Outcomes by Class of Anticoagulant Use for Nonvalvular Atrial Fibrillation in Patients With Active Cancer.

Background: The choice of anticoagulant agent for patients with nonvalvular atrial fibrillation (NVAF) in the setting of active cancer has not been well studied. Objectives: The aim of this study was to compare the rates of cerebrovascular accident (CVA), gastrointestinal bleeding (GIB), and intracranial hemorrhage (ICH) in patients treated with direct oral anticoagulant agents (DOACs) compared with warfarin for NVAF in patients with active cancer. Methods: This was a retrospective electronic medical record review of eligible patients treated at a cancer hospital. The outcome events were CVA; GIB; ICH; the composite of GIB, CVA, or ICH; and overall mortality. Propensity score matching (1:1) was conducted to select comparable patients receiving warfarin vs DOACs. Fine-Gray models were fitted for each outcome event. Results: The study cohort included 1,133 patients (mean age 72 ± 8.8 years, 42% women), of whom 74% received DOACs (57% received apixaban). After propensity score matching, 195 patients were included in each anticoagulant agent group. When comparing warfarin with DOACs, there were similar risks for CVA (subdistribution HR: 0.738; 95% CI: 0.334-1.629); ICH (subdistribution HR: 0.295; 95% CI: 0.032-2.709); GIB (subdistribution HR: 1.819; 95% CI: 0.774-4.277); and the composite of GIB, CVA, or ICH (subdistribution HR: 1.151; 95% CI: 0.645-2.054). Conclusions: Patients with active cancer had similar risks for CVA, ICH, and GIB when treated with DOACs compared with warfarin for NVAF.

Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study.

BACKGROUND: Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort. METHODS: Rabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 µg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. PATIENTS: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan. RESULTS: Intravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%-79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 µV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged. CONCLUSIONS: Taken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

Intravitreal HDAC Inhibitor Belinostat Effectively Eradicates Vitreous Seeds Without Retinal Toxicity In Vivo in a Rabbit Retinoblastoma Model.

Purpose: Current melphalan-based regimens for intravitreal chemotherapy for retinoblastoma vitreous seeds are effective but toxic to the retina. Thus, alternative agents are needed. Based on the known biology of histone deacetylases (HDACs) in the retinoblastoma pathway, we systematically studied whether the HDAC inhibitor belinostat is a viable, molecularly targeted alternative agent for intravitreal delivery that might provide comparable efficacy, without toxicity. Methods: In vivo pharmacokinetic experiments in rabbits and in vitro cytotoxicity experiments were performed to determine the 90% inhibitory concentration (IC90). Functional toxicity by electroretinography and structural toxicity by optical coherence tomography (OCT), OCT angiography, and histopathology were evaluated in rabbits following three injections of belinostat 350 µg (2× IC90) or 700 µg (4× IC90), compared with melphalan 12.5 µg (rabbit equivalent of the human dose). The relative efficacy of intravitreal belinostat versus melphalan to treat WERI-Rb1 human cell xenografts in rabbit eyes was directly quantified. RNA sequencing was used to assess belinostat-induced changes in RB cell gene expression. Results: The maximum nontoxic dose of belinostat was 350 µg, which caused no reductions in electroretinography parameters, retinal microvascular loss on OCT angiography, or retinal degeneration. Melphalan caused severe retinal structural and functional toxicity. Belinostat 350 µg (equivalent to 700 µg in the larger human eye) was equally effective at eradicating vitreous seeds in the rabbit xenograft model compared with melphalan (95.5% reduction for belinostat, P < 0.001; 89.4% reduction for melphalan, P < 0.001; belinostat vs. melphalan, P = 0.10). Even 700 µg belinostat (equivalent to 1400 µg in humans) caused only minimal toxicity. Widespread changes in gene expression resulted. Conclusions: Molecularly targeted inhibition of HDACs with intravitreal belinostat was equally effective as standard-of-care melphalan but without retinal toxicity. Belinostat may therefore be an attractive agent to pursue clinically for intravitreal treatment of retinoblastoma.

Efficacy, Toxicity, and Pharmacokinetics of Intra-Arterial Chemotherapy Versus Intravenous Chemotherapy for Retinoblastoma in Animal Models and Patients.

Purpose: Through controlled comparative rabbit experiments and parallel patient studies, our purpose was to understand mechanisms underlying differences in efficacy and toxicity between intra-arterial chemotherapy (IAC) and intravenous chemotherapy (IVC). Methods: In rabbits, ocular tissue drug levels were measured following IAC and IVC. Retinal toxicity was assessed using electroretinography, fluorescein angiography, optical coherence tomography (OCT) and OCT angiography. Efficacy to eradicate retinoblastoma orthotopic xenografts was compared. In IAC and IVC patients, we measured blood carboplatin pharmacokinetics and compared efficacy and toxicity. Results: In rabbits receiving IAC, maximum carboplatin levels were 134 times greater in retina (P = 0.01) and 411 times greater in vitreous (P < 0.001), and total carboplatin (area under the curve) was 123 times greater in retina (P = 0.005) and 131 times greater in vitreous (P = 0.02) compared with IVC. Melphalan levels were 12 times greater (P = 0.003) in retina and 26 times greater in vitreous (P < 0.001) for IAC. Blood levels were not different. IAC melphalan (but not IV melphalan or IV carboplatin, etoposide, and vincristine) caused widespread apoptosis in retinoblastoma xenografts but no functional retinal toxicity or cytopenias. In patients, blood levels following IVC were greater (P < 0.001) but, when adjusted for treatment dose, were not statistically different. Per treatment cycle in patients, IVC caused higher rates of anemia (0.32 ± 0.29 vs. 0.01 ± 0.04; P = 0.0086), thrombocytopenia (0.5 ± 0.42 vs. 0.0 ± 0.0; P = 0.0042), and neutropenia (0.58 ± 0.3 vs. 0.31 ± 0.25; P = 0.032) but lower treatment success rates (P = 0.0017). Conclusions: The greater efficacy and lower systemic toxicity with IAC appear to be attributable to the greater ocular-to-systemic drug concentration ratio compared with IVC. Translational Relevance: Provides an overarching hypothesis for a mechanism of efficacy/toxicity to guide future drug development.

Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus: A Retrospective, Multicenter Study and Meta-Analysis of Existing Data.

AIM: To compare the safety and efficacy of direct oral anticoagulants (DOAC) relative to vitamin K antagonists (VKA) for the treatment of left ventricular thrombus (LVT). METHODS: This retrospective study enrolled patients diagnosed with LVT from 2014-2017. Patient characteristics and outcomes within 12 months of LVT diagnosis were recorded and analyzed. A meta-analysis was also performed by pooling our results with existing data in literature. RESULTS: 14 DOAC and 59 VKA patients were included. Baseline demographic and clinical characteristics were similar except for age. Although more strokes within 12 months occurred in VKA (15%) than in DOAC (0%) patients, this was not statistically significant (P = 0.189). There were no significant differences in outcomes between patients on DOAC and VKA for acute coronary syndrome (ACS) (7%, vs 3.4%, P = .477), LVT resolution (86% vs 76%, P = .499) or bleeding (14% vs 14%, P = 1) within 12 months. The meta-analysis included 6 studies (n = 408 for DOACs; n = 1207 for VKA). There were no significant differences between DOACs versus VKAs with respect to odds for unresolved thrombus (OR 0.61, 95% CI 0.26,1.41), embolic events (OR 1.24, 95% CI 0.90,1.69), embolic events and death (OR 1.10, 95% CI 0.84,1.45) or bleeding events (OR 1.13, 95% CI 0.74,1.72). CONCLUSIONS: Our study and meta-analysis suggest similar efficacy and safety of DOACs in the treatment of LVT compared to VKA. These findings underscore the need for a randomized controlled trial.

Independent Preoperative Predictors of Prolonged Length of Stay after Laparoscopic Appendectomy in Patients Over 30 Years of Age: Experience from a Single Institution.

Prompt discharge after laparoscopic appendectomy (LA) is a marker of quality of care, fiscally desirable and feasible in select patients. Patients over 30 comprise a more heterogeneous cohort known to experience worse outcomes after LA. We aimed to identify easily available preoperative risk factors portending a postoperative length of stay ≥2 days among patients above age 30. In this investigation, 296 included patients from a single institution who underwent LA for acute appendicitis from 2010 to 2014 were retrospectively reviewed for preoperative demographics, laboratory studies, comorbidities, presentation characteristics, radiographic finding, and other rationally selected factors for association with postoperative length of stay ≥2 days. Bivariate and multivariate analysis was conducted to determine independent risk factors, which were subsequently modeled via receiver-operating characteristic curve generation and Kaplan-Meier analysis. "Classic" presentation [odds ratio (OR) = 0.5, P = .02], elevated red cell distribution width (RDW; OR = 1.5/% increase, P = 0.004) as well as evidence of rupture on CT (OR = 6.9, P < 0.001) were independently associated with postoperative length of stay ≥ 2 days. Modeling length of stay using these factors generated an area under the curve of 0.713 ± 0.037. Kaplan-Meier analysis of "classic" presentation, elevated RDW, and evidence of rupture on CT through the fifth postoperative day generated log-rank P values of 0.02, 0.05, and ≤ 0.001, respectively. In summary, lack of "classic" presentation, elevated RDW, and CT evidence of rupture are novel risk factors for prolonged postoperative length of stay in LA patients over 30. These findings may help target patients most appropriate for prompt discharge.

Dual endothelin receptor antagonism with bosentan reverses established vascular remodeling and dysfunctional angiogenesis in diabetic rats: relevance to glycemic control.

AIMS: We have shown that diabetes causes cerebrovascular remodeling in part by the activation of the endothelin (ET-1) system in a glucose-dependent manner. We also reported increased yet dysfunctional cerebral angiogenesis in diabetes. Here, we tested the hypothesis that dual ET-1 receptor antagonism or glycemic control can reverse already established diabetes-induced vascular remodeling and neovascularization. MAIN METHODS: 18-week non-obese type-2 diabetic Goto-Kakizaki (GK) were treated with vehicle, metformin (300 mg/kg/day) or bosentan (100 mg/kg/day) for 4 weeks by oral gavage and compared to 10 and 18-weeks GK rats. Isolated middle cerebral artery (MCA) lumen diameter (LD), media thickness (MT), media:lumen (M:L) ratio, and cross-sectional area (CSA) were measured using pressurized arteriograph. Assessment of remodeling and angiogenesis in the brain parenchyma was achieved by three-dimensional reconstruction of fluorescently labeled images of the vasculature acquired by confocal microscopy, and measurement of neovascularization indices including vascular volume and surface area, branch density and tortuosity. KEY FINDINGS: MCA remodeling (increased M:L ratio and CSA, but decreased LD) occurred by 18 weeks and did not progress by 22 weeks in diabetic GK rats. Metformin and bosentan partially corrected large artery remodeling. Both treatments significantly reduced all indices of neovascularization compared to untreated diabetic rats. SIGNIFICANCE: Glycemic control or ET-1 antagonism can partially reverse diabetes-induced cerebrovascular remodeling and neovascularization. These results strongly suggest that either approach offers a therapeutic benefit and combination treatments need to be tested.