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Biopsy vs. extensive resection for first recurrence of glioblastoma: is a prospective clinical trial warranted? - BMC research notes
Glioblastoma is an aggressive and almost universally fatal tumor. The prognosis at the time of recurrence has generally been poor, with overall survival typically in the range of 4-40Â weeks. The merits of surgical resection (vs. open biopsy, to confirm recurrence via histology) in addition to conventional adjuvant chemotherapy have been the subject of longstanding debate. We wondered whether it would possible to conduct a trial at our institution to settle this question definitively with Class I evidence.Initially, we had hoped to conduct a randomized, unblinded prospective clinical trial. However on closer inspection it appeared that such an undertaking would pose significant practical challenges. Thus we present our protocol in draft form. In keeping with recommended outcomes for these tumors, the primary endpoint would be median progression free survival. Secondary end points would be: median overall survival (mOS, from time of recurrence) and change in Karnofsky Performance Status over time. Patients would be eligible at the time of first recurrence if they had received conventional treatment until that point and at least 1Â month had elapsed since the time of radiation. All patients would be considered potentially eligible for enrollment (unless the decision regarding resection was already clear-cut in view of other factors). Using Cox's proportional hazards model, we estimate that at least 456 patients would be necessary to demonstrate an increase in the hazard ratio to 1.3 for those undergoing biopsy alone. This magnitude of benefit is estimated based on a review of retrospective studies.If restricted to our Institution alone, which sees approximately 100-150 new cases of glioblastoma each year, a trial of this nature would be likely to take around 10Â years. Furthermore, there may be significant reluctance on the part of patients and physicians to participate. There is also the opportunity cost of excluding patients from other trials to consider. We recognize that the estimate of the magnitude of effect may be conservative. As things stand, we feel that multi-institutional collaboration would almost certainly be required for an undertaking of this kind.
The SVZ and Its Relationship to Stem Cell Based Neuro-oncogenesis. - Advances in experimental medicine and biology
Gliomas are primary cancers of the brain and the most lethal cancers known to man. In recent years the discovery of germinal regions in the postnatal brain containing neuronal stem and progenitor cell populations has led to the hypothesis that these cells may themselves serve as an origin of brain tumors. Stem cells that reside within the glioma tumor have been shown to display nonneoplastic stem-like characteristics, including expression of various stem cell markers, as well as capacity for self-renewal and multipotency. Furthermore, glioma tumors display marked similarities to the germinal regions of the brain. Investigations of human neural stem cells and their potential for malignancy may finally identify a cell-of-origin for human gliomas. This, in turn, may facilitate better therapeutic targeting leading to improved prognosis for glioma patients.
Comparing high-resolution microscopy techniques for potential intraoperative use in guiding low-grade glioma resections. - Lasers in surgery and medicine
Fluorescence image-guided surgery (FIGS), with contrast provided by 5-ALA-induced PpIX, has been shown to enable a higher extent of resection of high-grade gliomas. However, conventional FIGS with low-power microscopy lacks the sensitivity to aid in low-grade glioma (LGG) resection because PpIX signal is weak and sparse in such tissues. Intraoperative high-resolution microscopy of PpIX fluorescence has been proposed as a method to guide LGG resection, where sub-cellular resolution allows for the visualization of sparse and punctate mitochondrial PpIX production in tumor cells. Here, we assess the performance of three potentially portable high-resolution microscopy techniques that may be used for the intraoperative imaging of human LGG tissue samples with PpIX contrast: high-resolution fiber-optic microscopy (HRFM), high-resolution wide-field microscopy (WFM), and dual-axis confocal (DAC) microscopy.Thick unsectioned human LGG tissue samples (nâ€‰=â€‰7) with 5-ALA-induced PpIX contrast were imaged using three imaging techniques (HRFM, WFM, DAC). The average signal-to-background ratio (SBR) was then calculated for each imaging modality (5 images per tissue, per modality).HRFM provides the ease of use and portability of a flexible fiber bundle, and is simple and inexpensive to build. However, in most cases (6/7), HRFM is not capable of detecting PpIX signal from LGGs due to high autofluorescence, generated by the fiber bundle under laser illumination at 405â€‰nm, which overwhelms the PpIX signal and impedes its visualization. WFM is a camera-based method possessing high lateral resolution but poor axial resolution, resulting in sub-optimal image contrast.Consistent successful detection of PpIX signal throughout our human LGG tissue samples (nâ€‰=â€‰7), with an acceptable image contrast (SBR >2), was only achieved using DAC microscopy, which offers superior image resolution and contrast that is comparable to histology, but requires a laser-scanning mechanism to achieve optical sectioning.Â© 2015 Wiley Periodicals, Inc.
