The evolving role of lenvatinib at the new era of first-line hepatocellular carcinoma treatment

Emergence of multi-targeted kinase inhibitors (MTIs) and immune checkpoint inhibitors (ICI) have changed the landscape of management in hepatocellular carcinoma (HCC). Combination therapy involving ICI has superseded sorafenib as the first-line treatment option for advanced HCC due to their superior response rates and survival benefits based on recently published phase III trials. However, the role of first-line lenvatinib remains uncertain as no prospective trials have compared its efficacy with ICI in advanced HCC. Several retrospective studies have shown that first-line lenvatinib may not be inferior to ICI combination. Indeed, a growing body of evidence suggests that ICI treatment is associated with inferior treatment outcome in non-viral HCC patients, questioning the supremacy of ICI treatment in all patients and rendering first-line lenvatinib as a potential preferred treatment option. Furthermore, in high-burden intermediate-stage HCC, accumulating evidence supports first-line lenvatinib, or in combination with transarterial chemoembolization (TACE), as a preferred treatment option over TACE alone. In this Review, we describe the latest evidence surrounding the evolving role of first-line lenvatinib in HCC

Macaque anterior cingulate cortex deactivation impairs performance and alters lateral prefrontal oscillatory activities in a rule-switching task

© 2019 Ma et al. In primates, both the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (dlPFC) are key regions of the frontoparietal cognitive control network. To study the role of the dACC and its communication with the dlPFC in cognitive control, we recorded local field potentials (LFPs) from the dlPFC before and during the reversible deactivation of the dACC, in macaque monkeys engaging in uncued switches between 2 stimulus-response rules, namely prosaccade and antisaccade. Cryogenic dACC deactivation impaired response accuracy during maintenance of—but not the initial switching to—the cognitively demanding antisaccade rule, which coincided with a reduction in task-related theta activity and the correct-error (C-E) difference in dlPFC beta-band power. During both rule switching and maintenance, dACC deactivation prolonged the animals’ reaction time and reduced task-related alpha power in the dlPFC. Our findings support a role of the dACC in prefrontal oscillatory activities that are involved the maintenance of a new, challenging task rule

A Parametric Study of an Effective Stress Liquefaction Model

A method for evaluating the soil parameters required for effective stress analyses of the earthquake liquefaction potential of saturated sands is described. By means of parametric studies, it is demonstrated that the drained volume change and rebound constants required, may be backfitted to match a given field liquefaction strength curve. By means of this technique, fully coupled effective stress response analyses and site liquefaction evaluations can become a more routine engineering tool

High affinity germinal center B cells are actively selected into the plasma cell compartment

A hallmark of T cell–dependent immune responses is the progressive increase in the ability of serum antibodies to bind antigen and provide immune protection. Affinity maturation of the antibody response is thought to be connected with the preferential survival of germinal centre (GC) B cells that have acquired increased affinity for antigen via somatic hypermutation of their immunoglobulin genes. However, the mechanisms that drive affinity maturation remain obscure because of the difficulty in tracking the affinity-based selection of GC B cells and their differentiation into plasma cells. We describe a powerful new model that allows these processes to be followed as they occur in vivo. In contrast to evidence from in vitro systems, responding GC B cells do not undergo plasma cell differentiation stochastically. Rather, only GC B cells that have acquired high affinity for the immunizing antigen form plasma cells. Affinity maturation is therefore driven by a tightly controlled mechanism that ensures only antibodies with the greatest possibility of neutralizing foreign antigen are produced. Because the body can sustain only limited numbers of plasma cells, this “quality control” over plasma cell differentiation is likely critical for establishing effective humoral immunity

Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer.

