The major mechanism for the repair of DNA double-strand breaks (DSBs) in mammalian cells is non-homologous end-joining (NHEJ), a process that involves the DNA-dependent protein kinase [1] [2], XRCC4 and DNA ligase IV [3] [4] [5] [6]. Rodent cells and mice defective in these components are radiation-sensitive and defective in V(D)J-recombination, showing that NHEJ also functions to rejoin DSBs introduced during lymphocyte development [7] [8]. 180BR is a radiosensitive cell line defective in DSB repair, which was derived from a leukaemia patient who was highly sensitive to radiotherapy [9] [10] [11]. We have identified a mutation within a highly conserved motif encompassing the active site in DNA ligase IV from 180BR cells. The mutated protein is severely compromised in its ability to form a stable enzyme-adenylate complex, although residual activity can be detected at high ATP concentrations. Our results characterize the first patient with a defect in an NHEJ component and suggest that a significant defect in NHEJ that leads to pronounced radiosensitivity is compatible with normal human viability and does not cause any major immune dysfunction. The defect, however, may confer a predisposition to leukaemia.

Object. A multidisciplinary team devised a protocol for long-term care of patients with skull base chordomas. In this study they describe their approach. Methods. Forty-two patients presented between 1986 and 1998 and were treated by maximum surgical cytoreduction and photon radiation therapy. Tumor volume—doubling time determined on the basis of magnetic resonance imaging, immunostaining, and cell proliferation (Ki67 labeling index [LI]) studies indicated growth rates of individual chordomas. The best outlook was associated with the greatest extent of tumor removal achieved during the first operation. There were no deaths associated with patients who underwent first-time surgery, but there was a 7.1% mortality rate associated with those who underwent subsequent operations. Cerebrospinal fluid leaks, additional cranial nerve palsies, and pharyngeal wound problems were the most difficult management problems encountered after second and subsequent surgeries. The time interval between operations was usually between 2 years and 3 years after the first surgery; very few patients required a second surgery, with a quiescent period in excess of 5 years. Life-table 5- and 10-year survival rates were 77% and 69%, respectively. Conclusions. The authors believe that this series of skull base chordomas provides new insights into the management of these lesions, particularly with regard to techniques that increase survival times and studies that aid in formulating prognoses.

SDH-B mutation carriers develop disease early and predominantly in extra-adrenal locations. Disease penetrance is incomplete. Metastatic disease is prominent but levels are less than previously reported. Clinical manifestations may include papillary renal cell carcinoma and macrovascular disease.

National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.