Control of growth of vestibular schwannomas with low-dose Gamma Knife surgery.

Object: The treatment of solitary vestibular schwannomas by performing Gamma Knife surgery is well established. It has been reported that decreasing the surface dose reduces patient morbidity, especially facial weakness and numbness. The authors of this retrospective study examine patient data from a single center to determine if low-dose (< or = 14 Gy) GKS controls tumor growth as effectively as higher doses (> 14 Gy).

Activation of the cholesterol pathway and Ras maturation in response to stress.

All cells depend on sterols and isoprenoids derived from mevalonate (MVA) for growth, differentiation, and maintenance of homeostatic functions. In plants, environmental insults like heat and sunlight trigger the synthesis of isoprene, also derived from MVA, and this phenomenon has been associated with enhanced tolerance to heat. Here, we show that in human prostate adenocarcinoma PC-3M cells heat shock leads to activation of the MVA pathway.

Phenylacetate and phenylbutyrate as novel, nontoxic differentiation inducers.

Phenylacetate and analogs represent a new class of pleiotropic growth regulators that alter tumor cell biology by affecting gene expression at both the transcriptional and post transcriptional levels. Based on these findings, NaPA and NaPB entered clinical trials at the National Cancer Institute. Ongoing phase I studies with NaPA, involving adults with prostate and brain cancer, have confirmed that therapeutic levels can be achieved with no significant toxicities, and provide preliminary evidence for benefit to patients with advanced disease (Thibault et al.

Gamma knife for glioma: selection factors and survival.

Purpose: To determine factors associated with survival differences in patients treated with radiosurgery for glioma.

Methods And Materials: We analyzed 189 patients treated with Gamma Knife radiosurgery for primary or recurrent glioma World Health Organization (WHO) Grades 1-4.

Conclusion: The median minimum tumor dose was 16 Gy (8-30 Gy) and the median tumor volume was 5.

Transcriptional upregulation of gamma-globin by phenylbutyrate and analogous aromatic fatty acids.

Phenylbutyrate has been shown recently to induce fetal hemoglobin (HbF) production in patients with sickle cell anemia and beta thalassemia. We have now examined related aromatic fatty acids in order to define the range of active structures and identify plausible mechanisms of action. Structure-function analysis revealed that for effective stimulation of HbF in erythroid precursors: (1) the ideal length for the aliphatic side chain is four carbons; (2) oxygen or sulfur substitutions in the carboxylic chain are allowed, as evidenced by the equal or increased activity of phenoxypropionate, benzylthioglycolate, and benzyloxyacetate compared with phenylbutyrate; and (3) blocking the carboxylate group by conversion to the amide form greatly reduces potency.

Activation of a human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogs.

The aromatic fatty acid phenylacetate and its analogs induce tumor cytostasis and differentiation in experimental models. Although the underlying mechanisms of action are not clear, effects on lipid metabolism are evident. We have now examined whether these compounds, structurally similar to the peroxisome proliferator clofibrate, affect the human peroxisome proliferator-activated receptor (hPPAR), a homolog of the rodent PPAR alpha, a transcriptional factor regulating lipid metabolism and cell growth.

Gamma Knife treatment of 100 consecutive meningiomas.

Clinical and imaging results of Gamma Knife treatment of 100 consecutive patients with intracranial meningiomas are reported. Only 1 patient refused follow-up imaging and her symptoms remain improved after 1 year. Mean values for the patient and treatment parameters were age 61 years, duration of symptoms 3.

Cytostatic activity of phenylacetate and derivatives against tumor cells. Correlation with lipophilicity and inhibition of protein prenylation.

The aromatic fatty acid phenylacetate, a common metabolite of phenylalanine, shows promise as a relatively non-toxic drug for cancer treatment. This slowly metabolized fatty acid alters tumor cell lipid metabolism causing, among other effects, inhibition of protein prenylation critical to malignant growth. In pursuit of more potent analogues, we have examined the activity of related compounds against tumor cell lines established from patients with advanced prostatic carcinoma, glioblastomas, and malignant melanoma.

Cinnamic acid: a natural product with potential use in cancer intervention.

Cinnamic acid, a naturally occurring aromatic fatty acid of low toxicity, has a long history of human exposure. We now show that cinnamic acid induces cytostasis and a reversal of malignant properties of human tumor cells in vitro. The concentration causing a 50% reduction of cell proliferation (IC50) ranged from 1 to 4.

Transcriptional upregulation of TGF-alpha by phenylacetate and phenylbutyrate is associated with differentiation of human melanoma cells.

The aromatic fatty acids phenylacetate (PA) and phenylbutyrate (PB) induce tumour cell differentiation in experimental models and both are currently in clinical trials. The purpose of this study was to determine the effect of these antitumour agents on the expression of transforming growth factor-alpha (TGF-alpha) in neoplastic cells. Treatment of human melanoma 1011 cultures with either PA or PB caused over 40-fold increase in TGF-alpha biosynthesis and secretion into the media.

