Ventricular arrhythmias and sudden death events following acalabrutinib initiation.

Acalabrutinib, a next-generation Bruton's tyrosine kinase inhibitor (BTKi), associates with dramatic efficacy against B-cell malignancies. Recently, unexplained ventricular arrhythmias (VAs) with next-generation BTKi-therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow-up is unknown. Leveraging a large-cohort of 290 consecutive B-cell malignancy patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence of VAs. The primary-endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability-scores were assessed to determine likelihood of acalabrutinib-association. Incident rates as function of time-on-therapy were calculated. Weighted average observed incidence rates were compared with expected population rates using relative-risks. Absolute excess risk (AER) for acalabrutinib-associated VAs was estimated. Over 1063 person-years of follow-up, there were 8 cases of incident-VAs, including 6 in those without coronary disease (CAD) or heart failure (HF) and 1 sudden-death; median time-to-event 14.9 months. Among those without prior ibrutinib-use, CAD, or HF, the weighted average incidence was 394 per 100 000 person years compared with a reported incidence of 48.1 among similar-aged non-BTKi-treated subjects (relative risk, 8.2; P < .001; AER, 346). Outside of age, no cardiac or electrocardiographic variables associated with VA development. Collectively, these data suggest VAs may be a class-effect of BTKi therapies.

Estrogen-Associated Headaches Can Be Treated by Surgery: A Multicenter Retrospective Cohort Study.

BACKGROUND: Nerve decompression surgery has been successful in treating headaches refractory to traditional medical therapies. Nevertheless, a subset of patients remains unresponsive to surgical treatment. METHODS: The authors conducted a retrospective chart review of the two senior authors' (J.E.J. and W.G.A.) patient data from 2007 to 2020 to investigate differences in surgical outcomes in women reporting estrogen-associated headaches (headaches associated with menstrual period, oral contraceptives, pregnancy, or other hormonal drugs) compared with those who did not. For these two groups, the authors used the migraine headache index as the metric for headache severity and compared the mean percent change in migraine headache index score at 3 months and 1 year. RESULTS: Of the 99 female patients who underwent nerve decompression surgery and met inclusion criteria, 50 reported estrogen-associated headaches and were found to have significantly earlier age of onset ( p = 0.017) and initial presentation to clinic ( p = 0.046). At 1 year postoperatively, migraine headache index score had improved more than 80 percent in the majority of patients (67 percent), but there was a subset of patients whose score improved less than 5 percent (12.5 percent). The authors did not find a significant difference in percent change in postoperative migraine headache index score between women with estrogen-associated headaches and those without such headaches. CONCLUSIONS: Women with estrogen-associated headaches have surgical outcomes comparable to those of women without this association. Nerve decompression surgery should be offered to women experiencing estrogen-associated headaches as an option for treatment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation.

BACKGROUND: Post-market analyses revealed unanticipated links between first-generation Bruton's tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown. METHODS: Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed. RESULTS: Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P < 0.001), yet 34.1% lower than ibrutinib (12.9 observed-to-expected ratio, P < 0.001). In multivariable regression, prior arrhythmias and Black ancestry were associated with new hypertension (HR 1.63, HR 4.35, P < 0.05). The degree of SBP rise within 1 year of treatment initiation predicted MACE risk (42% HR increase for each + 5 mmHg SBP rise, P < 0.001). No single antihypertensive class prevented worsened acalabrutinib-related hypertension. CONCLUSIONS: Collectively, these data suggest that hypertension may be a class effect of BTKi therapies and precedes major cardiotoxic events.

A subset of topologically associating domains fold into mesoscale core-periphery networks.

Mammalian genomes are folded into a hierarchy of compartments, topologically associating domains (TADs), subTADs, and long-range looping interactions. The higher-order folding patterns of chromatin contacts within TADs and how they localize to disease-associated single nucleotide variants (daSNVs) remains an open area of investigation. Here, we analyze high-resolution Hi-C data with graph theory to understand possible mesoscale network architecture within chromatin domains. We identify a subset of TADs exhibiting strong core-periphery mesoscale structure in embryonic stem cells, neural progenitor cells, and cortical neurons. Hyper-connected core nodes co-localize with genomic segments engaged in multiple looping interactions and enriched for occupancy of the architectural protein CCCTC binding protein (CTCF). CTCF knockdown and in silico deletion of CTCF-bound core nodes disrupts core-periphery structure, whereas in silico mutation of cell type-specific enhancer or gene nodes has a negligible effect. Importantly, neuropsychiatric daSNVs are significantly more likely to localize with TADs folded into core-periphery networks compared to domains devoid of such structure. Together, our results reveal that a subset of TADs encompasses looping interactions connected into a core-periphery mesoscale network. We hypothesize that daSNVs in the periphery of genome folding networks might preserve global nuclear architecture but cause local topological and functional disruptions contributing to human disease. By contrast, daSNVs co-localized with hyper-connected core nodes might cause severe topological and functional disruptions. Overall, these findings shed new light into the mesoscale network structure of fine scale genome folding within chromatin domains and its link to common genetic variants in human disease.