We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, ...these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299) and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.
Objective
To retrospectively evaluate the clinical outcome of six patients with skull base hemangiopericytomas (HPCs) and that of a cohort of 37 similar patients identified by a systematic review of ...the literature.
Methods
The series constitutes of three men and three women with newly diagnosed skull base HPC who underwent multimodal treatment including surgery, external beam radiotherapy (EBRT) and pre-operative embolization. Furthermore, a systematic review off the literature identified 37 reports of primarily intracranial skull base HPCs.
Results
Four patients had a gross total resection (GTR) and two patients had a near total resection. Five patients were referred for adjuvant EBRT with a survival ranging from 15 to 47 months. All patients had an excellent outcome and resumed their previous activities. Literature review identified 37 additional patients with skull base HPC. Altogether, tumors were unevenly distributed above and below tentorium. GTR was achieved in half the patients, and 72.1% were referred to EBRT. Out of 37 reported patients in the literature, survival longer than 1 year was described in only 24. Within the combined cohort including the present series, survival was 83.6 months.
Conclusions
The present series shows that a radical resection of HPC can be achieved under the difficult anatomical conditions of skull base surgery. Pre-operative arterial embolization may be instrumental to maintain a clear visual field and prevent excessive blood loss. Finally, the results of the present cohort suggest that EBRT may be useful for local growth control, as an effective palliative measure for skull base HPCs.
Cerebral edema represents a major threat following traumatic brain injury. However, therapeutic measures for control of intracranial pressure alone have failed to restore cerebral metabolism and ...improve neurological outcome. Since mitochondrial damage results in ATP depletion and deactivation of membrane ionic pumps, we hypothesized that modulation of ATP bioavailability may directly affect cytotoxic edema. Intracranial pressure measurements were performed in Sprague-Dawley rats treated by intraperitoneal injection of dimethylsulfoxide (vehicle), cyclosporine A (CsA), or Oligomycin B (OligB) following cortical contusion and further correlated with water content, mitochondrial damage, and electron microscopic assessment of neuronal and axonal edema. As hypothesized, ultra-structural figures of edema closely correlated with intracranial pressure elevation, increased water content and mitochondrial membrane permeabilization expressed by loss of transmembrane mitochondrial potential. Further, mitochondrial damage evidenced ultra-structurally by figures of swollen mitochondria with severely distorted cristae correlated with both cytotoxic edema and mitochondrial dysfunction. Importantly, cerebral edema and mitochondrial impairment were significantly worsened by treatment with OligB, whereas a noticeable improvement could be observed in animals that received injections of CsA. Since OligB and CsA are responsible for symmetrical and opposite effects on oxidative metabolism, these findings support the hypothesis of a causative relationship between edema and mitochondrial function.
Objective Pregnancy is associated with substantial changes in the maternal circulatory physiology. Our aim was to investigate maternal cerebral blood flow (CBF) during normal pregnancies. Study ...Design We prospectively measured maternal CBF in 210 low-risk pregnant women at different gestational ages, and in 15 nonpregnant women. CBF was assessed by measuring blood flow volume in the internal carotid artery (ICA) by dual-beam angle-independent digital Doppler ultrasound. Results ICA blood flow volume increased during pregnancy from 318 mL/min ± 40.6 mL/min in the first trimester to 382.1 mL/min ± 50.0 mL/min during the third trimester, corresponding to CBF values of 44.4 and 51.8 mL/min–1 /100 g–1 , respectively ( P < .0001). CBF changes were associated with progressive decrease in cerebral vascular resistance and moderate increase in ICA diameter. Conclusion Maternal CBF is gradually increasing during normal pregnancy. Vasorelaxing impact of estrogens and other factors on cerebral vessels may explain the changes in CBF during pregnancy.
