Citations

Objective To provide evidence‐based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody–associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Methods Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel. Results We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low‐quality evidence supporting the recommendations. Conclusion This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.

Objective To develop a core outcome set (COS) for randomised controlled trials (RCTs) evaluating the effectiveness of interventions for the treatment of pregnant women with pregestational diabetes mellitus (PGDM). Design A consensus developmental study. Setting International. Population Two hundred and five stakeholders completed the first round. Methods The study consisted of three components. (1) A systematic review of the literature to produce a list of outcomes reported in RCTs assessing the effectiveness of interventions for the treatment of pregnant women with PGDM. (2) A three‐round, online eDelphi survey to prioritise these outcomes by international stakeholders (including healthcare professionals, researchers and women with PGDM). (3) A consensus meeting where stakeholders from each group decided on the final COS. Main outcome measures All outcomes were extracted from the literature. Results We extracted 131 unique outcomes from 67 records meeting the full inclusion criteria. Of the 205 stakeholders who completed the first round, 174/205 (85%) and 165/174 (95%) completed rounds 2 and 3, respectively. Participants at the subsequent consensus meeting chose 19 outcomes for inclusion into the COS: trimester‐specific haemoglobin A1c, maternal weight gain during pregnancy, severe maternal hypoglycaemia, diabetic ketoacidosis, miscarriage, pregnancy‐induced hypertension, pre‐eclampsia, maternal death, birthweight, large for gestational age, small for gestational age, gestational age at birth, preterm birth, mode of birth, shoulder dystocia, neonatal hypoglycaemia, congenital malformations, stillbirth and neonatal death. Conclusions This COS will enable better comparison between RCTs to produce robust evidence synthesis, improve trial reporting and optimise research efficiency in studies assessing treatment of pregnant women with PGDM. Tweetable abstract 165 key stakeholders have developed #Treatment #CoreOutcomes in pregnant women with #diabetes existing before pregnancy.

Background Carotid artery stent (CAS) placement may be used as an alternative to carotid endarterectomy in selected patients with symptomatic and asymptomatic carotid artery disease. Perhaps because stroke is an uncommon event after CAS, the angiographic predictors of stroke have been incompletely described. Methods A total of 1070 catheter-based angiograms were centrally reviewed in patients undergoing CAS enrolled in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Of these patients, 43 (4%) experienced periprocedural stroke. Angiograms were reviewed using qualitative and quantitative methodology before and after CAS. Reviews were done blinded to patient outcomes and strokes were adjudicated by a central committee blinded to results of angiography. The view showing the greatest carotid stenosis severity was selected. Extreme tortuosity was defined as 2 severe bends >90 degrees (maximum angulation/20 mm segment) beyond the target lesion, sequential lesions as lesions separated by ≥10 mm, and narrow mouth ulcer as a discrete area of contrast extension beyond the normal arterial lumen with a narrow inlet into the ulceration. Results The internal carotid artery reference diameter was 4.2 ± 0.8 mm, the minimal lumen diameter was 1.1 ± 0.6 mm, and the baseline % diameter stenosis was 74.1 ± 11.6%. There were no differences in vessel size or severity of the stenosis in patients with and without stroke. Morphologic predictors significantly related to the risk of subsequent stroke are listed in the Table . Calcification, lesion eccentricity, baseline flow, and distance from the bifurcation were not predictive of periprocedural stroke (p > 0.05). Conclusion In CREST, four angiographic variables were found to increase risk for stroke during and within 30 days after CAS: severe distal tortuosity, sequential lesions, lesion length > 20 mm, and narrow mouth ulcer. Angiographic characteristics beyond percent stenosis may help in patient selection in terms of best revascularization option.

