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Contains fulltext : 137932.pdf (publisher's version ) (Open Access), BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death

Integrated Ocean Drilling Program (IODP) Expedition 316 Sites C0006 and C0007 examined the deformation front of the Nankai accretionary prism offshore the Kii Peninsula, Japan. In the drilling area, the frontal thrust shows unusual behavior as compared to other regions of the Nankai Trough. Drilling results, integrated with observations from seismic reflection profiles, suggest that the frontal thrust has been active since similar to 0.78-0.436 Ma and accommodated similar to 13 to 34% of the estimated plate convergence during that time. The remainder has likely been distributed among out-of-sequence thrusts further landward and/or accommodated through diffuse shortening. Unlike results of previous drilling on the Nankai margin, porosity data provide no indication of undercompaction beneath thrust faults. Furthermore, pore water geochemistry data lack clear indicators of fluid flow from depth. These differences may be related to coarser material with higher permeability or more complex patterns of faulting that could potentially provide more avenues for fluid escape. In turn, fluid pressures may affect deformation. Well-drained, sand-rich material under the frontal thrust could have increased fault strength and helped to maintain a large taper angle near the toe. Recent resumption of normal frontal imbrication is inferred from seismic reflection data. Associated decollement propagation into weaker sediments at depth may help explain evidence for recent slope failures within the frontal thrust region. This evidence consists of seafloor bathymetry, normal faults documented in cores, and low porosities in near surface sediments that suggest removal of overlying material. Overall, results provide insight into the complex interactions between incoming materials, deformation, and fluids in the frontal thrust region.

Sediment dominated convergent margins typically record substantial horizontal shortening often associated with great earthquakes. The convergent margin south of Japan is arguably one of the most extensively investigated margins and previous studies have documented extensive evidence for accretion and horizontal shortening. Here, we show results from anelastic strains recovered from three partially lithified sediment samples (40~ porosities) across the southwest Japan accretionary prism and propose that the margin is dominated by horizontal extension rather than compression. The anelastic strain results are also consistent with stress directions interpreted from two independent techniques - bore hole breakout orientations and core-scale fault data. We interpret this unexpected result to reflect geologically recent underthrusting of a thick sediment package and concomitant weakening of the decollement.

Subduction zones are often characterized by wedge-shaped sedimentary complexes—called accretionary prisms—that form when sediments are scraped off the subducting plate and added to the overriding plate. Large, landward-dipping thrust faults can cut through such a prism: these faults, known as 'megasplay faults'1, 2, originate near the top of the subducting plate and terminate at the shallow, landward edge of the prism1, 3, 4, 5, 6. Megasplay faults have been the subject of numerous geological and geophysical studies4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, but their initiation and evolution through time remains poorly constrained. Here we combine seismic reflection data from the Nankai accretionary wedge with geological data collected by the Integrated Ocean Drilling Program (IODP) and find that the splay fault cutting this wedge initiated approx1.95 Million years (Myr) ago in the lower part of the prism as an out-of-sequence thrust (OOST). After an initial phase of high activity, the movement along the fault slowed down, but uplift and reactivation of the fault resumed about 1.55 Myr ago. The alternating periods of high and low activity along the splay fault that we document hint at episodic changes in the mechanical stability of accretionary prisms.

The Nankai accretionary prism is divided into three segments: outer and inner wedges and their transition zone. These wedges reflect different aspects of wedge taper, internal deformation, and basal plate boundary fault. The outer wedge is characterized by narrow critical taper, internal deformation by in-sequence-fold-and-thrust and aseismic décollement. The inner wedge represents a stable narrow taper, weakly deformed internal structure and seismogenic plate boundary fault along its base. The transition zone between the two wedges shows large critical taper with steep surface slope, internal structure of out-of-sequence thrust, and step-down of décollement onto the sediment–oceanic basement interface. The trench slope break and oceanward margin of forearc basin is located around the landward edge of this transition zone. These common aspects might be related to the lithification of both accreted and underthrust sediments and the resultant switch of the plate boundary fault. Deformation and lithification process recorded in exhumed on-land mélange of accretionary complexes suggest that the step-down of the plate boundary décollement occurs around the up-dip limit of seismogenic subduction zone.