Thermokinematic evolution of the Annapurna-Dhaulagiri Himalaya, central Nepal: The composite orogenic system

The Himalayan orogen represents a ‘‘Composite Orogenic System’’ in which channel flow, wedge extrusion, and thrust stacking operate in separate ‘‘Orogenic Domains’’ with distinct rheologies and crustal positions. We analyze 104 samples from the metamorphic core (Greater Himalayan Sequence, GHS) and bounding units of the Annapurna-Dhaulagiri Himalaya, central Nepal. Optical microscopy and electron backscatter diffraction (EBSD) analyses provide a record of deformation microstructures and an indication of active crystal slip systems, strain geometries, and deformation temperatures. These data, combined with existing thermobarometry and geochronology data are used to construct detailed deformation temperature profiles for the GHS. The profiles define a three-stage thermokinematic evolution from midcrustal channel flow (Stage 1, >7008C to 550–6508C), to rigid wedge extrusion (Stage 2, 400–6008C) and duplexing (Stage 3, <280–4008C). These tectonic processes are not mutually exclusive, but are confined to separate rheologically distinct Orogenic Domains that form the modular components of a Composite Orogenic System. These Orogenic Domains may be active at the same time at different depths/positions within the orogen. The thermokinematic evolution of the Annapurna-Dhaulagiri Himalaya describes the migration of the GHS through these Orogenic Domains and reflects the spatial and temporal variability in rheological boundary conditions that govern orogenic systems

Deformational temperatures across the Lesser Himalayan Sequence in eastern Bhutan and their implications for the deformation history of the Main Central Thrust

We postulate that the inverted metamorphic sequence in the Lesser Himalayan Sequence of the Himalayan orogen is a finite product of its deformation and temperature history. To explain the formation of this inverted metamorphic sequence across the Lesser Himalayan Sequence with a focus on the Main Central Thrust (MCT) in eastern Bhutan, we determined the metamorphic peak temperatures by Raman spectroscopy of carbonaceous material and established the deformation temperatures by Ti-in-quartz thermobarometry and quartz c axis textures. These data were combined with thermochronology, including new and published Ar-40/Ar-39 ages of muscovite and published apatite fission track, and apatite and zircon (U-Th)/He ages. To obtain accurate metamorphic, deformation, and closure temperatures of thermochronological systems, pressures and cooling rates for the period of interest were derived by inverse modeling of multiple thermochronological data sets, and temperatures were determined by iterative calculations. The Raman spectroscopy of carbonaceous material results indicate two temperature sequences separated by a thrust. In the external sequence, peak temperatures are constant across the structural strike, consistent with the observed hinterland-dipping duplex system. In the internal temperature sequence associated with the MCT shear zone, each geothermometer yields an apparent inverted temperature gradient although with different temperature ranges, and all temperatures appear to be retrograde. These observations are consistent with the quartz microfabrics. Further, all thermochronometers indicate upward younging across the MCT. We interpret our data as a composite peak and deformation temperature sequence that formed successively and reflects the broadening and narrowing of the MCT shear zone in which the ductile deformation lasted until similar to 11 Ma.Peer reviewe

Real-world treatment outcomes with brigatinib in patients with pretreated ALK+ metastatic non-small cell lung cancer.

Background The next-generation ALK inhibitor brigatinib is approved for use in patients with ALK inhibitor-naïve ALK-positive advanced NSCLC and in patients previously treated with crizotinib. A phase II trial showed that brigatinib is active in patients with ALK-positive metastatic NSCLC (mNSCLC) who had progressed on prior crizotinib (response rate 56 %, median PFS 16.7 months, median OS 34.1 months). We report final data from the UVEA-Brig study of brigatinib in ALK inhibitor-pretreated ALK-positive mNSCLC in clinical practice.Methods UVEA-Brig was a retrospective chart review of patients treated with brigatinib in Italy, Norway, Spain and the UK in an expanded access program. Adults with ALK-positive mNSCLC, including those with brain lesions, resistant to or intolerant of ≥1 prior ALK inhibitor and ECOG performance status ≤3 were eligible. Patients received brigatinib 180 mg once daily with a 7-day lead-in at 90 mg. The objectives were to describe patient characteristics, clinical disease presentation, treatment regimens used and clinical outcomes.Results Data for 104 patients (male: 43 %; median age: 53 [29-80] years; ECOG performance status 0/1/2/3: 41/41/10/5 %; brain/CNS metastases: 63 %) were analyzed. Patients had received a median of 2 (1-6) lines of systemic therapy prior to brigatinib (37.5 % received ≥3) and a median of 1 (1-5) lines of prior ALK inhibitor-containing therapy (crizotinib 83.6 %; ceritinib 50.0 %; alectinib 6.7 %; lorlatinib 4.8 %). At the time of analysis, 77 patients had discontinued brigatinib. Overall, the response rate was 39.8 %, median PFS was 11.3 (95 % CI:8.6-12.9) months and median OS was 23.3 (95 % CI: 16.0-NR) months. Four patients discontinued brigatinib treatment due to adverse events. 53 patients received systemic therapy after brigatinib, 42 with an ALK inhibitor (lorlatinib, n = 34).Conclusions These real-world data indicate the activity and tolerability of brigatinib in patients with ALK-positive mNSCLC who were more heavily pretreated than patients included in clinical trials