Abstract Recent experimental data have shown that hyperbaric oxygen therapy (HBOT) was associated increased Bcl-2 expression at the injury site that correlated with reduced apoptosis. We hypothesized ...that HBOT mediated enhancement of Bcl-2 expression and increased intracellular oxygen bio-availability may both contribute to preserve mitochondrial integrity and reduce the activation of the mitochondrial pathway of apoptosis. For this purpose, a cortical lesion was created in the parietal cortex of Sprague–Dawley rats by dynamic cortical deformation (DCD) and outcome measures in non-treated animals were compared with that of HBOT treated rats. Morphological analysis showed a profound reduction in neuronal counts in the perilesional area and a marked rarefaction of the density of the axonal–dentritic network. In treated animals, however, there was a significant attenuation of the impact of DCD over perilesional neurons, characterized by significantly higher cell counts and denser axonal network. In mitochondria isolated from injured brain tissue, there was a profound loss of mitochondrial transmembrane potential (ΔψM ) that proved to be substantially reversed by HBOT. This finding correlated with a significant reduction of caspases 3 and 9 activation in HBOT treated animals but not of caspase 8, indicating a selective effect over the intrinsic pathway of apoptosis. All together, our results indicate that the neuroprotective effect of HBOT may represent the consequence of preserved mitochondrial integrity and subsequent inhibition of the mPTP and reduction of the mitochondrial pathway of apoptosis.
Objective
The purpose of the study was to define and identify prognostic indicators within an elderly population of patients suffering from intracranial meningiomas. The clinical presentation of the ...patient with meningioma is diverse, manifesting as a different clinical entity in the elderly patient compared to a similar type of tumor in a young patient.
Methods
Two hundred fifty patients aged over 65 years admitted to RAMBAM Medical Center with meningiomas from 1995–2005 were characterized. We report the presenting symptoms, chronic illnesses, perioperative and long-term follow-up results for a 5-year period.
Results
Based on univariate and multivariate analysis, significant prognostic indicators were identified and were implemented into a new geriatric scoring system (GSS) including tumor size and location, peritumoral edema, neurological deficits, Karnofsky score (Clancey J Neurosci Nurs 27:220,
1995
; Crooks et al. J Gerontol 46:M139–M144,
1991
), and associated diabetes, hypertension or lung disease. Seven outcome parameters were retrospectively tested using the scoring system, namely mortality, Barthel Index score (Mahoney and Barthel Md State Med J 14:61–65,
1965
), Karnofsky score and consciousness expressed by the Glasgow Coma Scale score (Jennett and Bond Lancet 1:480–484,
1975
) 5 years after surgery, as well as recurrence within and beyond 12 months. Age proved to inversely correlate with outcome. Morbidity and mortality were significantly lower in women. The extent of surgical resection (Simpson J Neurol Neurosurg Psychiatry 20:22–39,
1957
) had no influence on functional outcome, although radical resection was associated with significantly lower mortality. Generally, a GSS score higher than 14 was associated with a significantly more favorable outcome.
Conclusion
The present results suggest that common experience-based considerations may be optimized and implemented into a simple scoring system that in turn may allow for outcome prediction and evidence-based decision making.
Abstract
OBJECTIVE
Decompressive craniectomy (DC) is a common practice for control of intracranial pressure (ICP) following traumatic brain injury (TBI), although the impact of this procedure on the ...fate of operated patients is still controversial.
METHODS
Cerebral blood flow (CBF) and metabolic rates were monitored prospectively and daily as a surrogate of neuronal viability in 36 TBI patients treated by DC and compared with those of 86 nonoperated patients. DC was performed either on admission (n = 29) or within 48 hours of admission (n = 7).
RESULTS
DC successfully controlled ICP levels and maintained CBF within a normal range although the cerebral metabolic rate of oxygen (CMRO2) was significantly lower in this group. In 7 patients, pre- and postoperative recordings showed a significant ICP decrease that correlated with CBF augmentation but not with concurrent improvement of CMRO2 that remained particularly low. Logistic regression analysis of all investigated variables showed that DC was not associated with higher mortality despite more severe injuries in this group. However, operated patients were 7-fold more likely to have poor functional outcomes than nonoperated patients. Good functional outcome was strongly associated with higher CMRO2 but not with higher CBF values. CMRO2 levels were significantly lower in the DC group, even after adjustment for injury severity, and showed a progressive and sustained trend of deterioration significantly different from that of the non-DC group.
CONCLUSION
These results suggest that DC may enhance survival in the presence of severe brain swelling, although it is unlikely to represent an adequate answer to mitochondrial damage responsible for cellular energy crisis and edema.
