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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. Like phenylacetate, derivatives containing α-carbon or ring substitutions induced cytostasis and phenotypic reversion at non-toxic concentrations. Potency was correlated with the degree of calculated lipophilicity of the aromatic fatty acid, and the extent of inhibition of protein prenylation. Remarkably, a parallel cytostatic activity was reported in embryonic plant cells, which respond to phenylacetate and its analogues in the same concentration range and the same rank order of lipophilicity. These data suggest that phenylacetate and its analogues may act through common mechanisms to inhibit the growth of vastly divergent, undifferentiated cell types, and provide a basis for the development of new agents for the treatment of human malignancies.

Follow-up angiography that no longer shows a cerebral arteriovenous malformation (AVM) after radio surgery is thought to indicate obliteration and protection from risk of hemorrhage. However, angiographically oc cult vascular malformations can bleed, so one might ques tion the degree of protection provided by radiosurgery. The patient reported here was anticoagulated for deep vein thrombosis after a cerebellar AVM had been "oblit erated" by treatment with a gamma knife. He subse quently suffered a fatal supratentorial hemorrhage. At au topsy, no bleeding was seen in the region of the throm bosed AVM. This case is presented as further evidence of the efficacy of radiosurgery in the treatment of cerebral AVMs.

Fifteen patients were treated in the Gamma Knife Unit and followed for 18 months or longer. Four patients had Cushing's disease, 4 had acromegaly, 3 had Nelson's syndrome and 3 had prolactinomas. One patient had no endocrinopathy. One of the patients with acromegaly and 2 of those with prolactinomas had been operated prior to Gamma Knife treatment. Radiological tumor localization was not an insuperable problem in this series. The effect of Gamma Knife treatment on the anterior pituitary neoplasia, as such, was consistently successful. All the tumors which received 10 Gy or more to the edge showed either a reduction in volume or at least cessation of growth. On the other hand, the effect of the treatment was less consistent in respect to the endocrinopathies. These results are discussed in respect of dose and tumor size. It is suggested that the role of the Gamma Knife in the treatment of pituitary adenomas requires further clarification, based on prospective studies.

An infrared frequency selective surface (FSS) with absorptive resonance near 6.5 μm was fabricated by electron-beam lithography using a patch design with dimensions reproducible by optical-projection lithography. By selective wet etching along with reactive-ion etching, the sample was divided into miniature FSS particles, which were released from the substrate. A large number of such particles could be implemented as a large area, conformal coating. Spectral reflectivity of the full FSS array as well as the FSS particles was measured and compared to electromagnetic simulations. To show the feasibility of this approach, the full array FSS design was fabricated using a g-line (λ = 436 nm) 5× projection lithography stepper and compared to the array fabricated by electron-beam lithography using scanning electron microscopy and Fourier transform infrared spectroscopy. Even though the resolution of the g-line stepper led to a poor fabrication output, the optical resonance was found to be robust, with only slight detuning attributed to the changes in unit cell geometry. This work highlights the utility of optical-projection lithography, coupled with the releasable particle fabrication procedure, to create a large area, conformal coating with specific infrared spectral properties.

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. Results: The median minimum tumor dose was 16 Gy (8–30 Gy) and the median tumor volume was 5.9 cc (1.3–52 cc.) Brachytherapy selection criteria were satisfied in 65% of patients. Median follow-up of all surviving patients was 65 weeks after radiosurgery. For primary glioblastoma patients, median survival from the date of pathologic diagnosis was 86 weeks if brachytherapy criteria were satisfied and 40 weeks if they were not ( p = 0.01), indicating that selection factors strongly influence survival. Multivariate analysis showed that increased survival was associated with five variables: lower pathologic grade, younger age, increased Karnofsky performance status (KPS), smaller tumor volume, and unifocal tumor. Survival was not found to be significantly related to radiosurgical technical parameters (dose, number of isocenters, prescription isodose percent, inhomogeneity) or extent of preradiosurgery surgery. We developed a hazard ratio model that is independent of the technical details of radiosurgery and applied it to reported radiosurgery and brachytherapy series, demonstrating a significant correlation between survival and hazard ratio. Conclusions: Survival after radiosurgery for glioma is strongly related to five selection variables. Much of the variation in survival reported in previous series can be attributed to differences in distributions of these variables. These variables should be considered in selecting patients for radiosurgery and in the design of future studies.

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 neuro- ectodermal tumors, i.e., gliomas, in laboratory models and in humans. This finding led us to explore the efficacy of phenylacetate and related aromatic fatty acids in melanoma. Phenylacetate and phenylbutyrate were found to a) induce selective cytostasis and maturation of cultured human melanoma cells, b) modulate the expression of genes implicated in tumor metastasis (type IV collagenase and tissue inhibitor of metalloproteinases-2) and immunogenicity (HLA class I); and c) enhance the efficacy of other agents of clinical interest, including retinoids, interferon-alpha, suramin, and 5-aza-2'-deoxycytidine. Reflecting on the phenotypic heterogeneity of melanoma, the degree of biologic alterations induced by phenylacetate, phenylbutyrate varied significantly among the tumor cell lines tested. Although losing invasive capacity and tumorigenicity in athymic mice, poorly differentiated cells exhibited only a marginal change in morphology, remained amelanotic, and resumed growth after treatment was discontinued. By contrast, treatment of melanoma cells that were in a more advanced stage of maturation resulted in profound alterations in cell growth, morphology, and pigmentation consistent with terminal differentiation. The in vitro antitumor activity was observed with nontoxic, pharmacologic concentrations of phenylacetate and phenylbutyrate, suggesting potential clinical use of these drugs in the treatment of melanomas.