BackgroundSipuleucel-T is a US Food and Drug Administration-approved immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its mechanism of action is not fully understood. This prospective trial evaluated the direct immune effects of systemically administered sipuleucel-T on prostatic cancer tissue in the preoperative setting.MethodsPatients with untreated localized prostate cancer were treated on an open-label Phase II study of sipuleucel-T prior to planned radical prostatectomy (RP). Immune infiltrates in RP specimens (posttreatment) and in paired pretreatment biopsies were evaluated by immunohistochemistry (IHC). Correlations between circulating immune response and IHC were assessed using Spearman rank order.ResultsOf the 42 enrolled patients, 37 were evaluable. Adverse events were primarily transient, mild-to-moderate and infusion related. Patients developed T cell proliferation and interferon-γ responses detectable in the blood following treatment. Furthermore, a greater-than-three-fold increase in infiltrating CD3(+), CD4(+) FOXP3(-), and CD8(+) T cells was observed in the RP tissues compared with the pretreatment biopsy (binomial proportions: all P < .001). This level of T cell infiltration was observed at the tumor interface, and was not seen in a control group consisting of 12 concurrent patients who did not receive any neoadjuvant treatment prior to RP. The majority of infiltrating T cells were PD-1(+) and Ki-67(+), consistent with activated T cells. Importantly, the magnitude of the circulating immune response did not directly correlate with T cell infiltration within the prostate based upon Spearman's rank order correlation.ConclusionsThis study is the first to demonstrate a local immune effect from the administration of sipuleucel-T. Neoadjuvant sipuleucel-T elicits both a systemic antigen-specific T cell response and the recruitment of activated effector T cells into the prostate tumor microenvironment

Development, Validation, and Limits of Freezing of Gait Detection Using a Single Waist-Worn Device

Objective: Freezing of Gait (FOG) often described as the sensation of “the feet being glued to the ground” is prevalent in people with Parkinson's disease (PD) and severely disturbs mobility. In addition to tracking disease progression, precise detection of the exact boundaries for each FOG episode may enable new technologies capable of “breaking” FOG in real time. This study investigates the limits of sensitivity and performance for automatic device-based FOG detection. Methods: Eight machine-learning classifiers (including Neural Networks, Ensemble & Support Vector Machine) were developed using (i) accelerometer and (ii) accelerometer and gyroscope data from a waist-worn device. While wearing the device, 107 people with PD completed a walking and mobility task designed to elicit FOG. Two clinicians independently annotated the precise FOG episodes using synchronized video according to international guidelines, which were incorporated into a flowchart algorithm developed for this study. Device-detected FOG episodes were compared to the annotated FOG episodes using 10-fold cross-validation to determine accuracy and with Interclass Correlation Coefficients (ICC) to assess level of agreement. Results: Development used 50,962 windows of data representing over 10 hours of data and annotated activities. Very strong agreement between clinicians for precise FOG episodes was observed (90% sensitivity, 92% specificity and ICC 1,1 = 0.97 for total FOG duration). Device-based performance varied by method, complexity and cost matrix. The Neural Network that used only 67 accelerometer features provided a good balance between high sensitivity to FOG (89% sensitivity, 81% specificity and ICC 1,1 = 0.83) and solution stability (validation loss ≤ 5%). Conclusion: The waist-worn device consistently reported accurate detection of precise FOG episodes and compared well to more complex systems. The superior agreement between clinicians indicates there is room to improve future device-based FOG detection by using larger and more varied data sets. Significance: This study has clinical implications with regard to improving PD care by reducing reliance on clinical FOG assessments and time-consuming visual inspection. It shows high sensitivity to automatically detect FOG is possible

Development, Validation, and Limits of Freezing of Gait Detection Using a Single Waist-Worn Device

