Biomedical subjects

Frederick F Lang

Publications and source records attributed to Frederick F Lang.

43 records · Page 3Linked to original sources

PubMed2002

Apoptosis induced by adenovirus-mediated p53 gene transfer in human glioma correlates with site-specific phosphorylation.

Therapeutic replacement of the p53 gene using an adenovirus vector (Ad-p53) may be an effective alternative to conventional therapies for the treatment of glioma. We have previously demonstrated that the introduction of Ad-p53 into glioma cells containing mutant p53 induces apoptosis, whereas glioma cells containing wild-type p53 are resistant. However, Ad-p53 will enhance the radiosensitivity of wild-type p53 glioma cells by increasing their tendency for apoptosis. The mechanism underlying these different responses to Ad-p53 has not been elucidated to date. Because phosphorylation of p53 at serines 15, 20, and 392 may play a role in regulating p53-mediated apoptotic activity, we determined the phosphorylation status of exogenous p53 in mutant and wild-type gliomas after Ad-p53 transfer. Monolayer cultures of glioma cell lines expressing mutant p53 (U251 and U373) or wild-type p53 (U87 and D54) were infected with Ad-p53 and analyzed by Western blotting. High levels of exogenous p53 were detected in both cell lines after Ad-p53 transfer. However, only apoptotic mutant p53 cells expressed high levels of phospho-Ser15-p53 and phospho-Ser20-p53. The levels of phospho-Ser15-p53 and phospho-Ser20-p53 were very low in wild-type p53 cells after Ad-p53 infection alone. When wild-type p53 glioma cells were exposed to radiation after Ad-p53 infection, phospho-Ser15-p53 and phospho-Ser20-p53 were detected at high levels, and the cells subsequently underwent apoptosis; no change in serine 392 was detected. The induction of apoptosis and the expression of phospho-Ser15 and phospho-Ser20 in these cells were also enhanced by the combination of Ad-p53 and other DNA-damaging agents such as cisplatin and bichloroethyl nitrosourea. Furthermore, the expression of phospho-Ser15-p53 and phospho-Ser20-p53 correlated with the amount of apoptosis; the apoptotic activity of p53 in glioma cells was partially inhibited by a mutation of p53 at serine 15. These results suggest that phosphorylation of p53 at serine 15 and serine 20 is critical for apoptosis induction in p53 gene therapy for gliomas.

Adenoviridae↗

PubMed2002

Visual-spatial neglect in a child following sub-cortical tumor resection.

Although clinical syndromes of visual-spatial neglect have been well described in adults, clinical features of neglect associated with subcortical dysfunction are infrequently reported in children and have not been described in detail. Unilateral visual-spatial neglect in a 7-year-old male following removal of a right subcortical juvenile pilocytic astrocytoma is reported. Preoperative baseline neurocognitive assessment of the patient established intact attentional and intellectual functioning. Postoperatively visual-spatial neglect was observed that was not accounted for by the patient's visual field deficit. Consistent with classic features of attentional neglect, increases in attentional demands led to greater errors in performance. The risk of unilateral neglect following resection of subcortical tumors that abut the thalamus or disrupt thalamo-cortical projections was confirmed in a retrospective analysis of patients referred for neurocognitive testing at our site. It was concluded that the ventral thalamus may play a role in visual-spatial attention early in development.

Astrocytoma↗

PubMed2002

Toward better early-phase brain tumor clinical trials: a reappraisal of current methods and proposals for future strategies.

Although no optimal treatment is currently available for malignant brain tumors, as the molecular mechanisms underlying brain tumor development have been delineated, new chemotherapeutic agents that act directly on specific molecular targets have become available. Defining a specific molecular target raises the possibility that the molecular effects of a given agent can be analyzed in patients in a clinical trial. Specifically, whereas standard phase I and II clinical trials classically determine the safety and efficacy of agents by using indirect global end points, these new biological agents afford the opportunity to incorporate molecular end points into phase I and II clinical trials to determine whether the agent under investigation is actually doing what it was intended to do. This work presents avenues for improving current brain tumor clinical trial designs based on the molecular specificity of new agents and the unique features of brain tumors. Specifically, the authors recommend brain-applicable phase I and II clinical trial strategies that take advantage of the targeted nature of new agents to maximize information about their efficacy, toxicity, and molecular effects.

Brain Neoplasms↗

PubMed2002

Necrosis and glioblastoma: a friend or a foe? A review and a hypothesis.