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. Minimum tumor doses varied from 8–30 Gy (mean, 17.5 Gy). Forty-five patients failed prior radiotherapy and 71 had no prior brain irradiation. Fifty-one patients had radiosurgery alone and 65 underwent combined radiosurgery with fractionated large-field radiotherapy (mean dose, 33.8 Gy). Results : Median survival was 11 months after radiosurgery and 20 months after diagnosis. Follow-up documented local tumor control in 99 patients (85%), tumor recurrence in 17 (15%), and documented radiation necrosis in one (1%). The 2-year actuarial tumor control rate was 67 ± 8%. Tumor histology affected survival (better for breast cancer, p = .004) and local control (better for melanoma and renal cell, p = .0003) in multivariate analyses. Combined fractionated radiotherapy and radiosurgery improved local control (p = .0111), but not survival in multivariate testing. Conclusion : Radiosurgery is effective in controlling solitary brain metastases with low morbidity. Further study is needed to better define optimum treatment parameters for radiosurgery.

The analysis of cDNA clones for human (1,2) and rat (3) insulin-like growth factor-II (IGF-II)1 has led to the prediction that the processed forms of the growth factors, i.e. Mr = 7422 (67 amino acids) for human IGF-II are synthesized as precursors with an extension of 89 amino acids at the carboxyl terminus. This extension is termed the E domain. Moses et al (4) identified two precursor forms of rat IGF-II (originally designated multiplication-stimulating activity) in the conditioned medium of Buffalo rat liver, i.e. BRL-3A, cells with appMrs = 16,270 (MSA-1) and 8,700 (MSA-II). Human serum, spinal fluid and tissue extracts also contain high Mr forms of IGF-II (5-8). Zumstein et al., (5) have purified a Mr = 10,000 variant form of IGF-II from serum that contained Cys-Gly-Asp for Ser33 in the C domain and an E domain extension of 21- amino acids. This 10 kDa IGF-II may be similar or identical to the “big IGF-II” that was reported to be present in human serum and in spinal fluid (6). We have isolated a still larger form of IGF-II from normal human serum (7). N-terminal amino acid sequence analysis through the first 28 residues and RRAs using rat placental membranes established it as a form of IGF-II. As evidenced from its mobility during SDS-PAGE, it has an appMr = 15,000. Very recently, Hudgins et al., (8) established that normal human serum contains several forms of precursor IGF- II with acidic isoelectric points, i.e. pI’s. The mass and acidic nature of one of these molecules with an apparent Mr= 15,000 was contributed, in part, by polysaccharides and sialic acids, respectively (8). These results may explain the observations of several investigators that extracts from the tissues and serum of patients with malignant tumors contain a broad size range of IGF-II (2,9,10).

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Methyl bonded silica effectively concentrates EGF, TGF-α, and TGF-β from urine. Fractional elution of the sorbent with aqueous acetonitrile released approximately 70 to 80% of the EGF at between 25 and 30% acetonitrile, 80% of TGF-α between 15 and 25% acetonitrile and 70% of TGF-β between 30 and 50% acetonitrile. Enrichment in a single step was 1400 fold for EGF, 200 fold for TGF-α, and 250 fold for TGF-β. Further chromatography on sizing gel, carboxymethyl cellulose, and HPLC provided complete separation of TGF-α from the much more abundant but bioactively similar EGF.

Extracts of serum-free conditioned medium from human rhabdomyosarcoma A673 cells contain high molecular weight (HMW) transforming growth factors (TGFs) that can be partially purified by Bio-Gel P-100 and carboxymethyl (CM)-cellulose chromatography (Todaro et al: Proc Natl Acad Sci USA 77:5258, 1980). Reverse-phase high performance liquid chromatography (HPLC) revealed a principal peak of epidermal growth factor (EGF) radioreceptor assay (RRA) activity and anchorage-independent growth (AIG) activity that coeluted with 25-26% acetonitrile. If a trailing shoulder of EGF RRA activity from the CM-C chromatography was included in the material for HPLC analysis, additional active fractions were observed at 21-22% acetonitrile. Importantly, both active regions from HPLC failed to compete in radioimmunoassays under reduced and denatured conditions for human EGF (hEGF), human TGF-alpha (hTGF-alpha), or rat TGF-alpha (rTGF-alpha) and failed to give positive signals in Western blots under conditions in which TGF-alpha was readily detected when using an antisera raised against the 17 C-terminal amino acids of rTGF-alpha. Nonreducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed EGF RRA and AIG activities in gel slices corresponding to Mr 15,000 and 22,000 in the 25-26% acetonitrile eluate and Mr 15,000, 20,000, 27,000, and 48,000 in the 21-22% acetonitrile eluate. The presence of multiple forms of EGF-receptor-binding peptides produced in vitro suggest size heterogeneity and possible immunologic diversity among high molecular weight members of the EGF/TGF-alpha family of growth-promoting polypeptides.

On etudie la distribution en produits de 15 reactions entre la guanosine et une serie de bromures de p-Y-benzyle, de chlorures de p-Y-benzyle et de N-nitroso N-(p-Y-benzyl) urees (ou Y=NO 2 , Cl, H, CH 3 , CH 3 O)

A tumor-associated growth factor was identified in a 22-liter pool of urine from patients with disseminated breast cancer using an isolation scheme which separates transforming growth factor-alpha (TGF-alpha) from the high level of human epidermal growth factor (hEGF) normally present in urine. Concentration of urinary proteins by adsorption onto methyl bonded microparticulate silica, selective elution by acetonitrile, and subsequent gel permeation, cation exchange, and high performance liquid chromatography, resolved an EGF-related growth factor which generated a competitive binding curve similar to that of synthetic rat TGF-alpha in radioimmunoassay. A 26-liter pool of urine from normal subjects, evaluated in the same manner as a part of another study, did not contain measureable quantities of this factor.