Postnatal growth of the human pons: a morphometric and immunohistochemical analysis. - The Journal of comparative neurology
Despite its critical importance to global brain function, the postnatal development of the human pons remains poorly understood. In the present study, we first performed magnetic resonance imaging (MRI)-based morphometric analyses of the postnatal human pons (0-18 years; n = 6-14/timepoint). Pons volume increased 6-fold from birth to 5 years, followed by continued slower growth throughout childhood. The observed growth was primarily due to expansion of the basis pontis. T2-based MRI analysis suggests that this growth is linked to increased myelination, and histological analysis of myelin basic protein in human postmortem specimens confirmed a dramatic increase in myelination during infancy. Analysis of cellular proliferation revealed many Ki67(+) cells during the first 7 months of life, particularly during the first month, where proliferation was increased in the basis relative to tegmentum. The majority of proliferative cells in the postnatal pons expressed the transcription factor Olig2, suggesting an oligodendrocyte lineage. The proportion of proliferating cells that were Olig2(+) was similar through the first 7 months of life and between basis and tegmentum. The number of Ki67(+) cells declined dramatically from birth to 7 months and further decreased by 3 years, with a small number of Ki67(+) cells observed throughout childhood. In addition, two populations of vimentin/nestin-expressing cells were identified: a dorsal group near the ventricular surface, which persists throughout childhood, and a parenchymal population that diminishes by 7 months and was not evident later in childhood. Together, our data reveal remarkable postnatal growth in the ventral pons, particularly during infancy when cells are most proliferative and myelination increases.Â© 2014 Wiley Periodicals, Inc.
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFÎ± in glioblastoma. - Science signaling
Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-Î± (TNFÎ±) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFÎ±-dependent activation of the transcription factor nuclear factor ÎºB (NF-ÎºB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.Copyright Â© 2014, American Association for the Advancement of Science.
Trends in fluorescence image-guided surgery for gliomas. - Neurosurgery
Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low-grade and high-grade glioma patients. However, radiographically complete resections are not often achieved in many cases because of the lack of sensitivity and specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas. Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins. Here, we provide a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care.
Predictors of functional recovery in adults with posterior fossa ependymomas. - Journal of neurosurgery
After complete resection and radiation therapy, the 10-year overall survival rates for adult patients with posterior fossa ependymomas approach 85%. This favorable outcome profile emphasizes the critical importance of functional preservation to this patient population. Here, the authors identify predictors of functional outcome following microsurgical resection of adult posterior fossa ependymomas.The authors identified adult patients with newly diagnosed WHO Grade II posterior fossa ependymomas who underwent microsurgical resection at the Barrow Neurological Institute from 1990 to 2011. Clinical and radiographic variables were collected, including volumetric extent of resection, foramen of Luschka extension, cystic changes, peritumoral T2 signal changes, Karnofsky Performance Scale (KPS) score, National Institutes of Health Stroke Scale (NIHSS) score, progression-free survival (PFS), and overall survival (OS).Forty-five patients were identified, with a median clinical follow-up of 103 months. The median PFS and OS were 6.8 and 8.6 years, respectively. Extent of resection and adjuvant radiotherapy were predictive of improved PFS (p = 0.005) and were nonsignificantly associated with improved OS. Univariate analysis revealed that tumor size (p < 0.001), cystic changes (p < 0.01), postoperative T2 signal (p < 0.01), and CSF diversion (p = 0.048) predicted functional and neurological recovery rates, based on KPS and NIHSS scores, respectively. Multivariate regression analysis identified tumor size (p < 0.001), cystic changes (p = 0.01), and CSF diversion (p = 0.02) as independent predictors of slower functional recovery, while only tumor size (p = 0.007) was an independent predictor of neurological recovery. Specifically, by 6 weeks postoperatively, baseline KPS score was recovered by only 43.8% of patients with tumors larger than 30 cm(3) (vs 72.4% patients with tumors < 30 cm(3)), 35.3% of patients with cystic tumors (vs 78.6% of patients with noncystic tumors), and 46.7% of patients requiring CSF diversion (vs 70% of patients not requiring CSF diversion).Greater extent of resection and adjuvant radiotherapy significantly improve PFS in adult patients with posterior fossa ependymomas. Tumor size, cystic changes, and the need for CSF diversion were independent predictors of the rate of functional recovery in this patient population. Taken together, these functional outcome predictors may guide preoperative estimations of recovery following microsurgical resection.
