Beyond the Detector Horizon:Forecasting Gravitational-Wave Strong Lensing

When gravitational waves pass near massive astrophysical objects, they can be gravitationally lensed. The lensing can split them into multiple wave-fronts, magnify them, or imprint beating patterns on the waves. Here we focus on the multiple images produced by strong lensing. In particular, we investigate strong lensing forecasts, the rate of lensing, and the role of lensing statistics in strong lensing searches. Overall, we find a reasonable rate of lensed detections for double, triple, and quadruple images at the LIGO--Virgo--KAGRA design sensitivity. We also report the rates for A+ and LIGO Voyager and briefly comment on potential improvements due to the inclusion of sub-threshold triggers. We find that most galaxy-lensed events originate from redshifts $z \sim 1-4$ and report the expected distribution of lensing parameters for the observed events. Besides forecasts, we investigate the role of lensing forecasts in strong lensing searches, which explore repeated event pairs. One problem associated with the searches is the rising number of event pairs, which leads to a rapidly increasing false alarm probability. We show how knowledge of the expected galaxy lensing time delays in our searches allow us to tackle this problem. Once the time delays are included, the false alarm probability increases linearly (similar to non-lensed searches) instead of quadratically with time, significantly improving the search. For galaxy cluster lenses, the improvement is less significant. The main uncertainty associated with these forecasts are the merger-rate density estimates at high redshift, which may be better resolved in the future

Long-Term Outcomes in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib: Focus on Hypertension and Cardiovascular Toxicity

BACKGROUND: Continuous ibrutinib administration is needed to maintain efficacy in patients with chronic lymphocytic leukemia (CLL) and, as such, long-term toxicity is a concern. The authors report the 5-year follow-up of patients with CLL who received treatment with ibrutinib with a focus on hypertension and cardiovascular toxicities. METHODS: Patient characteristics were assessed, including blood pressure, cardiovascular disease, disease progression, and death. Univariate logistic regression analysis assessed the relation of patient characteristics and the development of new or worsened hypertension. The incidence of hypertensive outcomes was evaluated using competing risk. Survival was estimated using the Kaplan-Meier method. RESULTS: Three hundred patients with CLL who were treated with ibrutinib on clinical trials were included. The median patient age at study enrollment was 65 years (range, 29-83 years). Seventy percent of patients were men, and 88% were Caucasian. Sixty-nine percent of patients had hypertension at baseline, and 47% were on antihypertensive medication. Eighty-eight percent had relapsed or refractory CLL. New-onset and worsening hypertension were common, occurring in 68.5% and 38% of patients, respectively. Systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg was observed in 16.9% of patients. Hypertension was reversible after ibrutinib discontinuation. Older age, male sex, tobacco use, and chronic kidney disease were associated with ibrutinib-related hypertension. Baseline hypertension was not associated with major adverse cardiovascular events in ibrutinib-treated patients nor with event-free or overall survival. CONCLUSIONS: Hypertension is a common toxicity in patients with CLL who receive ibrutinib but is manageable in most patients. Other than chronic kidney disease, baseline cardiovascular disease did not affect ibrutinib-related hypertension nor was hypertension associated with major adverse cardiovascular events or survival. PLAIN LANGUAGE SUMMARY: Ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia. Ibrutinib is a well tolerated therapy, however hypertension can develop or worsen in patients receiving ibrutinib and other cardiovascular events are significant challenges to the use of this drug. This may be particularly true in patients with heart disease. Short-term side effects may worsen heart disease, but the long-term impact is unknown. The long-term results of ibrutinib on heart disease and hypertension are described

Update in the management of chronic lymphocytic leukemia

Advances in the treatment of chronic lymphocytic leukemia (CLL) have improved initial overall response (OR) rates, complete response (CR) rates and progression free survival (PFS). Despite these advances, CLL remains incurable with standard therapies. Thus, there remains a need for more effective therapies in both the upfront and relapsed setting, particularly for patients with high-risk cytogenetic abnormalities such as del(11q22) and del(17p13). The 2008 American Society of Hematology (ASH) Annual Meeting featured several presentations which highlighted the ongoing clinical advances in CLL. The benefit of adding rituximab to purine analog therapy in the upfront setting was demonstrated by a large randomized study which showed that the addition of rituximab to fludarabine and cyclophosphamide (FCR) significantly improved OR, CR and PFS. The improvement in PFS directly resulted from an improved ability to eliminate minimal residual disease (MRD) in the peripheral blood, highlighting the importance of MRD eradication. However, a multi-center study suggested that the high CR rates to chemoimmunotherapy regimens such as FCR obtained in academic centers may not be reproducible when the same regimens are given in the community setting. The immunomodulatory drug lenalidomide is active in relapsed high-risk CLL, but two studies of lenalidomide in previously untreated CLL patients failed to achieve a CR and were associated with significant tumor lysis, tumor flare and hematologic toxicity. In the relapsed setting, a combination study of the bifunctional alkylator bendamustine and rituximab (BR) demonstrated a high OR rate in patients with del(11q22) and del(17p13), indicating that further studies to define's bendamustine activity are warranted in high-risk CLL. Similarly, the CDK inhibitor flavopiridol demonstrated significant clinical activity and durable remissions in heavily treated, refractory CLL patients with high-risk cytogenetic features and bulky lymphadenopathy. The monoclonal anti-CD20 antibody ofatumumab appeared to be superior to rituximab in relapsed CLL patients with bulky nodal disease or high-risk cytogenetic features. Ongoing studies of these agents and other novel therapeutic agents in clinical development hold forth the promise that treatment options for CLL patients will continue to expand and improve

Generation of Functional CLL-Specific Cord Blood CTL Using CD40-Ligated CLL APC

PMCID: PMC3526610This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The Emerging Role of Ofatumumab in the Treatment of Chronic Lymphocytic Leukemia

The treatment of chronic lymphocytic leukemia (CLL) has evolved over the past decade. Our better understanding of disease biology and risk stratification has allowed delivering more effective therapies. In fact, front-line chemoimmunotherapy has demonstrated improvement in overall survival when compared to chemotherapy in randomized studies. Yet, treatment of relapsed CLL remains challenging and few agents are effective in that setting. Ofatumumab (Ofa) is a humanized monoclonal antibody targeted against CD20 with demonstrable activity in rituximab-resistant CLL cell lines. This agent was recently approved for the treatment of relapsed/refractory CLL patients who have failed fludarabine and alemtuzumab. In this review, we provide a historical perspective on approaches to CLL as front-line and in the relapsed setting. We further summarize novel anti-CD20 antibodies with specific emphasis on ofa. We review studies that led to ofatumumab’s approval including pre-clinical data, trials using ofa in combination therapies, and adverse events/toxicities reported with this agent

On the detection and precise localization of merging black holes events through strong gravitational lensing

To unlock the full spectrum of astrophysical and cosmological applications of gravitational-wave detections, it is essential to localize the associated black hole mergers to high precision inside their host galaxies. One possible method to achieve this is to compare the properties of multiple detections of gravitationally lensed binary black hole merger events with the properties of strong gravitational lens systems located in the joint sky localization of the gravitational-wave detections. In this work, we simulate the population of binary black hole mergers lensed by galaxy-scale lenses and detectable by LIGO-Virgo-Kagra in the coming decade and the population of galaxy-scale strong lenses that will be detected by Euclid. We use these simulations to investigate the prospects for localizing strongly lensed binary black hole mergers inside the lensed galaxies of 'Euclid-like' galaxy-scale strong lenses. We find that for 20- of strongly lensed gravitational-wave events the lens system is detectable with Euclid, if the event falls in its survey footprint. Of these, we expect to correctly identify the strongly lensed host galaxy as likely (with posterior probability) host galaxy - based on Bayesian evidence ranking of candidate hosts - for 34.6- of quadruply lensed gravitational-wave events when given an a priori 1-5 gravitational-wave-only sky localization. For triply and doubly lensed gravitational-wave events, this becomes 29.8- and 16.4- respectively. If successfully identified, however, the localization can be better than a fraction of the host-galaxy size, i.e. of order milli-arcseconds. A first detection in the coming decade, however, probably requires dedicated deep and high-resolution follow-ups and continued upgrades in the current and planned gravitational-wave detectors