Symmetry-breaking effects on time-dependent dynamics: correct differential cross sections and other properties in H+ + C2H4 at ELab = 30 eV.

We present a computational procedure that introduces low degrees of symmetry breaking into a restricted Hartree-Fock (RHF) state in order to induce higher symmetry breaking during the state's subsequent dynamics. The symmetries herein considered are those of electronic HF states as classified by Fukutome; those symmetries affect bond dissociations and internal rotations among other phenomena. Therefore, this investigation extends a part of Fukutome's time-independent analysis of symmetry breaking to the time-dependent (dynamical) regime. The procedure is formulated in the framework of the simplest-level electron nuclear dynamics, a time-dependent, variational, on-the-fly and non-adiabatic method that employs classical dynamics for the nuclei and a Thouless single-determinantal state for the electrons. We test this procedure on the H+ + C2H4 reaction at 30 eV due to its conspicuous display of symmetry-breaking effects; this reaction is relevant in astrophysics and proton cancer therapy. Fukutome's axial spin density wave (ASDW) HF state is used to represent the symmetry-broken initial states. Through a Thouless parameter, small degrees of symmetry breaking are introduced into the initial ASDW states in a controlled manner. After starting the dynamics from those states, higher degrees of symmetry breaking emerge or not as determined by the direct-dynamics equations without external interventions. Simulations starting from symmetry-conforming states preserve symmetry features during dynamics, whereas simulations starting from symmetry-broken states display an upsurge of symmetry breaking when the reactants collide. Initial symmetry breaking increases the total integral cross sections of collision-induced fragmentations and of target-to-proton 1-electron-transfer reactions and decreases the scattering angle function and primary rainbow angle of the outgoing projectile. Remarkably, symmetry-breaking simulations reproduce the correct relative order and values of the experimental 0- and 1-electron-transfer differential cross sections, whereas symmetry-conforming simulations predict incorrect order and values. Our calculated scattering angle functions and differential cross sections also exhibit expected primary and secondary rainbow angle features that experiments fail to detect. A detailed discussion on the description of symmetry-breaking processes with the ASDW and Thouless states is included to provide a rigorous theoretical basis for this investigation.

Sequencing Treatment in BRAFV600 Mutant Melanoma: Anti-PD-1 Before and After BRAF Inhibition.

Novel agents targeting immune checkpoint molecules or mutated BRAF are active therapeutic options for patients with BRAF-mutant melanoma. However, the most effective first-line treatment and the optimal sequencing of these agents have not been well characterized. To explore this, we retrospectively assessed 114 patients from 4 centers with advanced, BRAF-mutant melanoma who received anti-programmed cell death-1 (PD-1)/PD-L1 antibodies. We evaluated clinical outcomes, including objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) to initial and subsequent therapies in patients that received anti-PD-1 first (n=56) versus those that received BRAF±MEK inhibitors (BRAFi) first (n=58). Median OS was similar between these groups (27.5 vs. 40.3 mo, P=0.71). Patients who progressed on anti-PD-1 during the study timeframe had worse outcomes after starting subsequent BRAFi than those who had not received prior anti-PD-1 (median PFS 5 vs. 7.4 mo, median OS 10.6 vs. 40.3 mo). Similarly, patients who previously progressed on BRAFi had seemingly inferior outcomes after starting anti-PD-1 compared with those without prior BRAFi, including ORR (25% vs. 41%), median PFS (2.8 vs. 10.6 mo) and median OS (8.2 vs. 27.6 mo). Notably, patients who benefited >6 months from BRAFi had superior ORR to subsequent anti-PD-1 compared with those with more rapid progression (<6 mo) on BRAFi (34% vs. 15%, P=0.04). We conclude that either BRAFi or anti-PD-1 may be effective regardless of treatment sequence in patients with BRAF-mutant melanoma, but clinical outcomes to front-line therapy are superior. In addition, we suggest a shared "responder phenotype" between BRAFi and anti-PD-1.

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era.

Survival with BRAF-mutant metastatic melanoma is prolonged with MAP-kinase pathway inhibitors (MAPKi). Among patients with brain metastases (BM), however, the clinical course of MAPKi-treated patients is not well described. We therefore explored these patients' survival patterns compared to contemporary patients not treated with MAPKi. We analyzed 106 patients who developed melanoma BM between 2007 and 2013. Of these, 37 (35%) received de novo MAPKi for BRAF-mutant disease, which preceded BM in 49%. Immunotherapy was given to 54% of MAPKi-treated patients and 94% of those who did not receive MAPKi. We evaluated the potential influence of patient characteristics, systemic therapies, and BM-directed treatments on time to appearance of new BM and overall survival. With a median follow-up of 8.0 months after initial BM, MAPKi use was an independent predictor of prolonged survival after BM diagnosis (median 14.1 vs 7.0 months, P = 0.03, adjusted hazard ratio 0.39). This survival advantage was driven by the 16.6-month median survival of patients who initiated MAPKi after BM were diagnosed, versus 5.6 months if initiated prior to BM development (P = 0.03). Median survival from the onset of any systemic metastases was 22 months regardless of the timing of MAPKi relative to BM appearance. Time to in-brain progression was longer among patients whose MAPKi course was started after BM diagnosis, but MAPKi initiation prior to BM diagnosis was associated with longer time to intracranial involvement. These findings are consistent with potential MAPKi activity in intracranial melanoma.

Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma.

BRAF inhibitors (BRAFi) have led to clinical benefit in patients with melanoma. The development of a blood-based assay to detect and quantify BRAF levels in these patients has diagnostic, prognostic, and predictive capabilities that could guide treatment decisions. Blood BRAF(V600E) detection and quantification were performed on samples from 128 patients with stage II (19), III (67), and IV (42) melanoma. Tissue BRAF analysis was performed in all patients with stage IV disease and in selected patients with stage II and III disease. Clinical outcomes were correlated to initial BRAF levels as well as BRAF level dynamics. Serial analysis was performed on 17 stage IV melanoma patients treated with BRAFi and compared with tumor measurements by RECIST. The assay was highly sensitive (96%) and specific (95%) in the stage IV setting, using a blood level of 4.8 pg as "positive." BRAF levels typically decreased following BRAFi. A subset of these patients (5) had an increase in BRAF(V600E) values 42 to 112 days before clinical or radiographic disease progression (PD). From 86 patients with resected, stage II or III melanoma, 39 had evidence of disease relapse (45.3%). Furthermore, BRAF mutation in the blood after surgical resection in these patients was not associated with a difference in relapse risk, although tissue BRAF status was only available for a subset of patients. In summary, we have developed a highly sensitive and specific, blood-based assay to detect BRAF(V600) mutation in patients with melanoma.