Background: In the ACUITY Trial, patients (pts) with chronic renal insufficiency (CRI) had significantly higher rates of ischemic events and major bleeding compared to pts without CRI at 30 days. Bivalirudin (Biv) monotherapy provided similar protection from ischemic events but with significantly less bleeding compared to heparin + a GPIIb/IIIa inhibitor (Hep+GPI). The impact of a Biv alone strategy on one year mortality is unknown. Methods: Pts with moderate and high risk acute coronary syndromes (ACS) were randomized to Hep + GPI, Biv + GPI, or Biv monotherapy. CRI was defined as baseline creatinine clearance (CrCl) <60 mL/min. We evaluated the impact of CRI and antithrombotic strategy on composite ischemia (death, MI, or revascularization) and mortality at one year. Results: Of the pts enrolled, 12,933 had baseline CrCl data: 2468 (19.1%) pts had CrCl ≥60 mL/min and 10,465 (80.9%) pts had CrCl <60 mL/min. Rates of major bleeding at 30 days in pts with CRI were significantly lower with Biv alone vs Hep+GPI (6.2% vs 9.8%, p<0.01). Pts with CRI had higher mortality at one year compared to those without CRI (8.7% vs 3.0%, p<0.001). There was no difference in composite ischemia for pts who received Biv monotherapy vs Hep + GPI (23.0% vs 21.4%, p=0.10). One year mortality by antithrombin strategy is shown in the Figure . Conclusions: CRI in pts with ACS is associated with higher rates of one year mortality. In these high risk pts, Biv monotherapy improved early clinical outcomes compared to Hep + GPI by reducing major bleeding, and resulted in similar rates of one year mortality. Cumulative Mortality at One Year, Patients with CRI

Purpose: Despite the large impact heart disease has on morbidity and mortality, many are unaware of the risk factors and the steps they can take to reduce their own risk. Participation in clinical trials for discovering new approaches for the prevention and treatment of heart disease is important. This study sought to determine interest in participation in clinical trials of those diagnosed with heart disease and hypertension as compared to those without such diagnoses, and to assess associated sociodemographic characteristics of interest in participation Methods: Analyses were conducted using data from the 2014 administration of the National Cancer Institute's Health Information National Trends Survey . HINTS is a nationally-representative survey of the US adult (18+) population. The primary outcome of interest was whether respondents expressed interest in participating in research. Bivariate analyses were conducted initially to explore potential associations between sociodemographic factors and having had a diagnosis of hypertension or heart disease. Multivariate logistic regression was used to assess relationships between sociodemographic factors and outcomes, controlling for relevant sociodemographic characteristics and prior diagnosis of hypertension or heart attack. Weighted analyses were done to obtain population-level estimates. Findings: Of the 3,498 respondents, 1,569 (33.3%,) reported having a prior diagnosis of hypertension; 362 of 3,493 (7.0%,) respondents indicated that they had a previously diagnosed heart condition. Logistic regression showed that younger hypertensive participants had higher odds of being interested in participating in clinical trials as compared to those aged 75 years and older (OR = 3.62, 95% CI = 1.94-6.78). Those with regular care providers had higher odds of being interested in clinical trial participation compared to those without regular providers (OR = 1.51, 95% CI = 1.07-2.11). Likewise, younger participants aged 18-34 reporting heart conditions (OR = 3.58, 95% CI = 1.79-7.16) had higher odds of being interested in clinical trial participation compared to those aged 75 and older. No statistical differences were seen in clinical trial awareness, participation, or interest across race or gender. Conclusions: Participants who have a diagnosis of heart disease or hypertension and report being interested in engaging in clinical trial research are generally younger and have a regular health care provider. Therefore, behavioral intervention efforts should focus on translating clinical trial participation interest to participation in younger adults. Clinical trial recruitment efforts should also focus on unique methods to increase interest and subsequent trial enrollment in older adults and those without regularly provided care.