Objective: Freezing of Gait (FOG) often described as the sensation of “the feet being glued to the ground” is prevalent in people with Parkinson's disease (PD) and severely disturbs mobility. In addition to tracking disease progression, precise detection of the exact boundaries for each FOG episode may enable new technologies capable of “breaking” FOG in real time. This study investigates the limits of sensitivity and performance for automatic device-based FOG detection. Methods: Eight machine-learning classifiers (including Neural Networks, Ensemble & Support Vector Machine) were developed using (i) accelerometer and (ii) accelerometer and gyroscope data from a waist-worn device. While wearing the device, 107 people with PD completed a walking and mobility task designed to elicit FOG. Two clinicians independently annotated the precise FOG episodes using synchronized video according to international guidelines, which were incorporated into a flowchart algorithm developed for this study. Device-detected FOG episodes were compared to the annotated FOG episodes using 10-fold cross-validation to determine accuracy and with Interclass Correlation Coefficients (ICC) to assess level of agreement. Results: Development used 50,962 windows of data representing over 10 hours of data and annotated activities. Very strong agreement between clinicians for precise FOG episodes was observed (90% sensitivity, 92% specificity and ICC 1,1 = 0.97 for total FOG duration). Device-based performance varied by method, complexity and cost matrix. The Neural Network that used only 67 accelerometer features provided a good balance between high sensitivity to FOG (89% sensitivity, 81% specificity and ICC 1,1 = 0.83) and solution stability (validation loss ≤ 5%). Conclusion: The waist-worn device consistently reported accurate detection of precise FOG episodes and compared well to more complex systems. The superior agreement between clinicians indicates there is room to improve future device-based FOG detection by using larger and more varied data sets. Significance: This study has clinical implications with regard to improving PD care by reducing reliance on clinical FOG assessments and time-consuming visual inspection. It shows high sensitivity to automatically detect FOG is possible

Quantum Kinks: Solitons at Strong Coupling

We examine solitons in theories with heavy fermions. These ``quantum'' solitons differ dramatically from semi-classical (perturbative) solitons because fermion loop effects are important when the Yukawa coupling is strong. We focus on kinks in a $(1+1)$--dimensional $\phi^4$ theory coupled to fermions; a large-$N$ expansion is employed to treat the Yukawa coupling $g$ nonperturbatively. A local expression for the fermion vacuum energy is derived using the WKB approximation for the Dirac eigenvalues. We find that fermion loop corrections increase the energy of the kink and (for large $g$) decrease its size. For large $g$, the energy of the quantum kink is proportional to $g$, and its size scales as $1/g$, unlike the classical kink; we argue that these features are generic to quantum solitons in theories with strong Yukawa couplings. We also discuss the possible instability of fermions to solitons.Comment: 21 pp. + 2 figs., phyzzx, JHU-TIPAC-92001

Mortality benefit of beta-blockade after successful elective percutaneous coronary intervention

AbstractObjectivesThe goal of this study was to evaluate the mortality benefit of beta-blockers after successful percutaneous coronary intervention (PCI).BackgroundBeta-blockers reduce mortality after myocardial infarction (MI), though limited data are available regarding their role after successful PCI.MethodsEach year from 1993 through 1999, the first 1,000 consecutive patients undergoing PCI were systematically followed up. Patients presenting with acute or recent MI, shock, or unsuccessful revascularization procedures were excluded from the analysis. Clinical, procedural, and follow-up data of beta-blocker-treated and non-beta-blocker-treated patients were compared. A multivariate survival analysis model using propensity analysis was used to adjust for heterogeneity between the two groups.ResultsOf the 4,553 patients, 2,056 (45%) were treated with beta-blockers at the time of the procedure. Beta-blocker therapy was associated with a mortality reduction from 1.3% to 0.8% at 30 days (p = 0.13) and a reduction from 6.0% to 3.9% at one year (p = 0.0014). This survival benefit of beta-blockers was independent of left ventricular function, diabetic status, history of hypertension, or history of MI. Using propensity analysis, beta-blocker therapy remained an independent predictor for one-year survival after PCI (hazard ratio, 0.63; 95% confidence interval, 0.46 to 0.87; p = 0.0054).ConclusionsWithin this large prospective registry, beta-blocker use was associated with a marked long-term survival benefit among patients undergoing successful elective percutaneous coronary revascularization