Peripheral benzodiazepine receptors (PBR) are widely distributed in peripheral tissues, astrocytes, and microglia of the brain. They are involved in apoptosis, proliferation, and many other ...processes, such as steroidogenesis in adrenal glands, male and female gonads, biological adaptation to stress, etc. It has been established that the expression of PBR in astrocytomas is higher than in the normal brain. The goal of this study was to explore the correlation of the immunohistochemical expression of PBR in astrocytomas with the grade of malignancy and rates of apoptosis, proliferation and survival. In 130 cases of astrocytomas (25 grade I, 25 grade II, 20 grade III, 60 grade IV), paraffin sections were stained immunohistochemically for PBR and MIB-1(Ki-67). TUNEL assay was used for evaluation of apoptosis. It was found that the intensity and extent of staining for PBR had a strong direct correlation with the grade of malignancy of the tumor, along with proliferative and apoptotic indices. The highest expression of PBR was in glioblastomas grade IV, especially around areas of necrosis. There was a strong negative correlation between PBR expression and survival. The results of this study may be applied in the pathological diagnosis of astrocytomas as an additional clue in establishing tumor grade; they may be used in the imaging of astrocytomas, both for diagnosis and follow-up, by the application of positron emission tomography scanning with PBR specific ligands. Targeting of PBR in high-grade gliomas may be a promising approach, achieving more specific anti-tumor effect.
Background
Intracranial pressure (ICP) monitoring has been for decades a cornerstone of traumatic brain injury (TBI) management. Nevertheless, in recent years, its usefulness has been questioned in ...several reports. A group of neurosurgeons and neurointensivists met to openly discuss, and provide consensus on, practical applications of ICP in severe adult TBI.
Methods
A consensus conference was held in Milan on October 5, 2013, putting together neurosurgeons and intensivists with recognized expertise in treatment of TBI. Four topics have been selected and addressed in pro-con presentations: 1) ICP indications in diffuse brain injury, 2) cerebral contusions, 3) secondary decompressive craniectomy (DC), and 4) after evacuation of intracranial traumatic hematomas. The participants were asked to elaborate on the existing published evidence (without a systematic review) and their personal clinical experience. Based on the presentations and discussions of the conference, some drafts were circulated among the attendants. After remarks and further contributions were collected, a final document was approved by the participants.
Summary and conclusions
The group made the following recommendations: 1) in comatose TBI patients, in case of normal computed tomography (CT) scan, there is no indication for ICP monitoring; 2) ICP monitoring is indicated in comatose TBI patients with cerebral contusions in whom the interruption of sedation to check neurological status is dangerous and when the clinical examination is not completely reliable. The probe should be positioned on the side of the larger contusion; 3) ICP monitoring is generally recommended following a secondary DC in order to assess the effectiveness of DC in terms of ICP control and guide further therapy; 4) ICP monitoring after evacuation of an acute supratentorial intracranial hematoma should be considered for salvageable patients at increased risk of intracranial hypertension with particular perioperative features.
Background: As an expected consequence of the civil war in Syria, emergent neurosurgical care for battlefield trauma has been provided for severely head-injured Syrians transferred to Northern ...Israel.
Methods: Sixty-six patients suffering from brain injury were brought to the border and then referred to the institution after initial resuscitation. Both the time and type of injury were recorded based on paramedic testimony, forensic material or on details provided by patients. A retrospective analysis of all medical charts and imaging material was performed.
Results: Most injuries were combat-related, either caused by blast (13.6%), shrapnel (24.2%), assault (28.8%) or gunshot wound (15.2%). Only a minority of patients (18.2%) suffered from injuries that were not directly caused by weapon. A total of 55 surgical procedures were performed in 46 out of 66 patients, including craniotomies in 40 patients, burr hole alone for placement of intraparenchymal intracranial pressure (ICP) sensor in nine instances and ventricle peritoneal shunt in two patients. Decompressive craniectomy was used only for the treatment of gunshot wound and was performed in eight out of 10 patients. The most common complication consisted in cerebrospinal fluid fistulas (16.7%). Post-operative infections occurred in seven patients (10.6%). Short-term outcomes were favourable in 60.7%, with a mortality rate of 4.5%.
Discussion: The present findings suggest that aggressive surgery and neuro-intensive care measures may lead to good functional results, even in the presence of seemingly devastating injuries in some selected patients.
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