Anaplastic variant of medulloblastoma mimicking a vestibular schwannoma.
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Adolescent↗
Biomedical subjects
Santosh Kesari
Publications and source records attributed to Santosh Kesari.
Central nervous system metastases from imatinib mesylate resistant gastrointestinal stromal tumor.
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Antineoplastic Agents↗
Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib.
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Antineoplastic Agents↗
The bad seed: PDGF receptors link adult neural progenitors to glioma stem cells.
In this issue of Neuron, Jackson et al. show that adult neural stem cells (B cells) express PDGF receptors. Functional analysis of PDGF signaling in these neural progenitors resonates in provocative ways with an older body of literature on PDGF autocrine loops in malignant glioma and with more recent observations on the bHLH transcription factor Olig2.
Adult↗
Medical management of patients with brain tumors.
The most common medical problems in brain tumor patients include the management of seizures, peritumoral edema, medication side effects, venous thromboembolism (VTE), fatigue and cognitive dysfunction. Despite their importance, there are relatively few studies specifically addressing these issues. There is increasing evidence that brain tumor patients who have not had a seizure do not benefit from prophylactic antiepileptic medications. Patients on corticosteroids are at greater risk of Pneumocystis jerovecii pneumonia and may benefit from prophylactic therapy. There is also growing evidence suggesting that anticoagulation may be more effective than inferior vena cava IVC) filtration devices for treating VTE in brain tumor patients and the risk of hemorrhage with anticoagulation is relatively small. Low-molecular weight heparin may be more effective than coumadin. Medications such as modafinil and methylphenidate have assumed an increasing role in the treatment of fatigue, while donepezil and memantine may be helpful with memory loss.
Adrenal Cortex Hormones↗
Development of NG2 neural progenitor cells requires Olig gene function.
In the adult central nervous system, two distinct populations of glial cells expressing the chondroitin sulfate proteoglycan NG2 have been described: bipolar progenitor cells and more differentiated "synantocytes." These cells have diverse neurological functions, including critical roles in synaptic transmission, repair, and regeneration. Despite their potential importance, the genetic factors that regulate NG2 cell development are poorly understood, and the relationship of synantocytes to the oligodendroglial lineage, in particular, remains controversial. Here, we show that >90% of embryonic and adult NG2 cells express Olig2, a basic helix-loop-helix transcription factor required for oligodendrocyte lineage specification. Analysis of mice lacking Olig function demonstrates a failure of NG2 cell development at embryonic and perinatal stages that can be rescued by addition of a transgene containing the human OLIG2 locus. These findings show a general requirement for Olig function in NG2 cell development and highlight further roles for Olig transcription factors in neural progenitor cells.
Animals↗
Targeted molecular therapy of malignant gliomas.
Malignant gliomas are the most common form of primary brain tumors in adults. Despite advances in diagnosis and standard therapies such as surgery, radiation, and chemotherapy, the prognosis remains poor. Recent scientific advances have enhanced our understanding of the biology of gliomas and the role of tyrosine kinase receptors and signal transduction pathways in tumor initiation and maintenance, such as the epidermal growth factor receptors, platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs such as small molecular inhibitors of these receptors and signaling pathways are showing some activity in initial studies. As we learn more about these drugs and how to optimize their use as single agents and in combination with radiation, chemotherapy, and other targeted molecular agents, they will likely play an increasing role in the management of this devastating disease. This review summarizes the current results with targeted molecular agents in malignant gliomas and strategies under evaluation to increase their effectiveness.
Journal Article↗
Characterization of lymphocytic infiltrates in progressive multifocal leukoencephalopathy: co-localization of CD8(+) T cells with JCV-infected glial cells.
We characterized inflammatory infiltrates in archival brain biopsy and autopsy samples from 26 HIV(+) and 20 HIV(-) patients with progressive multifocal leukoencephalopathy (PML). The predominant inflammatory cells were CD8(+) T lymphocytes. We defined CD8(+) T cell distribution with regard to JCV-infected glial cells, PML lesions and the extent of demyelination. In most samples from either HIV(+) and HIV(-) patients, we found positive correlations between the parenchymal CD8(+) T cells and JCV-infected glial cells and conversely, negative correlations between the perivascular CD8(+) T cells and JCV-infected glial cells in the surrounding brain. Most of these correlations remained significant after accounting for the degree of demyelination and location of the cells relative to lesions. Moreover, high numbers of CD8(+) T cells were found within and at the border of active PML lesions. These results suggest that CD8(+) T cells are primarily associated with JCV-infected glial cells in most PML cases and that an active ongoing recruitment of CD8(+) T cells and possibly viral antigen-specific retention could occur. These observations are discussed in the context of the recent evidence of PML in multiple sclerosis and Crohn's patients treated with natalizumab, underscoring the role of CD8(+) T lymphocytes in continued immunosurveillance of the CNS.
Adult↗
Comparison of linear and volumetric criteria in assessing tumor response in adult high-grade gliomas.
