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We have cloned the cDN} encodiig human peroxisomal acyl-CoA oxidase, the first enzyme in the peroxisomal 13-oxidation of very long cha in fatty acids. Its nucleotv e sequence was foundl to be h ighly homologous (85' to the rat cDNA countei part.An 88% homology betveen rat and h was found in the COOH-terminal end of the cDNA w ch includes the Ser-Lys-Leu peroxisomal targeting signal common to many peroxisomal proteins. The gene spans 30-40 kb and is poorly polymorphic. Southern blot analyses were performed in two previously reported siblings with an isolated peroxisomal acyl-CoA oxidase deficiency (pseudoneonatal adrenoleukodystrophy). A deletion of at least 17 kb, starting downstream from exon 2 and extending beyond the 3' end of the gene, was observed in the two patients. These observations provide a molecular basis for the observed acyl-CoA oxidase deficiency in our family. In addition, our study will enable the characterization of the genetic defect in unrelated families with suspected acyl-CoA oxidase disorders. (J. Clin. Invest. 1994. 94:526-531.)

Exercise interventions alone may not reverse the long-term sequelae of breast cancer treatment and allow young adult patients to return to work.

5007 Background: Skeletal fractures, pathological or not, are a frequent and underestimated side-effect of systemic treatment of metastatic castration resistant prostate cancer (mCRPC). The ERA223 trial (NCT02043678) was recently unblinded following the report of a significant increase in the fracture rates when abiraterone is combined with Ra223. Hence, FDA and EMA advised against this combination. The question whether mandated use of bone protecting agents (BPA), zoledronic acid or denosumab, would have mitigated the fracture risk and whether this risk also exists in the enzalutamide/Ra223 combination is presently unknown. Methods: The phase III EORTC-1333-GUCG/PEACEIII (NCT02194842) trial compares enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic mCRPC patients (https://www.eortc.org/research_field/clinical-detail/1333/). After the unblinding of ERA223, the trial was amended (v4.0, April 19, 2018) to mandate that all patients must start a BPA. We report the fracture rate in the safety population of 146 treated patients as of 28/01/2019. Results: Overall, 54.2% of the patients in the enza/Ra223 arm and 51.4% of the enza arm did not receive BPA; 18.0% in the enza/Ra223 arm and 27.0% in the enza arm did not use BPA at randomization, but started during protocol treatment according to the v4.0 amendment. 27.8% and 21.6% respectively, received BPA as of randomization. In total, 45.8% of enza/Ra223 patients and 48.6% of enza only patients receive bone protection on treatment. The fracture rate is reported in the table. Conclusions: There is a 13% risk of fracture with enzalutamide in asymptomatic mCRPC, in line with previous reports. This risk is significantly increased to 33% when Ra223 is added to enzalutamide. Strikingly, the risk is almost abolished by mandatory continuous administration of BPA starting at least 6 weeks before the first injection of Ra223, thus emphasizing the importance of treating mCRPC patients with BPA. Clinical trial information: NCT02194842. [Table: see text]

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