Bone turnover biomarkers identify unique prognostic risk groups in men with castration resistant prostate cancer and skeletal metastases: Results from SWOG S0421.

BACKGROUND: Skeletal metastases often occur in men with castration-resistant prostate cancer (CRPC) where bone biomarkers are prognostic for overall survival (OS). In those with highly elevated markers, there is preferential benefit from bone-targeted therapy. In the phase IIIS0421 docetaxel +/- atrasentan trial, clinical covariates and bone biomarkers were analyzed to identify CRPC subsets with differential outcomes. SUBJECTS AND METHODS: Markers of bone resorption [N-telopeptide-NTx; pyridinoline-PYD] and formation [C-terminal collagen propeptide-CICP; bone alkaline phosphatase-BAP] were measured in pre-treatment sera. Bone biomarkers and clinical covariates were included in a Cox model for OS; bone markers were added in a stepwise selection process. Receiver operating characteristic (ROC) curves were constructed for risk factor models +/- bone markers. Significant variables were allowed to compete in a classification and regression tree (CART) analysis. Hazard ratios(HR) were calculated by comparing OS in each of the terminal nodes to a reference group in a Cox model. RESULTS: 750 patients were included. Each bone marker significantly contributed to the risk factor-adjusted OS Cox model, with higher levels associated with worse OS. BAP (HR = 1.15, p = 0.008), CICP (HR = 1.27, p < 0.001), and PYD (HR = 1.21, p = 0.047) in combination were significantly associated with OS. Prognostic accuracy was improved by addition of bone markers to clinical covariates. CART analysis selected CICP, BAP, hemoglobin, and pain score for the final OS model, identifying five prognostic groups. CONCLUSIONS: Elevated serum bone biomarker levels are associated with worse OS in bone-metastatic CRPC. Bone biomarkers can identify unique prognostic subgroups. These results further define the role of bone biomarkers in the design of CRPC trials.

The evolution of chemotherapy for the treatment of prostate cancer.

Chemotherapy has been explored as a treatment option for metastatic prostate cancer since the early 1980s. Docetaxel, a taxane chemotherapeutic, was approved for the treatment of men with metastatic castration-resistant prostate cancer in 2004, and is now standard of care for late stage disease. Recent clinical studies demonstrated that patients with metastatic castration-sensitive disease, and possibly those with high-risk localized prostate cancer also benefit from docetaxel administration, expanding the role of chemotherapy in the prostate cancer treatment landscape. Another taxane, cabazitaxel, is approved for post-docetaxel metastatic castration-resistant prostate cancer. Taxanes and other chemotherapeutics, such as carboplatin, are now being tested in combination regimens. This review presents an outline of recent and ongoing clinical studies assessing docetaxel and its derivative cabazitaxel at different stages of the disease, and in various combinations with other agents. We summarize current knowledge on biomarkers predictive of response to chemotherapy, which may in future be used to guide individualized treatment decisions.

Cortical variability and asymmetry in normal aging and Alzheimer's disease.

The onset of Alzheimer's disease (AD) is accompanied by a complex and distributed pattern of neuroanatomic change, difficult to distinguish clinically from dynamic alterations in normal aging. Extreme variations in the sulcal patterns of the human cortex have made it difficult to identify diffuse and focal variations in cortical structure in neurodegenerative disease. We report the first comprehensive 3D statistical analysis of deep sulcal structure in vivo, in both normal aging and dementia. High-resolution 3D T1-weighted fast SPGR (spoiled GRASS) MRI volumes were acquired from 10 patients diagnosed with AD (NINCDS-ARDRA criteria; age: 71.9 +/- 10.7 years) and 10 normal subjects matched for age (72.9 +/- 5.6 years), gender, educational level and handedness. Scans were digitally transformed into Talairach stereotaxic space. To determine specific patterns of cortical variation in dementia patients, 3D average and probabilistic maps of primary deep sulci were developed for both normal and AD groups. Major sulci (including supracallosal, cingulate, marginal, parieto-occipital, anterior and posterior calcarine sulci, and Sylvian fissures) were modeled as complex systems of 3D surfaces using a multi-resolution parametric mesh approach. Variations and asymmetries in their extents, curvature, area and surface complexity were evaluated. Three-dimensional maps of anatomic variability, structural asymmetry and local atrophy indicated severe regionally selective fiber loss in AD. A midsagittal area loss of 24.5% at the corpus callosum's posterior midbody (P < 0.025) matched increases in structural variability in corresponding temporo-parietal projection areas. Confidence limits on 3D cortical variation, visualized in 3D, exhibited severe increases in AD from 2 to 4 mm at the callosum to a peak SD of 19.6 mm at the posterior left Sylvian fissure. Normal Sylvian fissure asymmetries (right higher than left; P < 0.0005), mapped for the first time in three dimensions, were accentuated in AD (P < 0.0002), and were greater in AD than in controls (P < 0.05). Severe AD-related increases in 3D variability and asymmetry may reflect disease-related disruption of the commissural system connecting bilateral temporal and parietal cortical zones, regions known to be at risk of early metabolic dysfunction, perfusion deficits and selective neuronal loss in AD.

