Citations

Senescent cells exacerbate COVID-19 Cellular senescence is a state elicited in response to stress signals and is associated with a damaging secretory phenotype. The number of senescent cells increases with advanced age and this in turn drives age-related diseases. Camell et al. show that senescent cells have an amplified inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see the Perspective by Cox and Lord). This response is communicated to nonsenescent cells, suppressing viral defense mechanisms and increasing the expression of viral entry proteins. In old mice infected with a SARS-CoV-2–related virus, treatment with senolytics to reduce the senolytic cell burden reduced mortality and increased antiviral antibodies. Science , abe4832, this issue p. eabe4832 ; see also abi4474, p. 281

7502 Background: The BCL-2i venetoclax is active in certain HMs but can increase the risk of tumor lysis syndrome (TLS), requiring a 5-week dose ramp-up for CLL patients. Cases of severe neutropenia with venetoclax treatment have also been reported. Lisaftoclax is a novel, potent, selective BCL-2i that is active against HMs and is under clinical development. Methods: This first-in-human global phase I dose study assessed the safety, PK, PD, efficacy, and MTD/RP2D of lisaftoclax in patients with R/R CLL and other HMs. Lisaftoclax was orally administered daily in a 28-day cycle. Patients with CLL or intermediate-high TLS risk were initiated on a daily ramp-up schedule until the assigned dose before the study cycles. Results: On January 7, 2021, 35 pts had been enrolled and treated with lisaftoclax at doses ranging from 20 to 1,200 mg, with a median (range) of 2 (1-13) prior lines of treatment, and had diagnoses of R/R CLL or SLL (n = 15), MM (n = 6), FL (n = 5), WM (n = 4), and either AML, MCL, DLBCL, MDS, or HCL (n = 1 each). No DLT has been observed, even though 1,200 mg was considered as the highest dose treated. The MTD has not been reached, and no laboratory or clinical TLS has been reported. Any grade TRAEs in > 10% of pts included neutropenia (22.9%) and anemia (17.1%; hematologic), and fatigue (28.6%), diarrhea (17.1%), and nausea (11.4%; nonhematologic). Grade >3 TRAEs were neutropenia (14.3%) and thrombocytopenia, leukopenia, lymphopenia, fatigue, and nausea (2.9% of pts each). In CLL/SLL pts, grade 3-4 TRAEs included neutropenia (13.3%) and thrombocytopenia (6.7%), which did not cause treatment-related discontinuation. In all, 12 of 35 pts (34.3%) had non-treatment-related SAEs, and only two pts experienced > 1 SAE. With a median (range) treatment of 7 (3-20) cycles, 12 of 14 evaluable R/R CLL/SLL pts achieved PR, for an ORR of 85.7% and a median (range) time to response of 3 (2-7) cycles. Absolute lymphocyte counts (ALCs) were reduced at lisaftoclax doses as low as 20 mg/day. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 20 to 1,200 mg (average half-life: 4-5 hours). On BH3 profiling, lisaftoclax rapidly triggered changes in BCL-2 complex in CLL/SLL pt samples, which were consistent with rapid clinical reductions in ALCs. Conclusions: Lisaftoclax was well tolerated up to 1,200 mg/day. No TLS was observed, even with the daily ramp-up schedule. There were no significant new or unmanageable safety findings, and the ORR in R/R CLL/SLL pts was 85.7%. Grade 3-4 TRAEs were infrequent, even at dose levels of 800 mg and above. BCL-2i lisaftoclax offers a treatment alternative for patients with R/R CLL/SLL and other HMs, with a daily ramp-up schedule that may be more pt “user friendly” and a favorable preliminary safety profile. Internal study identifier APG2575-001. Clinical trial information: NCT03537482.