Abstract Large cell carcinoma (LCC) is an aggressive lung cancer subtype with poor prognosis and no targeted therapies. We previously reported that tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we report that MMP1 is overexpressed specifically in LCC cell lines. Notably, silencing MMP1 expression in LCC cancer cell lines using shRNA revealed that MMP1 expression by LCC cells is necessary for induction of fibroblast senescence in coculture experiments with normal pulmonary fibroblasts, as revealed by the analysis of a panel of standard senescence markers, including β-galactosidase (SA-βgal) staining, permanent growth arrest and expression of senescence-associated secretory factors. Injecting control (shScr) or shMMP1 LCC cells into immunodeficient nude mice revealed that tumor growth, tumor take and cancer cell dissemination to the lung were reduced in shMMP1 H460 tumors compared to control tumors. We also observed fewer senescent fibroblasts in tumors from shMMP1 H460 cells using Sentragor staining, which allows identification of senescent cells in paraffin embedded tissues. Moreover, we found that recombinant active MMP1 in combination with TGF-β1 were sufficient to induce normal fibroblast senescence. In terms of the potential underlying mechanisms, treatment with the antioxidant n-acetyl cysteine (NAC) significantly attenuated the increase in SA-βgal+ fibroblasts elicited by co-stimulation with rMMP1 and TGF-β1, and its corresponding conditioned medium elicited a significantly lower growth and invasion in LCC cancer cells, revealing the oxidative stress implication in fibroblast senescence induction and associated pro-tumorigenic secretome. In summary, our results establish a new role for MMP1 in cancer and support that LCC cells elicit a tumor-supporting niche through the aberrant secretion of MMP1 and TGF-β1 to induce senescence in adjacent fibroblasts. Furthermore, we implicate oxidative stress in MMP1/TGF-β1-induced TAF senescence and support a novel therapeutic strategy in LCC based on targeting senescent TAFs. Citation Format: Marta Gabasa, Evette S. Radisky, Rafael Ikemori, Giulia Bertolini, Marselina Arshakyan, Alexandra Hockla, Paula Duch, Ornella Rondinone, Alejandro Llorente, Maria Maqueda, Alexandre Perera, Noemí Reguart, Luca Roz, Derek C. Radisky, Jordi Alcaraz. MMP1 and TGF-β1 cooperate to drive tumor progression in large cell carcinoma of the lung through fibroblast senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2515.

Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.

Background Prostaglandins, such as cyclooxygenase (COX), may play an important role in regulating the cerebral blood flow response to a stimulus. We have previously shown that the vasodilatory response to a chemical stimulus decreases with age, and this difference is abolished by COX inhibition. However, the effects of COX inhibition on the cerebrovascular response to an increase in metabolic demand during a cognitive challenge is unknown. This information is important due to the frequent use of COX inhibitors for pain management. Thus, the purpose of this study was to determine the effect of COX inhibition on the cerebrovascular response to a metabolic stimulus in young and older adults. Methods Seventy‐six participants, including 42 young adults (YA; 26 ± 5 y) and 34 older adults (OA; 64 ± 6 y) completed the Stroop Color Word Test, which is a test of executive function. A subset of 42 participants (n = 22 YA, n = 20 OA) also completed the N‐back Test, which is a test of working memory. Beat‐to‐beat middle cerebral artery velocity (MCAv) and mean arterial pressure (MAP) were measured at baseline and in response to each cognitive test. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. The response to each cognitive test was calculated as the peak percent change (%Δ) from baseline. Oral administration of the COX inhibitor Indomethacin (Indo) was given at 1.2mg/kg. Cognitive tests were then repeated after a 120‐minute wash‐in period. Results At baseline, YA had higher MCAv, CVCi, and lower MAP (p<0.01 for all) compared to OA. There were no significant differences between groups in the %Δ from baseline during the Stroop or N‐back test (p>0.05). During Indo, YA had higher MCAv (p<0.01), CVCi (p<0.01), and lower MAP (p<0.05) compared to OA. Indo decreased baseline MCAv and CVCi in both groups (p<0.01 for all) but had no effect on MAP (p>0.05). During Indo, the %Δ in MCAv during Stroop and N‐back was lower in YA (p<0.01) compared to baseline in YA. During Indo, the %Δ in MCAv was lower during Stroop in OA (p<0.01), with a trend for significance in OA during N‐back (p=0.06) compared to baseline. In YA during Indo, the %Δ in MAP was lower during Stroop (p<0.01) with a trend for significance during Nback (p=0.08) compared to baseline. In OA, the %Δ in MAP during N‐back was lower during Indo compared to baseline (p<0.05). Indo had no effect on the %Δ in CVCi (p>0.05). Importantly, there were group differences in the %Δ in MAP during Indo, such that the change was greater in OA compared with YA during Stroop (14.1 ± 1.3% vs. 10.6 ± 1.0%; p<0.05). Conclusion After administration of Indo, OA increased MAP to a greater extent during the Stroop test when compared to YA. These results suggest that OA required a larger increase in blood pressure to complete a test of executive function during COX inhibition. Because some COX inhibitors attenuate cerebral blood flow, OA may need to augment blood pressure to complete this metabolically‐challenging task. Support or Funding Information This research was funded by NIH grant HL118154. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .