Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

BACKGROUND AND PURPOSE:Bisphosphonates are drugs that decrease bone turnover by inhibiting osteoclast activity. An association between the use of bisphosphonates and osteonecrosis of the maxilla and mandible has recently been described. This study describes the imaging findings of bisphosphonate-associated osteonecrosis of the jaws.

Objective: We sought to determine the incidence and associations of lobar microbleeds (LMBs) in a longitudinal cohort with 11 C-Pittsburgh compound B (PiB) PET imaging.Methods: One hundred seventy-four participants from the observational Australian Imaging, Biomarkers and Lifestyle Study of Ageing (97 with normal cognition [NC], 37 with mild cognitive impairment [MCI], and 40 with Alzheimer disease [AD] dementia) were assessed at 3 time points over 3 years with 3-tesla susceptibility-weighted MRI and 11 C-PiB PET. MRIs were inspected for microbleeds, siderosis, infarction, and white matter hyperintensity severity, blind to clinical and PiB findings. Neocortical PiB standardized uptake value ratio, normalized to cerebellar cortex, was dichotomized as positive or negative (PiB1/2, standardized uptake value ratio .1.5). Annualized LMB incidence was calculated, and logistic regression was used to determine the association of incident LMBs with PiB, APOE e41 status, and cerebrovascular disease.Results: LMBs were present in 18.6% of NC, 24.3% of MCI, and 40% of AD participants (p , 0.05 vs NC). LMB incidence was 0.2 6 0.6 per year in NC participants, 0.2 6 0.5 in MCI, and 0.7 6 1.4 in AD (p , 0.03 vs NC) and was 6-fold higher in PiB1 than PiB-NC. Incident LMBs were associated with age, APOE e41, PiB1, and baseline LMBs. Incidence of multiple LMBs was also associated with lacunar infarction and white matter hyperintensity severity. Conclusions:Older age, baseline LMBs, higher b-amyloid burden, and concomitant cerebrovascular disease may all confer higher risk of incident LMBs. This should be considered when designing protocols for amyloid-modifying clinical trials. Neurology ® 2014;82:1266-1273 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; AIBL 5 Australian Imaging, Biomarkers and Lifestyle Study of Ageing; CAA 5 cerebral amyloid angiopathy; CI 5 confidence interval; FLAIR 5 fluid-attenuated inversion recovery; GRE 5 gradient-recall echo; LMB 5 lobar microbleed; MCI 5 mild cognitive impairment; MP-RAGE 5 magnetization-prepared rapid-acquisition gradient echo; NC 5 normal cognition; OR 5 odds ratio; PiB 5 Pittsburgh compound B; SS 5 superficial siderosis; SUVR 5 standardized uptake value ratio; SWI 5 susceptibility-weighted imaging; TE 5 echo time; TR 5 repetition time; VRF 5 vascular risk factor; WMH 5 white matter hyperintensity.

ACTRN12610000915055.