OBJECTIVE Optimizing patient discharge after surgery has been shown to impact patient recovery and hospital/physician workflow and to reduce healthcare costs. In the current study, the authors sought to identify risk factors for nonroutine discharge after surgery for cervical myelopathy by using a national spine registry. METHODS The Quality Outcomes Database cervical module was queried for patients who had undergone surgery for cervical myelopathy between 2016 and 2018. Nonroutine discharge was defined as discharge to postacute care (rehabilitation), nonacute care, or another acute care hospital. A multivariable logistic regression predictive model was created using an array of demographic, clinical, operative, and patient-reported outcome characteristics. RESULTS Of the 1114 patients identified, 11.2% (n = 125) had a nonroutine discharge. On univariate analysis, patients with a nonroutine discharge were more likely to be older (age ≥ 65 years, 70.4% vs 35.8%, p < 0.001), African American (24.8% vs 13.9%, p = 0.007), and on Medicare (75.2% vs 35.1%, p < 0.001). Among the patients younger than 65 years of age, those who had a nonroutine discharge were more likely to be unemployed (70.3% vs 36.9%, p < 0.001). Overall, patients with a nonroutine discharge were more likely to present with a motor deficit (73.6% vs 58.7%, p = 0.001) and more likely to have nonindependent ambulation (50.4% vs 14.0%, p < 0.001) at presentation. On multivariable logistic regression, factors associated with higher odds of a nonroutine discharge included African American race (vs White, OR 2.76, 95% CI 1.38–5.51, p = 0.004), Medicare coverage (vs private insurance, OR 2.14, 95% CI 1.00–4.65, p = 0.04), nonindependent ambulation at presentation (OR 2.17, 95% CI 1.17–4.02, p = 0.01), baseline modified Japanese Orthopaedic Association severe myelopathy score (0–11 vs moderate 12–14, OR 2, 95% CI 1.07–3.73, p = 0.01), and posterior surgical approach (OR 11.6, 95% CI 2.12–48, p = 0.004). Factors associated with lower odds of a nonroutine discharge included fewer operated levels (1 vs 2–3 levels, OR 0.3, 95% CI 0.1–0.96, p = 0.009) and a higher quality of life at baseline (EQ-5D score, OR 0.43, 95% CI 0.25–0.73, p = 0.001). On predictor importance analysis, baseline quality of life (EQ-5D score) was identified as the most important predictor (Wald χ2 = 9.8, p = 0.001) of a nonroutine discharge; however, after grouping variables into distinct categories, socioeconomic and demographic characteristics (age, race, gender, insurance status, employment status) were identified as the most significant drivers of nonroutine discharge (28.4% of total predictor importance). CONCLUSIONS The study results indicate that socioeconomic and demographic characteristics including age, race, gender, insurance, and employment may be the most significant drivers of a nonroutine discharge after surgery for cervical myelopathy.

Abstract Background We hypothesized that the addition of receptor tyrosine kinase inhibitors (RTKis, e.g., lapatinib, erlotinib, cetuximab, bevacizumab, panitumumab) to radiotherapy-based treatment for solid tumors does not increase overall survival but may increase toxicity. Methods Population, Intervention, Control, Outcome, Study Design; Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify prospective randomized studies including patients with solid tumor cancers treated with radiotherapy with or without RTKis. Extracted variables included use of radiotherapy vs chemoradiotherapy, RTKi type (antibody vs small molecule), outcomes, and toxicities. The primary endpoint was overall survival; the secondary endpoint was grade 3+ toxicity. Random-effects meta-analyses were performed for each outcome measure. All statistical tests were 2-sided. Results A total of 405 studies met the initial search criteria, of which 13 prospective randomized trials of radiotherapy with or without RTKi met the inclusion criteria, encompassing 5678 patients. The trials included cancers of the head and neck (6 trials, 3295 patients), esophagus (3 trials, 762 patients), lung (2 trials, 550 patients), and brain (2 trials, 1542 patients). Three studies evaluated a small molecule and radiotherapy in 949 patients, and 10 studies evaluated antibodies and radiotherapy in 4729 patients. The addition of RTKis to radiotherapy-based treatment did not improve overall survival (hazard ratio = 1.02, 95% confidence interval = 0.90 to 1.15, P = .76) but increased grade 3+ toxicity (relative risk = 1.18, 95% confidence interval = 1.06 to 1.33, P = .009). Conclusions The addition of RTKis to radiotherapy does not improve survival and worsens toxicity.

