Quasiclassical approach to low-dimensional topological insulators and superconductors

In this work we apply the quasiclassical formalism, an established tool in the context of superconducting heterostructures, to topological insulators and superconductors in one and two dimensions, with focus on the former. We derive topological invariants in terms of the quasiclassical Green's function in the regions terminating the disordered one-dimensional wire geometries, and demonstrate the existence of edge modes in the corresponding topologically non-trivial phases. A generalisation to two-dimensional geometries is established by the concepts of compactification and dimensional reduction. The second part of this work is devoted to Majorana fermions in disordered topological quantum wires. We apply the quasiclassical approach developed in the first part of this work to a setup used in recent experiments, where the evidence for Majorana edge modes is drawn from zero-bias peaks in tunnelling experiments. Analytically we derive a formalism that lays the foundation for an efficient numerical method to calculate physical observables. Studying in particular the averaged local density of states, we show that effects arising from disorder may overshadow an unambiguous detection of Majorana edge modes in tunnelling experiments. In the last part of this work we briefly discuss ongoing research on how disorder effects in one-dimensional quantum wires may actually lead to the formation of local topological domains and may stabilise these domains. Based on the numerical method introduced in the second part, we present results that point towards formation of such local domains

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial

Elacestrant; Càncer de mamaElacestrant; Cáncer de mamaElacestrant; Breast cancerPURPOSE Patients with pretreated estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer

Effect of manual lymph drainage in addition to guidelines and exercise therapy on arm lymphoedema related to breast cancer: randomised controlled trial

Objective To determine the preventive effect of manual lymph drainage on the development of lymphoedema related to breast cancer

Disease management patterns for postmenopausal women in Europe with hormone-receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer.

peer reviewedAbstract Background: International guidelines for hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (BC) recommend sequential lines of hormonal therapy (HT), and only recommend chemotherapy for patients with extensive visceral involvement or rapidly progressive disease. This study evaluated actual physician-reported treatments for advanced BC in Europe. Methods: We conducted a retrospective chart review of 355 postmenopausal women with HR+, HER2- advanced BC who progressed on >/=1 line of HT (adjuvant or advanced) and completed >/=1 line of chemotherapy (advanced). Treatment choice was evaluated for each line of therapy. Results: Of 355 patients, 111 (31%) received first-line chemotherapy, whereas 218 (61%) and 26 (7%) switched from HT to chemotherapy in second and third line, respectively. More patients receiving first-line HT had bone metastases (73% vs 27% chemotherapy). Patients treated with first-line chemotherapy had more brain (12% vs 3% HT) or extensive liver (13% vs 6% HT) metastases. Subgroup analysis of 188 patients who received first-line HT and had de novo advanced BC or relapsed/recurrent disease more than 1 year after adjuvant therapy found that the majority (89%; n = 167) of these patients switched to chemotherapy in second line. However, among these 167 patients, 27% had no significant changes in metastases between first and second line. Among the 73% of patients who had significant changes in metastases, 20% had no brain metastases or extensive visceral disease. Conclusions: Our study suggests that the guideline-recommended use of multiple HT lines is open to interpretation and that optimal treatment for European postmenopausal women with HR+, HER2- advanced BC who responded to HT may not be achieved

Zone Encryption with Anonymous Authentication for V2V Communication

Vehicle-to-vehicle (V2V) communication systems are currently being prepared for real-world deployment, but they face strong opposition over privacy concerns. Position beacon messages are the main culprit, being broadcast in cleartext and pseudonymously signed up to 10 times per second. So far, no practical solutions have been proposed to en- crypt or anonymously authenticate V2V messages. We propose two cryptographic innovations that enhance the privacy of V2V communication. As a core contribution, we introduce zone-encryption schemes, where vehicles generate and authentically distribute encryption keys associated to static geographic zones close to their location. Zone encryption provides security against eavesdropping, and, combined with a suitable anonymous authentication scheme, ensures that messages can only be sent by genuine vehicles, while adding only 224 Bytes of cryptographic overhead to each message. Our second contribution is an authentication mechanism fine-tuned to the needs of V2V which allows vehicles to authentically distribute keys, and is called dynamic group signatures with attributes. Our instantiation features unlimited locally generated pseudonyms, negligible credential download-and-storage costs, identity recovery by a trusted authority, and compact signatures of 216 Bytes at a 128-bit security level

Integrated Data Analysis of Six Clinical Studies Points Toward Model-Informed Precision Dosing of Tamoxifen

Introduction: At tamoxifen standard dosing, ∼20% of breast cancer patients do not reach proposed target endoxifen concentrations >5.97 ng/mL. Thus, better understanding the large interindividual variability in tamoxifen pharmacokinetics (PK) is crucial. By applying non-linear mixed-effects (NLME) modeling to a pooled ‘real-world’ clinical PK database, we aimed to (i) dissect several levels of variability and identify factors predictive for endoxifen exposure and (ii) assess different tamoxifen dosing strategies for their potential to increase the number of patients reaching target endoxifen concentrations. Methods: Tamoxifen and endoxifen concentrations with genetic and demographic data of 468 breast cancer patients from six reported studies were used to develop a NLME parent-metabolite PK model. Different levels of variability on model parameters or measurements were investigated and the impact of covariates thereupon explored. The model was subsequently applied in a simulation-based comparison of three dosing strategies with increasing degree of dose individualization for a large virtual breast cancer population. Interindividual variability of endoxifen concentrations and the fraction of patients at risk for not reaching target concentrations were assessed for each dosing strategy. Results and Conclusions: The integrated NLME model enabled to differentiate and quantify four levels of variability (interstudy, interindividual, interoccasion, and intraindividual). Strong influential factors, i.e., CYP2D6 activity score, drug–drug interactions with CYP3A and CYP2D6 inducers/inhibitors and age, were reliably identified, reducing interoccasion variability to <20% CV. Yet, unexplained interindividual variability in endoxifen formation remained large (47.2% CV). Hence, therapeutic drug monitoring seems promising for achieving endoxifen target concentrations. Three tamoxifen dosing strategies [standard dosing (20 mg QD), CYP2D6-guided dosing (20, 40, and 60 mg QD) and individual model-informed precision dosing (MIPD)] using three therapeutic drug monitoring samples (5–120 mg QD) were compared, leveraging the model. The proportion of patients at risk for not reaching target concentrations was 22.2% in standard dosing, 16.0% in CYP2D6-guided dosing and 7.19% in MIPD. While in CYP2D6-guided- and standard dosing interindividual variability in endoxifen concentrations was high (64.0% CV and 68.1% CV, respectively), it was considerably reduced in MIPD (24.0% CV). Hence, MIPD demonstrated to be the most promising strategy for achieving target endoxifen concentrations