An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity. - Journal of neurosurgery
Despite improvements in the medical and surgical management of patients with glioblastoma, tumor recurrence remains inevitable. For recurrent glioblastoma, however, the clinical value of a second resection remains uncertain. Specifically, what proportion of contrast-enhancing recurrent glioblastoma tissue must be removed to improve overall survival and what is the neurological cost of incremental resection beyond this threshold?The authors identified 170 consecutive patients with recurrent supratentorial glioblastomas treated at the Barrow Neurological Institute from 2001 to 2011. All patients previously had a de novo glioblastoma and following their initial resection received standard temozolomide and fractionated radiotherapy.The mean clinical follow-up was 22.6 months and no patient was lost to follow-up. At the time of recurrence, the median preoperative tumor volume was 26.1 cm(3). Following re-resection, median postoperative tumor volume was 3.1 cm(3), equating to an 87.4% extent of resection (EOR). The median overall survival was 19.0 months, with a median progression-free survival following re-resection of 5.2 months. Using Cox proportional hazards analysis, the variables of age, Karnofsky Performance Scale (KPS) score, and EOR were predictive of survival following repeat resection (p = 0.0001). Interestingly, a significant survival advantage was noted with as little as 80% EOR. Recursive partitioning analysis validated these findings and provided additional risk stratification at the highest levels of EOR. Overall, at 7 days after surgery, a deterioration in the NIH stroke scale score by 1 point or more was observed in 39.1% of patients with EOR â‰¥ 80% as compared with 16.7% for those with EOR < 80% (p = 0.0049). This disparity in neurological morbidity, however, did not endure beyond 30 days postoperatively (p = 0.1279).For recurrent glioblastomas, an improvement in overall survival can be attained beyond an 80% EOR. This survival benefit must be balanced against the risk of neurological morbidity, which does increase with more aggressive cytoreduction, but only in the early postoperative period. Interestingly, this putative EOR threshold closely approximates that reported for newly diagnosed glioblastomas, suggesting that for a subset of patients, the survival benefit of microsurgical resection does not diminish despite biological progression.
Epileptic seizures in diffuse low-grade gliomas in adults. - Brain : a journal of neurology
Diffuse low-grade gliomas are highly epileptogenic brain tumours. We aimed to explore the natural course of epileptic seizures, their predictors and the prognostic significance of their occurrence in adult patients harbouring a diffuse low-grade glioma. An observational retrospective multicentre study examined 1509 patients with diffuse low-grade gliomas to identify mutual interactions between tumour characteristics, tumour course and epileptic seizures. At diagnosis, 89.9% of patients had epileptic seizures. Male gender (P = 0.003) and tumour location within functional areas (P = 0.001) were independent predictors of a history of epileptic seizures at diagnosis. Tumour volume, growth velocity, cortical location, histopathological subtype or molecular markers did not significantly affect epileptic seizure occurrence probability. Prolonged history of epileptic seizures (P < 0.001), insular location (P = 0.003) and tumour location close to functional areas (P = 0.038) were independent predictors of uncontrolled epileptic seizures at diagnosis. Occurrence of epileptic seizures (P < 0.001), parietal (P = 0.029) and insular (P = 0.002) locations were independent predictors of uncontrolled epileptic seizures after oncological treatment. Patient age (P < 0.001), subtotal (P = 0.007) and total (P < 0.001) resections were independent predictors of total epileptic seizure control after oncological treatment. History of epileptic seizures at diagnosis and total surgical resection were independently associated with increased malignant progression-free (P < 0.001 and P < 0.001) and overall (P < 0.001 and P = 0.016) survivals. Epileptic seizures are independently associated with diffuse low-grade glioma prognosis. Patients diagnosed with epileptic seizures and those with complete and early surgical resections have better oncological outcomes. Early and maximal surgical resection is thus required for diffuse low-grade gliomas, both for oncological and epileptological purposes.
The impact of extent of resection on malignant transformation of pure oligodendrogliomas. - Journal of neurosurgery
Recent evidence suggests that a greater extent of resection (EOR) extends malignant progression-free survival among patients with low-grade gliomas (LGGs). These studies, however, rely on the combined analysis of oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas-3 histological subtypes with distinct genetic and molecular compositions. To assess the value of EOR in a homogeneous LGG patient population and delineate its impact on LGG transformation, the authors examined its effect on newly diagnosed supratentorial oligodendrogliomas.The authors identified 93 newly diagnosed adult patients with WHO Grade II oligodendrogliomas treated with microsurgical resection at Barrow Neurological Institute. Clinical, laboratory, and radiographic data were collected retrospectively, including 1p/19q codeletion status and volumetric analysis based on T2-weighted MRI.The median preoperative and postoperative tumor volumes and EOR were 29.0 cm(3) (range 1.3-222.7 cm(3)), 5.2 cm(3) (range 0-156.1 cm(3)), and 85% (range 6%-100%), respectively. Median follow-up was 75.4 months, and there were 14 deaths (15%). Progression and malignant progression were identified in 31 (33%) and 20 (22%) cases, respectively. A greater EOR was associated with longer overall survival (p = 0.005) and progression-free survival (p = 0.004); however, a greater EOR did not prolong the interval to malignant progression, even when controlling for 1p/19q codeletion.A greater EOR is associated with an improved survival profile for patients with WHO Grade II oligodendrogliomas. However, for this particular LGG patient population, the interval to tumor transformation is not influenced by cytoreduction. These data raise the possibility that the capacity for microsurgical resection to modulate malignant progression is mediated through biological mechanisms specific to nonoligodendroglioma LGG histologies.
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