In the last decade, we have witnessed the emergence of the oral non-vitamin K oral anticoagulants (NOACs), which have numerous advantages compared with the vitamin K antagonists, particularly their lack of need for monitoring; as a result their use is increasing. Nonetheless, the NOACs face two major challenges: the need for reliable laboratory assays to assess their anticoagulation effect, and the lack of approved antidotes to reverse their action. This article provides an overview of monitoring the anticoagulant effect of NOACs and their potential specific antidotes in development.
Albright's hereditary osteodystrophy (AHO) is a rare inherited syndrome involving the molecular defects in the gene encoding the α subunit of the stimulatory G protein (Gsα). AHO has several variants, mainly pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP). We present a family that share the same inactivating GNAS1 mutation, the daughter being affected by PPHP and her late father with PHP. The daughter, in her late teens, presented with a long history of presyncopal and syncopal attacks. Her father died suddenly in his mid-40 s. As expected, her laboratory tests to date have shown normal biochemistry and hormonal levels. Subsequently, an implantable loop recorder was inserted. This demonstrated extreme sinus pauses of >11 s and also high-grade atrioventricular block. A dual-chamber pacemaker was therefore inserted.
Background and objectivesHigh monocyte counts are related to adverse outcomes in cardiovascular disease. Their role in prognostication in patients with atrial fibrillation (AF) is unknown. We investigated whether monocyte counts are useful as a marker of prognosis in patients with AF.MethodsMonocyte counts were obtained from blood samples in 881 AF patients. Study outcomes were (i) all-cause death; (ii) major adverse cardiovascular events; (iii) stroke, TIA or other systemic embolism (SSE); and (iv) major bleeding.ResultsMedian follow up was 7.2 years; 44% of patients died, 48% developed MACE; 9% had SSE and 5% had major bleeding. On Cox regression, after adjustment for CHA2DS2-VASc score, the highest quartile of monocyte counts (i.e., ≥580 μL vs. other quartiles) was associated with increased risk of death (hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.31–2.05, p<0.001) and MACE (HR 1.58, 95% CI 1.28–1.96, p<0.001). Persistent monocyte levels ≥580 per μL during follow up were associated with further increase in risk of death (HR 1.52, 95% CI 1.10–2.11, p = 0.01) and MACE (HR 1.54, 95% CI 1.13–2.09, p = 0.006). Persistent monocyte levels ≥580 per μL during were associated with a significant increase in major bleeding events (HR 2.77, 95% CI 1.36–5.67, p = 0.005, after adjustment for HAS-BLED score).ConclusionHigh monocyte counts independently predict the occurrence of MACE, major bleeding and mortality, but not SSE. Understanding the pathophysiological mechanisms involved would help understand the relationships between monocytes, and adverse thrombotic and bleeding outcomes in AF patients.
Introduction While combination therapy is the standard of care for relapsed/ refractory non-Hodgkin lymphoma (RR-NHL), the choice of combinations for an individual patient is empirical, and response rates remain poor. Here we explore the use of a hybrid experimental/analytic method termed Quadratic Phenotypic Optimization Platform (QPOP), for prediction of optimal drug combinations from limited clinical material. This high-throughput platform identifies optimal drug-combinations on ex-vivo biopsies using an orthogonal array composite design to maximise search space. These features are potentially useful to assess personalized efficacious combinations among a set of drugs with single agent pre-clinical or clinical activity in lymphoma. Methods We performed a prospective cohort study of QPOP analysis in RR-NHL. Participants included RR-NHL patients across two tertiary oncology centres in Singapore, with disease amenable to biopsy or blood/ marrow aspiration, recruited between 1 st November 2017 and 5 th May 2021 - with a median follow up of 24.5 months. CD20, CD3 or CD56 selection was performed to enrich for B, T or NK cells respectively, depending on the specimen type. QPOP drug combination scores were derived from lymphoma samples (approximately 1,000,000 cells/ patient) using a matrix of drugs with known pre-clinical or clinical efficacy against NHL. Results were shared with the treating physician, and off-label QPOP-guided therapy was offered in the absence of standard options. The primary outcomes were feasibility and turnaround time of QPOP analysis. The secondary outcomes were identification of recurrent 2 and 3 drug-combinations, and concordance of QPOP results with clinical responses. Results In this interim analysis period, we recruited 63 patients comprising 36 B-NHL and 27 T/NK-NHL, with a median age of 57 years and median 2 prior lines of treatment. Successful QPOP analysis (Z' score >0.5) was feasible in 56/63 cases with an average turn-around time of 6 (±2.1) days. QPOP predicted frequent sensitivities to Copanlisib- and Venetoclax-based combinations in B-NHL, and Romidepsin-based combinations in T/NK-NHL. Importantly, efficacy of specific combinations was not entirely dependent on single agent dose responses. Greater variability in ex-vivo responses was seen with combinations of targeted therapy and cytotoxic therapy compared with combinations of cytotoxic agents. Clinical responses were evaluable for 29 independent treatments in 26 patients. QPOP had a positive predictive value of 60% and a negative predictive value of 78.6% with an area under the curve of 0.672 (95%CI 0.47-0.87; p=0.12) for partial response or better (n=29, p= 0.06). Complete responses were achieved with novel QPOP derived drug combinations in patients refractory to standard therapy. Examples include Palbociclib-Everolimus for diffuse large B-cell lymphoma (figure 1) and Romidepsin-copanlisib for extra nodal natural killer T-cell lymphoma. Conclusions Prediction of sensitivity to drug-combinations in a clinically applicable time-frame is feasible for RR-NHL cases through QPOP analysis. The relatively small number of patients treated with QPOP directed regimens makes a definitive conclusion on concordance with clinical outcomes difficult at this stage. QPOP was however able to identify novel clinically effective combinations in patients refractory to standard therapy. These data provide the basis for a prospective clinical trial evaluating QPOP based therapy in RR-NHL. Figure 1 Figure 1. Disclosures Chng: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria. OffLabel Disclosure: everolimus palbociclib for diffuse large B cell lymphoma and rhomidepsin Bortezomib for extra nodal NK T cell lymphoma
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