The Response Evaluation Criteria in Solid Tumors, or RECIST criteria (one-dimensional [1D] measurement), are widely used to measure response in tumors, but there are few studies evaluating these criteria in brain tumors. We compared linear and volumetric measurements in adult high-grade supratentorial enhancing gliomas to determine the agreement between measurements, in defining responses and in their subsequent relation to survival. We hypothesized that the 1D RECIST criteria maybe suitable for response assessment in adult high-grade gliomas. Tumor size on MRI scans in 104 patients with high-grade enhancing gliomas treated on clinical trial protocols was measured by using 1D (greatest length), 2D (two-dimensional: product of the two longest perpendicular diameters), 3D (three dimensional: product of the longest perpendicular diameters in one plane and the longest orthogonal diameter to that plane), enhancing volume (EV), and total volume (TV). A total of 388 T1 postgadolinium MRI scans (104 baseline and 284 follow-up scans) were evaluated. Volumetric analysis (EV and TV) was performed with commercially available software. Intraobserver and interobserver correlations (rho) were high for all modalities (rho > 0.92 and rho > 0.71, respectively). Correlation was excellent (rho > 0.9) among all modalities except for 3D (rho < 0.6). Patient response rates ranged from 12% to 26%. Median progression-free survival (mPFS) and six-month progression-free survival (6mPFS) were not significantly different among the methods (range, 5.3 months to 5.9 months and 42% to 48%, respectively). Landmark analyses of response at two months using linear methods predicted overall survival with hazard ratios of 0.19 to 0.29 (P < 0.005). These results suggest high concordance among 1D, 2D, TV, and EV, but not 3D, methods in assessing enhancing tumor progression and in estimating mPFS and 6mPFS in adult brain tumor patients. The tumor response at two months assessed by linear methods correlated better with overall survival. Thus, linear methods are comparable to volumetric methods, but simpler to implement for routine clinical use and for designing clinical trials of brain tumors.
Adult↗
Malignant gliomas: strategies to increase the effectiveness of targeted molecular treatment.
Recently, there has been increasing interest in the use of targeted molecular agents for the treatment of malignant gliomas. These agents are generally well tolerated but have demonstrated only modest activity. In this article, the current status of targeted molecular agents for malignant gliomas will be reviewed and strategies to improve their effectiveness will be discussed.
Brain Neoplasms↗
Targeted molecular therapy of malignant gliomas.
Malignant gliomas are the most common form of primary brain tumors in adults. Despite advances in diagnosis and standard therapies such as surgery, radiation, and chemotherapy, the prognosis remains poor. Recent scientific advances have enhanced our understanding of the biology of gliomas and the role of tyrosine kinase receptors and signal transduction pathways in tumor initiation and maintenance, such as the epidermal growth factor receptors, platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs such as small molecular inhibitors of these receptors and signaling pathways are showing some activity in initial studies. As we learn more about these drugs and how to optimize their use as single agents and in combination with radiation, chemotherapy, and other targeted molecular agents, they will likely play an increasing role in the management of this devastating disease. This review summarizes the current results with targeted molecular agents in malignant gliomas and strategies under evaluation to increase their effectiveness.
Angiogenesis Inhibitors↗
Brain metastases.
PURPOSE OF REVIEW: Brain metastases occur in 10-30% of cancer patients, and they are associated with a dismal prognosis. Radiation therapy has been the mainstay of treatment for patients without surgically treatable lesions. For patients with good prognostic factors and a single metastasis, surgical resection is recommended. The management of patients with multiple metastases, poor prognostic factors, or unresectable lesions is, however, controversial. Recently published data will be reviewed. RECENT FINDINGS: Radiation therapy has been shown to substantially reduce the risk of local recurrence after surgical resection of brain metastases, although this does not translate into improved survival. Recently, stereotactic radiosurgery has emerged as an increasingly important alternative to surgery that appears to be associated with less morbidity and similar outcomes. Other potentially promising therapies under investigation include interstitial brachytherapy, new chemotherapeutic agents that cross the blood-brain barrier, and targeted molecular agents. SUMMARY: Patients with brain metastases are now eligible for a number of treatment options that are increasingly likely to improve outcomes. Randomized, prospective trials are necessary to better define the utility of radiosurgery versus surgery in the management of patients with brain metastases. Future investigations should address quality of life and neurocognitive outcomes, in addition to traditional outcome measures such as recurrence and survival rates. The potentially substantial role for chemotherapeutics that cross the blood-brain barrier and for novel targeted molecular agents is now being elucidated.
Antineoplastic Agents↗
Digital rendition of visual migraines.
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Adult↗
Malignant gliomas.
Malignant gliomas are the most common type of primary brain tumor. Although therapy for patients with these tumors remains limited, there has been important progress recently. In this review, some of these advances are discussed, with an emphasis on targeted molecular therapies.
Antineoplastic Agents↗
Therapy for recurrent malignant glioma in adults.
Malignant gliomas are the most common form of primary brain tumors in adults. Although the prognosis remains poor, there has been recent progress in the treatment of these tumors. Standard therapy for patients with this disease will be reviewed, together with more novel approaches such as targeted molecular therapies, angiogenesis inhibitors, immunotherapies, gene therapies and intratumoral therapies.
Adult↗
Leptomeningeal metastases.
LM is an increasingly common neurologic complication of cancer with variable clinical manifestations. Although there are no curative treatments, currently available therapies can preserve neurologic function and potentially improve quality of life. Further research into the mechanisms of leptomeningeal metastasis will elucidate molecular and cellular pathways that may allow identification of potential targets to interrupt this process early or to prevent this complication. Animal models are needed to further define the pathophysiology of LM and to provide an experimental system to test novel treatments [242-245]. There is an urgent need to develop new drug-based or radiation-based treatments for patients with LM. Randomized clinical trials are the appropriate study design to determine the efficacy of new treatments for LM. However, surrogate markers for response must be developed to facilitate the identification of effective regimens. Survival is not the optimal end point for such studies as most patients who develop this complication already have advanced, incurable cancer. Prevention of or delay in neurologic progression is one objective that has been utilized in recent randomized trials in patients with LM, and this end point deserves further attention. Although the development of LM represents a poor prognostic marker in patients with cancer it is important for physicians to recognize the symptoms and signs of the disease and establish the diagnosis as early in the disease course as possible. This may provide an opportunity for effective intervention that can improve quality of life, prevent further neurologic deterioration and, for a subset of patients, improve survival.
Humans↗