Differentiation of cultured human melanoma cells induced by the aromatic fatty acids phenylacetate and phenylbutyrate.

The increasing incidence of melanoma and the poor responsiveness of disseminated disease to conventional treatments call for the development of new therapeutic approaches. Phenylacetate, a nontoxic differentiation inducer, can suppress the growth of other neuroectodermal tumors, i.e.

Patients' attitude about outcomes and the role of gamma knife radiosurgery in the treatment of vestibular schwannomas.

In one strategy for the treatment of unilateral vestibular schwannomas measuring up to 3 cm in diameter, decision analysis shows that gamma knife radiosurgery has probabilistic dominance over microsurgical resection. That is, radiosurgery produces better results for any value assigned to treatment outcomes (ranked from best to worst) of the following: no complications, hearing loss only, residual/recurrent tumor, facial paralysis, major disability, or death. This little-known principle of decision analysis will be explained.

A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis.

Purpose: A multi-institutional experience in radiosurgery for solitary brain metastases was combined to identify factors associated with safety, efficacy, tumor control, and survival.

Materials And Methods: A review of 116 patients with solitary brain metastases who underwent gamma knife stereotactic radiosurgery at five institutions was performed. The median follow-up was 7 months following radiosurgery and 12 months following diagnosis.

Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria.

Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults.

Glycosylated insulin-like growth factor II promoted expansion of granulocyte-macrophage colony-forming cells in serum-deprived liquid cultures of human peripheral blood cells.

This report presents the results of studies investigating the effect of a glycosylated form of insulin-like growth factor II with an apparent molecular weight of 15,000 (appM(r) = 15K IGF-II) and one with a molecular weight of 7500 (M(r) = 7.5K IGF-II) on the expansion of granulocyte-macrophage colony-forming cells (GM-CFC) in human peripheral blood cells. Blood cells were enriched for GM-CFC and other CFCs, and liquid cultures of these cells were established in serum-deprived medium supplemented with either interleukin-3 (IL-3) alone (no insulin or IGF added to the medium) or with IL-3 plus M(r) = 7.

Gamma knife radiosurgery: brain surgery without an incision.

Radiosurgery is the precise targeting of ionizing radiation to inactivate or destroy pathologic tissue while sparing adjacent tissue. Like surgery, radiosurgery is done in a single treatment; unlike surgery, radiosurgery does not require an anesthetic or an incision. A specific device for neurosurgery, the gamma knife, uses 201 separate 60Co sources to crossfire gamma rays through a collimator helmet across an intracranial target.

Decision analysis of the treatment of AVMs with radiosurgery.

Decision analysis uses a tree-like diagram to describe treatment outcomes, the likelihood and value of which are obtained from the literature. A personal computer program entitled 'D-Tree' was used to compare radiosurgery to both microsurgery and nonoperative management of cerebral arteriovenous malformations (AVMs). The results indicated that radiosurgery is the treatment of choice for all AVMs up to 3 cm in diameter, not just those considered inoperable.

The identification of O-glycosylated precursors of insulin-like growth factor II.

A procedure that combined ion exchange, gel permeation, and insulin-like growth factor-binding protein 3 (IGF-BP-3) affinity chromatography with chromatofocusing and reversed-phase high pressure liquid chromatography was used to isolate high molecular weight precursors of human insulin-like growth factor II (IGF-II) from acetic acid extracts of Cohn fraction IV1. Two precursors had isoelectric points (pI) of 5.1 and 5.

Comparison of urinary transforming growth factor-alpha in women with disseminated breast cancer and healthy control women.

In an effort to explore the use of polypeptide growth factors as potential markers for cancer detection, we have identified the presence of transforming growth factor-alpha (TGF-alpha) in pooled urine of patients with metastatic breast cancer by a commercial radioimmunoassay (RIA) based on a rabbit antiserum raised to the C-terminal 17aa synthetic fragment of rat TGF-alpha. This TGF-alpha RIA detected both high molecular weight (HMW) and low molecular weight (LMW) forms of TGF-alpha in the conditioned media of a breast cancer cell line (MDA-MB-231) and in the urine of healthy women and those with breast cancer. The ratio of HMW to LMW species of TGF-alpha by RIA after Bio-Gel P-100 chromatography was approximately equal in pooled urine samples from both healthy women and those with breast cancer, and in the conditioned media from the cell line MDA-MB-231.

Variant forms of rat epidermal growth factor present in the urine of nude rats bearing human tumors.

Epidermal growth factor (EGF) receptor-binding peptides from the urine of tumor patients have been reported to differ in molecular weight and relative hydrophobicity from those of normal individuals. Nude rats bearing human large cell lung carcinomas or chondrosarcomas and non-tumor-bearing sibling control rats were used to investigate the contributions of tumor and host to urinary EGF-related peptide growth factors. Peptides were adsorbed from urine onto methyl-bonded silica and eluted according to their relative hydrophobicity by a stepwise gradient of aqueous acetonitrile.