Sulcal variability in the Alzheimer's brain: correlations with cognition.

We mapped the three dimensional (3D) extents and variability of selected sulci in the Alzheimer's brain and explored the relationship between sulcal pattern and patient's cognitive performance. High-resolution MRIs of 10 patients with probable Alzheimer's disease (AD) were linearly transformed into a standard "normalized" 3D atlas (known as the Talairach coordinate system) and, on each relevant slice, contours of the left and right Sylvian fissure, anterior and posterior calcarine, callosal, parietooccipital, and cingulate sulci and the floor of the temporal horn of the lateral ventricle were traced. These landmarks were chosen because of their relative invariant location across individuals and because they demarcate functional boundaries relevant in AD. The sulcal contours were resolved into two-dimensional surfaces that cut through a brain volume. All 10 patients' sulcal surfaces were averaged to determine their mean spatial locations in the Talairach coordinate system. The 3D spatial extents of each patient's sulci were compared with their disease severity based on neuropsychological performance. The 3D sulcal variability, within the "normalized" atlas space, ranged from 4.0 mm for the left callosal sulcus to 9.1 mm for the left Sylvian fissure. Significant correlations were found among the spatial extents for the posterior floor of the right temporal horn of the lateral ventricle (r = -0.89, p < 0.001 for vertical extent) and right anterior calcarine sulcus (r = -0.75, p < 0.01 for anterior-posterior extent) with copying ability of the Rey-Osterrieth Complex Figure; the right anterior calcarine also had a significant relationship (r = -0.72, p = 0.02 for anterior-posterior extent) with performance on the Block Design subtest from the Wechsler Adult Intelligence Scale-Revised. Verbal fluency performance measured by the Controlled Oral Word Association Test was significantly related to the left cingulate (r = 0.91, p < 0.001 for anterior-posterior extent, and r = -0.82, p < 0.01 for vertical extent) and right cingulate (r = -0.72, p < or = 0.02 for vertical extent) sulci. This exploratory study is the first to evaluate the relationship between 3D sulcal variability and cognition; our preliminary findings suggest that the 3D pattern of sulci in the AD brain is related to the severity of the disease as reflected by cognitive performance. In the Talairach brain atlas, sulcal variability, within an AD population, approaches 1 cm. This large variability requires correction when functional imaging data are transformed into the Talairach atlas space to "normalize" individual morphologic differences.

Postmortem cryosectioning as an anatomic reference for human brain mapping.

This study examined the densitometric and topographic detail of high resolution 3D digital postmortem cryosectioned brain images. Anatomic image data and histology from cryosectioned human brain were compared to in vivo MRI for the ability to delineate neuroanatomic structure. 3D surface reconstructions in the Talairach and Tournoux atlas ("Co-planar stereotaxic atlas of the human brain", Thieme, New York, 1988) coordinate system enabled morphometric comparisons for a representative sample of neuroanatomic structures. Spatial resolution of cryosection images averaged 200 and 170 microns/pixel for whole head and brain, respectively, and 40 microns/pixel for isolated the brain regions. Anatomic detail was far superior to MRI, particularly in deep subcortical regions such as the basal ganglia and in mesencephalic nuclei and tracts. Digital repositioning in the Talairach coordinate system enabled efficient structure localization and morphometric comparison. Histology from collected tissue sections provided cytologic detail that could be mapped to its approximate 3D context. This approach permits comprehensive morphometric analyses necessary for an anatomic framework to a digital atlas of the human brain.