OBJECTIVE: Two main forms of cell death are encountered in biology: apoptosis (i.e., programmed cell death) and necrosis (i.e., accidental cell death). Because necrosis and apoptosis can lead to cell removal, one might intuit that they are both desirable in cancer treatment. However, in the setting of glioblastoma multiforme, a malignant brain tumor for which the presence of necrosis is an important diagnostic feature, clinical studies indicate that as the degree of necrosis advances, the patient's prognosis worsens. Despite the apparent importance of this form of cell death, the mechanism of development of necrosis in glioblastomas remains unelucidated. The purpose of this article is to try to resolve this dilemma by hypothesizing the mechanism of necrosis formation in these tumors. METHODS: On the basis of an extensive review of the literature, we present a hypothesis for the mechanism of necrosis formation in glioblastoma multiforme. RESULTS: One of the many possible pathways leading to necrosis formation may involve increased tumor cell secretion of tumor necrosis factor. Procoagulation and antiapoptotic mechanisms resulting from certain pathways could prevent the completion of tumor necrosis factor-induced apoptosis and could promote necrosis as the final mode of cell death. Such a hypothesis would explain the inverse correlation that exists between tumor necrosis and the survival of patients with glioblastomas, because the hypoxia that results from procoagulation selects for tumor cells that are more aggressive and more resistant to apoptosis-inducing therapies. CONCLUSION: A complete understanding of the series of events surrounding necrosis development in glioblastomas that is evidence-based is likely to provide targets for future therapies. On the basis of the potential mechanisms of development of necrosis described in this article, we postulate that effective therapies may have to be directed against the pathways that result in the formation of necrosis.

Apoptosis↗

PubMed2002

PTV margin determination in conformal SRT of intracranial lesions.

The planning target volume (PTV) includes the clinical target volume (CTV) to be irradiated and a margin to account for uncertainties in the treatment process. Uncertainties in miniature multileaf collimator (mMLC) leaf positioning, CT scanner spatial localization, CT-MRI image fusion spatial localization, and Gill-Thomas-Cosman (GTC) relocatable head frame repositioning were quantified for the purpose of determining a minimum PTV margin that still delivers a satisfactory CTV dose. The measured uncertainties were then incorporated into a simple Monte Carlo calculation for evaluation of various margin and fraction combinations. Satisfactory CTV dosimetric criteria were selected to be a minimum CTV dose of 95% of the PTV dose and at least 95% of the CTV receiving 100% of the PTV dose. The measured uncertainties were assumed to be Gaussian distributions. Systematic errors were added linearly and random errors were added in quadrature assuming no correlation to arrive at the total combined error. The Monte Carlo simulation written for this work examined the distribution of cumulative dose volume histograms for a large patient population using various margin and fraction combinations to determine the smallest margin required to meet the established criteria. The program examined 5 and 30 fraction treatments, since those are the only fractionation schemes currently used at our institution. The fractionation schemes were evaluated using no margin, a margin of just the systematic component of the total uncertainty, and a margin of the systematic component plus one standard deviation of the total uncertainty. It was concluded that (i) a margin of the systematic error plus one standard deviation of the total uncertainty is the smallest PTV margin necessary to achieve the established CTV dose criteria, and (ii) it is necessary to determine the uncertainties introduced by the specific equipment and procedures used at each institution since the uncertainties may vary among locations.

Brain Neoplasms↗

PubMedDate not supplied

Prospective clinical trials of brain tumor therapy: the critical role of neurosurgeons.

Prospective clinical trials are critical to the scientific evaluation of new treatments for brain tumors. This paper reviews basic concepts of early and late phase prospective clinical trials that are most relevant to neurosurgical oncologists, with an emphasis on the challenges associated with conducting clinical trials of brain tumor therapies. Novel clinical trial designs that meet these challenges by incorporating pretreatment 'molecular profiling' and post-treatment 'molecular endpoints' are described. Because of their ability to obtain brain tumor specimens from patients before and after treatment, neurosurgeons have been required to play an increasingly important role in the execution of these molecular-based clinical trials. Potential avenues for enhancing the participation of neurosurgeons in the design and development of clinical trials are discussed.

Brain Neoplasms↗

PubMedDate not supplied

Current surgical management of glioblastoma.

Surgical resection is a critical aspect of the management of a patient with a glioblastoma (GBM). An intimate knowledge of the anatomy of a GBM, as well as familiarity with particular surgical techniques and adjunctive technologies is required for safe surgical resection. The goals of resection include diagnosis, relief of mass effect, and cytoreduction. A recent study showed that resection of 98% or more of the tumor mass can result in a statistically significant survival advantage. Even in functionally critical areas, "gross total" resections are possible if proper techniques are employed. It is recommended that a "gross total" resection of the enhancing portion of a GBM be performed whenever possible. With this philosophy, the mortality rate is 3% and the rate of major neurologic morbidity is less than 10%.

Brain Mapping↗