Background: Brain metastases (BM) from differentiated thyroid cancer are rare. Stereotactic radiosurgery (SRS) is commonly used for the treatment of BMs; however, the experience with SRS for thyroid cancer BMs remains limited. The goal of this international, multi-centered study was to evaluate the efficacy and safety of SRS for thyroid cancer BMs. Methods: From 10 institutions participating in the International Radiosurgery Research Foundation, we pooled patients with established papillary or follicular thyroid cancer diagnosis who underwent SRS for histologically confirmed or radiologically suspected BMs. We investigated patient overall survival (OS), local tumor control, and adverse radiation events (AREs). Results: We studied 42 (52% men) patients who underwent SRS for 122 papillary (83%) or follicular (17%) thyroid cancer BMs. The mean age at SRS was 59.86 ± 12.69 years. The mean latency from thyroid cancer diagnosis to SRS for BMs was 89.05 ± 105.49 months. The median number of BMs per patient was 2 (range: 1–10 BMs). The median SRS treatment volume was 0.79 cm 3 (range: 0.003–38.18 cm 3 ), and the median SRS prescription dose was 20 Gy (range: 8–24 Gy). The median survival after SRS for BMs was 14 months (range: 3–58 months). The OS was significantly shorter in patients harboring ≥2 BMs, when compared with patients with one BM (Log-rank = 5.452, p = 0.02). Two or more BMs (odds ratio [OR] = 3.688; confidence interval [CI]: 1.143–11.904; p = 0.03) and lower Karnofsky performance score at the time of SRS (OR = 0.807; CI: 0.689–0.945; p = 0.008) were associated with shorter OS. During post-SRS imaging follow-up of 25.21 ± 30.49 months, local failure (progression and/or radiation necrosis) of BMs treated with SRS was documented in five (4%) BMs at 7.2 ± 7.3 months after the SRS. At the last imaging follow-up, the majority of patients with available imaging data had stable intracranial disease (33%) or achieved complete (26%) or partial (24%) response. There were no clinical AREs. Post-SRS peritumoral T2/fluid attenuated inversion recovery signal hyperintensity was noted in 7% BMs. Conclusion: The SRS allows durable local control of papillary and follicular thyroid cancer BMs in the vast majority of patients. Higher number of BMs and worse functional status at the time of SRS are associated with shorter OS in patients with thyroid cancer BMs. The SRS is safe and is associated with a low risk of AREs.

AbstractInformation about the effects of angiotensin II receptor blocker (ARB) therapy on the hemodynamic and cardiac structure in patients with chronic aortic regurgitation (CAR) and isolated systolic hypertension (ISH) is limited.This study planned to test the hypothesis that l-arginine could further enhance the beneficial effect of an ARB, losartan, and provide a favorable effect on the natural history of CAR and ISH.Sixty patients with CAR and ISH were enrolled in a randomized, double-blind trial comparing hemodynamic and ultrasonic change in two treatment arms: losartan + l-arginine and losartan-only treated groups. Serial echocardiographic and hemodynamic studies were evaluated before and after treatment.Both groups had a significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP), left ventricular end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), LV mass index (LVMI), and LV mean wall stress after 6- and 12-month treatment (p <0.01 in all comparisons). Both groups had a significant increase in LV ejection fraction and exercise duration after 6- and 12-month treatment (p < 0.01 in all comparisons). Using multivariate linear regression analysis, only losartan + l-arginine therapy achieved a significantly lower LVESVI (38.89 ± 0.23 mL/m2), LVEDVI (102.3 ± 0.3 mL/m2), LVMI (107.6 ± 0.3 g/m2), SBP (123.5 ± 1.0 mm Hg), and greater exercise duration (7.38 ± 0.02 minutes) than those of the losartan-only treated groups (p <0.01 in all comparisons).These findings suggest that early co-administrative strategy provides a beneficial approach to favorably influence the natural history of CAR.

