BACKGROUND Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors. METHODS We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. RESULTS VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2. CONCLUSIONS VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.

Flav-2-enes, flavones, and 3-alkyl ethers of flavonols add alcohols and carboxylic acids in the presence of N-bromosuccinimide to give 2-alkoxy-and 2-acyloxy-3-bromoflavans which provide routes to cis-3-bromoflavans by reduction and to 3,4-diols by elimination and reaction with osmium tetraoxide. The 2-acyloxyflavans react with alcohols yielding 2-alkoxyflavans. Flavonols react with N-brornosuccinimide and alcohols to give bromine-free hemiacetals, the known 2,3-dialkoxy-3-hydroxyflavanones.Flav-2-enes and flav-2-en-4-ones (flavones) are readily available compounds which, in view of their expected reactivity, might be more widely exploited for the synthesis of other flavonoids. In this paper we describe some reactions of these compounds which we have used (see later papers) for the synthesis of polyflavonoids. ( 1 ) R' = R 2 = ,Q3= R 4 = H Flav-2-enes.-We obtained many of the flav-2-enes we required by the reduction of flavylium salts with lithium ( 2 ) R 3 = ~0 2 ,~' = R'= R4 = H aluminium hydride ' which is a quick and convenient method ( 3 ) R 3 = OMe. R'= R2= R 4 = H and appears to be of general applicability for the preparation (4) R ' = R2 = R 3 = R = OMe of flav-2enes unsubstituted at C-3 or C-2'. 3-and 2'-Substituted flavylium salts give considerable quantities of flav-3-enes on reduction with lithium aluminium hydride:3,4'-dimethoxyflavylium chloride gave 40% of the 3ene ' and we have obtained 3-methylflav-3ene (22%) and 3-methylflav-2-ene (53%) from 3-methylflavylium perchlorate and mixtures of the 2-and 3enes from 2'-benzoyloxy-and 2'-methoxyflavylium salts so that the method is less useful for the preparation of 3-and 2'-substituted flav-2enes. We have investigated the reduction of flavylium salts in acetic acid with sodium borohydride and with sodium cyanoborohydride. With sodium borohydride, flavylium perchlorate (1) gave 54% of flav-2-ene (5) containing a small proportion of a contaminant which was apparently (t.1.c.) flavan (10) (Scheme 1). With sodium cyanoborohydride, 4'-nitroflavylium perchlorate (2) gave 90% of 4'-nitroflav-2ene (6); 4'-methoxyflavylium perchlorate (3), however, gave 79% of 4'-msthoxyflavan (1 1) and the yield was similar (86%) with sodium borohydride in acetic acid. Analogously, 2'-methoxyflavylium perchlorate gave 62% of 2'-methoxyflavan with sodium cyanoborohydride. It seems probable that a flav-2-ene is always the initial product and that for further reduction to occur this enol ether must be protonated at C-3 [structure (g)], a reaction which can occur under these mild conditions only if the resulting positive charge is stabilised by a + M substituent suitably placed in the Bring. In accordance with this mechanism, we have found that flav-2-ene (5), 3-bromoflav-2-ene (12), and 4-phenylflav-2-ene (13) are not reduced by sodium cyanoborohydride in acetic acid but that 4'-methoxy-(7), 3',4',5,7-tetramethoxy-(g), and 4'-methoxy-4-phenylflav-2-ene (14) give 60-80% yields of the corresponding flavans. 4-Phenylflav-2-ene (13) and 4'-methoxy-4-phenylflav-2ene (14) were prepared b...

A series of substituted 1,2-benzisothiazol-3-ones was synthesized, and the compounds were tested for ability to inhibit platelet aggregation induced by adenosine diphosphate and collagen in rats and guinea pigs ex vivo. Alkyl substituents at the 2-position bearing a basic group were necessary for ex vivo activity. Several of the compounds were potent inhibitors of adenosine diphosphate induced first-phase aggregation, but adverse toxicological findings terminated their further development. Preliminary studies suggested that inhibition of aggregation was not attributable to inhibition of prostanoid synthesis or to raised levels of cyclic 3',5'-adenosine monophosphate.

We have isolated a cDNA clone corresponding to a substantial portion of the human tissue-type plasminogen activator (t-PA) protein. It encodes almost all of the protein B chain and part of the 3' untranslated region. We have used this clone to screen bacteriophage lambda and cosmid libraries of human genomic DNA. Several related genomic clones were isolated. One of these, a cosmid clone, carried approx. 40 kb of human DNA. Mapping experiments indicate that the region containing the protein-coding exons is approx. 20 kb in length. The cosmid, containing the t-PA gene and the aminoglycosyl-3'-phosphotransferase dominant-selection marker, was introduced into mouse L cells. Approximately half of the transformants were shown to produce human t-PA. We demonstrated that the fibrinolytic t-PA activity could be specifically quenched by anti-t-PA antibody and that the recombinant t-PA was of similar size (by SDS-polyacrylamide gel electrophoresis) to the t-PA produced by the human Bowes melanoma cell line. Our results suggest that the cosmid clone carries the whole t-PA coding region together with the regulatory elements necessary for its expression.

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