their location. 2. There was a quantitative and proportional linear growth of frequency of palliative procedures performed over the last 25 years; a wider spectrum of available therapeutic options increased the scope of neurosurgical interventions. 3. Combination of stereotactic, endoscopic and neuronavigational techniques is of considerable benefit in the treatment of brain tumours in children.

Accuracy of intraoperative registration during electromagnetic neuronavigation in intracranial procedures performed in children.

BACKGROUND AND PURPOSE: The aim of the study was to evaluate registration accuracy in an electromagnetic navigation system applied to image-guided intracranial procedures in children. MATERIAL AND METHODS: In a group of 34 children aged from 2 weeks to 17 years, 38 procedures were performed using electromagnetic navigation, including 24 neuroendoscopic procedures, 10 craniotomies, and 4 shunting or drainage procedures. Thirty-three registrations based on 7 to 10 anatomical landmarks were digitised, and three-dimensional models of patients' heads were constructed using magnetic resonance images (MRI) (23 cases) or computed tomography scans (CT) (10 cases) and used for further analysis. Registration error calculated by the system was used as a measure of registration accuracy. RESULTS: Registration error in the study group ranged from 0.7 mm to 4.4 mm (median 2.1 mm, mean 2.24 +/- 0.7 mm). It was shown that registration accuracy increased with patients' age. Differences between mean registration errors in procedures based on MRI or CT studies were not significant. There was no correlation between the number of landmarks registered and registration accuracy. CONCLUSIONS: Electromagnetic neuronavigation, which does not require firm head fixation, can be used in the youngest age group. Nevertheless, registration accuracy is lower in newborns and infants. Neither imaging modality (MRI or CT) used for creation of a three-dimensional model of the patient's head nor registration of more than 6 landmarks have an impact on registration accuracy.

[Osteoblastoma of the dens axis in a 14-year-old boy. A case report]. / Guz zeba kregu obrotowego (osteoblastoma) u 14-letniego chlopca. Opis przypadku.

We present a case of osteoblastoma of C1 in a 14-year-old boy. The case deserves attention because it is a conglomerate of issues important from the point of view of clinical practice. Key issues associated with this interdisciplinary pathology are discussed, such as diagnostic problems, stabilisation of the cervical spine and extensive surgery associated with the risk of severe bleeding in a Jehovah Witness. A short review of pertinent literature is included.

[Treatment results of patients over 3 years of age with medulloblastoma]. / Wyniki leczenia pacjentów powyzej trzeciego roku zycia z medulloblastoma/PNET leczonych wedlug wlasnego protokolu w Instytucie "Pomnik - Centrum Zdrowia Dziecka".

UNLABELLED: THE AIM of the study was to assess the survival of patients with medulloblastoma (MB)/PNET treated according to own protocol and to compare it with the earlier treatment protocol group. MATERIALS AND METHODS: Analysis of 77 patients was undertaken. For the purpose of this study we divided our patients into 2 groups. First group consisted of 34 patients (21 high risk, 12 standard risk, 1 unknown) treated with surgery and radiotherapy and surgery followed by chemo- and radiotherapy. Among the second group including 43 patients (23 HRMB, 6 SRMB, 11 supratentorial PNET's, 3 unknown) treated according to own protocol since 1997. Surgery was performed in all patients. 4 courses of chemotherapy were administered (VCR, VP, CBDCA, CTX, IF, CDDP) and craniospinal irradiation was implemented. Maintenance chemotherapy consisting of 8 courses of VCR, CDDP, CCNU, was given. Event free survival (EFS) in two groups and in high-risk patients of both groups were compared. RESULTS: In the earlier treated group 4 yrs EFS was 50% versus 78% in recently treated patients. In high-risk patients 4 yrs EFS was 40% (with no plateau on the curve) in the historical group and 76% in currently treated. CONCLUSIONS: Introduction of our protocol resulted in marked improvement of treatment results, especially since most of our patients were in the high-risk group.

[Neuroendoscopy in the treatment of third ventricular hydrocephalus accompanying tumors of the posterior part of the third ventricle in children]. / Neuroendoskopia w leczeniu wodoglowia trójkomorowego w przebiegu guzów tylnej czesci komory trzeciej mózgu u dzieci.

OBJECTIVE: The aim of the study was to evaluate the effectiveness of endoscopic third ventriculostomy (ETV) in non-communicating hydrocephalus secondary to tumour of the posterior part of the third ventricle tumours in children. MATERIAL AND METHODS: The study group consisted of 32 patients (13 girls and 19 boys) treated at the Department of Neurosurgery Children's Memorial Health Institute in Warsaw in the years 1996-2000. In 22 cases benign tectal mass (BTM) and 10 malignant neoplasms (including 9 germ cell tumours and 1 ependymoma) were diagnosed. The follow-up period after ETV ranged from 5 months to 4 years (mean 21 months). The retrospective analysis of medical reports and control CTs, MRs, and PC MR-cine studies was performed. RESULTS: In all the patients the early (up to 3 months postop) outcomes were good. 8 patients with malignant neoplasms after initial chemotherapy underwent residual tumor excision (more than 3 months after ETVs) and in two of them the CFS meningeal tumor spreads were detected. In 26 (81%) of the patients permanent control of hydrocephalus was achieved. The recurrence of active hydrocephalus was observed in 6 cases (19%). 3 of them were children with benign tectal masses and 3 with malignant tumours. The reason of failure in 2 cases was associated with meningeal tumor dissemination, and in one with postoperative bleeding after surgical tumor excision (communicating hydrocephalus). In 2 cases with benign tumours reasons of failures were not clear (patent stomies on PC MR-cine) and in 1 case late stomy occlusion on PC-MR flow study was diagnosed. Five out of 6 patients underwent shunt placements and in 1 case with late ventriculostomy occlusion another endoscopic procedure (after 26 months) was successfully performed. CONCLUSIONS: The endoscopic third ventriculostomy was an efficient method to control non-communicating hydrocephalus in children with posterior part of the third ventricle brain tumours. The PC MR flow study was a useful diagnostic tool in the stomy patency evaluation and in further treatment planning in cases of failures. It seems that recurrence of active hydrocephalus can be successfully treated with repeated ETV when the stomy occlusion is detected on MR flow studies. Other cases of failures ought to be treated by shunt implantations.