AbstractThe application of scaffold‐based stem cell transplantation to enhance peripheral nerve regeneration has great potential. Recently, the neuroregenerative potential of tacrolimus (a U.S. Food and Drug Administration‐approved immunosuppressant) has been explored. In this study, a fibrin gel‐based drug delivery system for sustained and localized tacrolimus release was combined with rat adipose‐derived mesenchymal stem cells (MSC) to investigate cell viability in vitro. Tacrolimus was encapsulated in poly(lactic‐co‐glycolic) acid (PLGA) microspheres and suspended in fibrin hydrogel, using concentrations of 0.01 and 100 ng/ml. Drug release over time was measured. MSCs were cultured in drug‐released media collected at various days to mimic systemic exposure. MSCs were combined with (i) hydrogel only, (ii) empty PLGA microspheres in the hydrogel, (iii) 0.01, and (iv) 100 ng/ml of tacrolimus PLGA microspheres in the hydrogel. Stem cell presence and viability were evaluated. A sustained release of 100 ng/ml tacrolimus microspheres was observed for up to 35 days. Stem cell presence was confirmed and cell viability was observed up to 7 days, with no significant differences between groups. This study suggests that combined delivery of 100 ng/ml tacrolimus and MSCs in fibrin hydrogel does not result in cytotoxic effects and could be used to enhance peripheral nerve regeneration.

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial. Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region. Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P >0.05). Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.

OBJECTIVE The ideal surgical management of grade I lumbar spondylolisthesis has not been determined despite extensive prior investigations. In this cohort study, the authors used data from the large, multicenter, prospectively collected Quality Outcomes Database to bridge the gap between the findings in previous randomized trials and those in a more heterogeneous population treated in a typical practice. The objective was to assess the difference in patient-reported outcomes among patients undergoing decompression alone or decompression plus fusion. METHODS The primary outcome measure was change in 24-month Oswestry Disability Index (ODI) scores. The minimal clinically important difference (MCID) in ODI score change and 30% change in ODI score at 24 months were also evaluated. After adjusting for patient-specific and clinical factors, multivariable linear and logistic regressions were employed to evaluate the impact of fusion on outcomes. To account for differences in age, sex, body mass index, and baseline listhesis, a sensitivity analysis was performed using propensity score analysis to match patients undergoing decompression only with those undergoing decompression and fusion. RESULTS In total, 608 patients who had grade I lumbar spondylolisthesis were identified (85.5% with at least 24 months of follow-up); 140 (23.0%) underwent decompression alone and 468 (77.0%) underwent decompression and fusion. The 24-month change in ODI score was significantly greater in the fusion plus decompression group than in the decompression-only group (−25.8 ± 20.0 vs −15.2 ± 19.8, p < 0.001). Fusion remained independently associated with 24-month ODI score change (B = −7.05, 95% CI −10.70 to −3.39, p ≤ 0.001) in multivariable regression analysis, as well as with achieving the MCID for the ODI score (OR 1.767, 95% CI 1.058–2.944, p = 0.029) and 30% change in ODI score (OR 2.371, 95% CI 1.286–4.371, p = 0.005). Propensity score analysis resulted in 94 patients in the decompression-only group matched 1 to 1 with 94 patients in the fusion group. The addition of fusion to decompression remained a significant predictor of 24-month change in the ODI score (B = 2.796, 95% CI 2.228–13.275, p = 0.006) and of achieving the 24-month MCID ODI score (OR 2.898, 95% CI 1.214–6.914, p = 0.016) and 24-month 30% change in ODI score (OR 2.300, 95% CI 1.014–5.216, p = 0.046). CONCLUSIONS These results suggest that decompression plus fusion in patients with grade I lumbar spondylolisthesis may be associated with superior outcomes at 24 months compared with decompression alone, both in reduction of disability and in achieving clinically meaningful improvement. Longer-term follow-up is warranted to assess whether this effect is sustained.

Human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) diagnostic testing algorithms recommended by the Centers for Disease Control involve up to three tests and rely mostly on detection of viral antigen and host antibody responses. HIV-1 p24 antigen/HIV-1/HIV-2 antibody-reactive specimens are confirmed with an immunochromatographic HIV-1/HIV-2 antibody differentiation assay, and negative or indeterminate results from the differentiation assay are resolved by an HIV-1-specific nucleic acid amplification test (NAT).