Coupling deformation with fluid flow and mineral reactions based on natural shear zones – From field observations to numerical simulations

At convergent tectonic plate boundaries rocks are brought down into the Earth’s mantle. Due to the deep burial, this material is either recycled and contributes to the formation of new and growing orogens or transported further into the mantle. Furthermore, subduction of both oceanic and continental crust assists the Earth’s water cycle, which is essential for life on Earth. H2O bound within the crystal lattice of minerals is brought down into great depth and released by dehydration processes. This released H2O plays a major role in fluid-rock interaction, since it triggers transformation processes, which subsequently initiate chemical-mechanical changes of the downgoing and surrounding material. Such interdependencies cause metamorphic transition as well as emerging rheological inhomogeneities and deformation of the affected rocks. Especially when dry and rigid rocks of the continental crust are subducted, infiltrating fluids, H2O in particular, mobilize, promote and increase the efficiency of the chemical-mechanical processes. How fluid-rock interaction, deformation, rheology, and fluids are coupled and how they affect subducting rocks has long been part of the research. However, investigations of these processes are highly challenging because they occur at great depth where no in-situ analysis is possible. Therefore, studies often use either field-derived data, laboratory data, partially obtained by the analysis of synthetic materials, or complex numerical simulations. This thesis provides a comprehensive dataset arising from detailed field observations and selected samples being analyzed using various methods and equipment. Subsequently, the petrological results were employed for numerical simulations. With this interdisciplinary approach I give new insights into how an infiltrating fluid, mainly H2O, successively transforms a dry and metastable crustal rock. The fluid infiltration triggers a progressive eclogitization, a transient weakening, and a ductile deformation of the affected host rock. I highlight the role of water, stored in nominally anhydrous minerals (NAMs), which constitute large volumes of the continental crust. Additionally, I present new estimates about the physical-chemical properties, timing, and spatial scales of the addressed metamorphic and dynamic processes. One of the best natural laboratories to study the transformation and deformation of crustal rocks based on an infiltrating external fluid are the rocks exposed on Holsnøy (western Norway). Various studies have shown that the eclogite-facies shear zone network developed on Holsnøy was formed due to an interplay of brittle and ductile deformation assisted by fluid infiltration. The shear zones widen during strain accumulation, deformation and progressive metamorphism and partially eclogitize the highly reactive granulite. However, it is still a matter of debate how long fluid was available and to what spatial extent. How does it affect the resulting geometries, microstructures and rheology of the system? To better understand the addressed interconnections, the effect of fluid availability on the evolving shear zone geometry and widening was assed first. The results show that only a substantial amount of fluid enables the geometrical evolution as observed in the field. This fluid was either injected by numerous fluid pulses during individual events or by one large influx. Furthermore, it was possible to decipher that the hydration occurs in two contemporaneous types. By a diffusional hydrogen (H+/H2) influx, and simultaneous inflow of an aqueous fluid (H2O and H+/H2). The hydrogen influx caused a hydration of the NAMs, due to an incorporation of OH-groups within the crystal lattice, and progressed further into the wall rock. The supply of H2O and additional hydrogen through an inflow of aqueous fluid, caused further incorporation of OH-groups during recrystallization into a hydrated eclogite-facies mineral assemblage. Both influxes, where the diffusional hydrogen influx is one order of magnitude faster than the aqueous fluid inflow, initiate a transient weakening of the system. To fit the observed shear zone geometries with numerical simulations, the hydrated granulite must be two orders of magnitude weaker, and the equilibrating eclogite four orders of magnitude weaker compared to the dry and rigid granulite host rock. If inflow of aqueous fluid is modelled only, the eclogite is only three orders of magnitude weaker compared to the granulite. Hence, the hydrogen influx has an appreciable effect on the rheology of the granulite. Furthermore, the conducted numerical simulations provide new time constraints for the granulite hydration and shearing of less than ten years at low shear velocities of < 10-2 cm/a. Hence, the results presented here significantly contribute to a better understanding of the fluid-assisted transient weakening and eclogitization of subducted continental crust

Numerical Simulations Reproduce Field Observations Showing Transient Weakening During Shear Zone Formation by Diffusional Hydrogen Influx and H2O Inflow

Exposures on Holsnøy island (Bergen Arcs, Norway) indicate fluid infiltration through fractures into a dry, metastable granulite, which triggered a kinetically delayed eclogitization, a transient weakening during fluid-rock interaction, and formation of shear zones that widened during shearing. It remains unclear whether the effects of grain boundary-assisted aqueous fluid inflow on the duration of granulite hydration were influenced by a diffusional hydrogen influx accompanying the fluid inflow. To better estimate the fluid infiltration efficiencies and the parameter interdependencies, a 1D numerical model of a viscous shear zone is utilized and validated using measured mineral phase abundance distributions and H2O-contents in nominally anhydrous minerals of the original granulite assemblage to constrain the hydration by aqueous fluid inflow and diffusional hydrogen influx, respectively. Both hydrations are described with a diffusion equation and affect the effective viscosity. Shear zone kinematics are constrained by the observed shear strain and thickness. The model fits the phase abundance and H2O-content profiles if the effective hydrogen diffusivity is approximately one order of magnitude higher than the diffusivity for aqueous fluid inflow. The observed shear zone thickness is reproduced if the viscosity ratio between dry granulite and deforming, reequilibrating eclogite is ∼104 and that between dry granulite and hydrated granulite is ∼102. The results suggest shear velocities <10−2 cm/a, hydrogen diffusivities of ∼10−13±1 m2/s, and a shearing duration of <10 years. This study successfully links and validates field data to a shear zone model and highlights the importance of hydrogen diffusion for shear zone widening and eclogitization

How fluid infiltrates dry crustal rocks during progressive eclogitization and shear zone formation: insights from H2O contents in nominally anhydrous minerals

Granulites from Holsnøy (Bergen Arcs, Norway) maintained a metastable state until fluid infiltration triggered the kinetically delayed eclogitization. Interconnected hydrous eclogite-facies shear zones are surrounded by unreacted granulites. Macroscopically, the granulite–eclogite interface is sharp and there are no significant compositional changes in the bulk chemistry, indicating the fluid composition was quickly rock buffered. To better understand the link between deformation, fluid influx, and fluid–rock interaction one cm-wide shear zone at incipient eclogitization is studied here. Granulite and eclogite consist of garnet, pyroxene, and plagioclase. These nominally anhydrous minerals (NAMs) can incorporate H2O in the form of OH groups. H2O contents increase from granulite to eclogite, as documented in garnet from ~ 10 to ~ 50 µg/g H2O, pyroxene from ~ 50 to ~ 310 µg/g H2O, and granulitic plagioclase from ~ 10 to ~ 140 µg/g H2O. Bowl-shape profiles are characteristic for garnet and pyroxene with lower H2O contents in grain cores and higher at the rims, which suggest a prograde water influx into the NAMs. Omphacite displays a H2O content range from ~ 150 to 425 µg/g depending on the amount of hydrous phases surrounding the grain. The granulitic plagioclase first separates into a hydrous, more albite-rich plagioclase and isolated clinozoisite before being replaced by new fine-grained phases like clinozoisite, kyanite and quartz during ongoing fluid infiltration. Results indicate a twofold fluid influx with different mechanisms to act simultaneously at different scales and rates. Fast and more pervasive proton diffusion is recorded by NAMs that retain the major element composition of the granulite-facies equilibration where hydrogen decorates pre-existing defects in the crystal lattice and leads to OH increase. Contemporaneously, slower grain boundary-assisted aqueous fluid influx enables element transfer and results in progressive formation of new minerals, e.g., hydrous phases. Both mechanisms lead to bulk H2O increase from ~ 450 to ~ 2500 µg/g H2O towards the shear zone and convert the system from rigid to weak. The incorporation of OH groups reduces the activation energy for creep, promotes formation of smaller grain sizes (phase separation of plagioclase), and synkinematic metamorphic mineral reactions. These processes are part of the transient weakening, which enhance the sensitivity of the rock to deform

ISTH guidelines for antithrombotic treatment in COVID-19

Antithrombotic agents reduce risk of thromboembolism in severely ill patients. Patients with coronavirus disease 2019 (COVID-19) may realize additional benefits from heparins. Optimal dosing and timing of these treatments and benefits of other antithrombotic agents remain unclear. In October 2021, ISTH assembled an international panel of content experts, patient representatives, and a methodologist to develop recommendations on anticoagulants and antiplatelet agents for patients with COVID-19 in different clinical settings. We used the American College of Cardiology Foundation/American Heart Association methodology to assess level of evidence (LOE) and class of recommendation (COR). Only recommendations with LOE A or B were included. Panelists agreed on 12 recommendations: three for non-hospitalized, five for non-critically ill hospitalized, three for critically ill hospitalized, and one for post-discharge patients. Two recommendations were based on high-quality evidence, the remainder on moderate-quality evidence. Among non-critically ill patients hospitalized for COVID-19, the panel gave a strong recommendation (a) for use of prophylactic dose of low molecular weight heparin or unfractionated heparin (LMWH/UFH) (COR 1); (b) for select patients in this group, use of therapeutic dose LMWH/UFH in preference to prophylactic dose (COR 1); but (c) against the addition of an antiplatelet agent (COR 3). Weak recommendations favored (a) sulodexide in non-hospitalized patients, (b) adding an antiplatelet agent to prophylactic LMWH/UFH in select critically ill, and (c) prophylactic rivaroxaban for select patients after discharge (all COR 2b). Recommendations in this guideline are based on high-/moderate-quality evidence available through March 2022. Focused updates will incorporate future evidence supporting changes to these recommendations

Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study

Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome. Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS). Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema. Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment

Widening of Hydrous Shear Zones During Incipient Eclogitization of Metastable Dry and Rigid Lower Crust— Holsnøy, Western Norway

The partially eclogitized crustal rocks on Holsnøy in the Bergen Arcs, Norway, indicate that eclogitization is caused by the interplay of brittle and ductile deformation promoted by fluid infiltration and fluid-rock interaction. Eclogitization generated an interconnected network of millimeterto- kilometer-wide hydrous eclogite-facies shear zones, which presumably caused transient weakening of the mechanically strong lower crust. To decipher the development of those networks, we combine detailed lithological and structural mapping of two key outcrops with numerical modeling. Both outcrops are largely composed of preserved granulite with minor eclogite-facies shear zones, thus representing the beginning phases of eclogitization and ductile deformation. We suggest that deformation promoted fluidrock interaction and eclogitization, which gradually consumed the granulite until fluid-induced reactions were no longer significant. The shear zones widen during progressive deformation. To identify the key parameters that impact shear zone widening, we generated scale-independent numerical models, which focus on different processes affecting the shear zone evolution: (i) rotation of the shear zones caused by finite deformation, (ii) mechanical weakening due to a limited amount of available fluid, and (iii) weakening and further hydration of the shear zones as a result of continuous and unlimited fluid supply. A continuous diffusion-type fluid infiltration, with an effective diffusion coefficient around 2 10 16 m s D , coupled with deformation is prone to develop structures similar to the ones mapped in field. Our results suggest that the shear zones formed under a continuous fluid supply, causing shear zone widening, rather than localization, during progressive deformation

Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study

The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progressionfree (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary realworld cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT

Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG

BACKGROUND: Despite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM. METHOD: We assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Of 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95% CI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95% CI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95% CI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB. CONCLUSIONS: In patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1

Primary Analysis of Phase 2 Results for Cemiplimab in Patients (pts) with Locally Advanced Basal Cell Carcinoma (laBCC) who Progress on or are Intolerant to Hedgehog Inhibitors (HHIs)

Abstract not available