Latent Class Analysis Reveals COVID-19-related Acute Respiratory Distress Syndrome Subgroups with Differential Responses to Corticosteroids.

Rationale: Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with coronavirus disease (COVID-19) is unknown. Objectives: To identify clinically relevant, novel subgroups in COVID-19-related ARDS and compare them with previously described ARDS subphenotypes. Methods: Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis was used to identify subgroups with baseline clinical, respiratory, and laboratory data serving as partitioning variables. A previously developed machine learning model was used to classify patients as the hypoinflammatory and hyperinflammatory subphenotypes. Baseline characteristics and clinical outcomes were compared between subgroups. Heterogeneity of treatment effect for corticosteroid use in subgroups was tested. Measurements and Main Results: From March 2, 2020, to April 30, 2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class latent class analysis model best fit the population (P = 0.0075). Class 2 (23%) had higher proinflammatory markers, troponin, creatinine, and lactate, lower bicarbonate, and lower blood pressure than class 1 (77%). Ninety-day mortality was higher in class 2 versus class 1 (75% vs. 48%; P < 0.0001). Considerable overlap was observed between these subgroups and ARDS subphenotypes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. Heterogeneity of treatment effect to corticosteroids was observed (P = 0.0295), with improved mortality in the hyperinflammatory phenotype and worse mortality in the hypoinflammatory phenotype, with the caveat that corticosteroid treatment was not randomized. Conclusions: We identified two COVID-19-related ARDS subgroups with differential outcomes, similar to previously described ARDS subphenotypes. SARS-CoV-2 PCR cycle threshold had differential value for predicting mortality in the subphenotypes. The subphenotypes had differential treatment responses to corticosteroids.

Synthesis and Characterization of Diol-Based Unsaturated Polyesters: Poly(diol fumarate) and Poly(diol fumarate-co-succinate).

In this work, we describe the synthesis and characterization of variants of poly(diol fumarate) and poly(diol fumarate-co-succinate). Through a Fischer esterification, α,ω-diols and dicarboxylic acids were polymerized to form aliphatic polyester comacromers. Because of the carbon-carbon double bond of fumaric acid, incorporating it into the macromer backbone structure resulted in unsaturated chains. By choosing α,ω-diols of different lengths (1,6-hexanediol, 1,8-octanediol, and 1,10-decanediol) and controlling the amount of fumaric acid in the dicarboxylic acid monomer feed (33, 50, and 100 mol %), nine diol-based macromer variants were synthesized and characterized for molecular weight, number of unsaturated bonds per chain, and thermal properties. Degradation and in vitro cytotoxicity were also measured in a subset of macromers. As proof-of-principle, macromer networks were photo-cross-linked to demonstrate the ability to perform free radical addition using the unsaturated macromer backbone. Cross-linked macromer networks were also characterized for physicochemical properties (swelling, sol fraction, compressive modulus) based on diol length and amount of unsaturated bonds. A statistical model was built using data generated from these diol-based macromers and macromer networks to evaluate the impact of monomer inputs on final macromer and macromer network properties. With the ability to be modified by free radical addition, biodegradable unsaturated polyesters serve as important macromers in the design of devices such as drug delivery vehicles and tissue scaffolds. Given the ability to extensively control final macromer properties based on monomer input parameters, poly(diol fumarate) and poly(diol fumarate-co-succinate) represent an exciting new class of macromers.

Outcomes After Supraventricular Tachycardia Ablation in Patients With Group 1 Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is associated with right ventricular pressure overload and atrial remodeling, which may result in supraventricular tachycardias (SVTs). The outcomes of catheter SVT ablation in patients with World Health Organization (WHO) group 1 PH are incompletely characterized. Methods: We conducted a retrospective cohort study of all patients with WHO group 1 PH undergoing catheter SVT ablation during a 10-year period at a major academic tertiary care hospital. Baseline patient characteristics and procedural outcomes at 3 months and 1 year were extracted from the electronic medical record. Results: Ablation of 60 SVTs was attempted in 38 patients with group 1 PH. The initial procedural success rates were 80% for atrial fibrillation (AF, n = 5), 89.7% for typical atrial flutter (AFL, n = 29), 57.1% for atypical AFL (n = 7), 60% for atrial tachycardia (AT, n = 15), and 75% for atrioventricular nodal reentrant tachycardia (AVNRT, n = 4). The 1-year post-procedural recurrence rates were 100% for AF (n = 4), 25% for typical AFL (n = 20), 50% for atypical AFL (n = 2), and 28.6% for AT (n = 7). No patients had recurrent AVNRT (n = 2). There were seven (18.4%) peri-procedural decompensations requiring pressor initiation and transfer to intensive care and one (2.6%) peri-procedural death. Conclusions: The study demonstrates that SVT ablation in group 1 PH can be performed relatively safely and effectively, albeit with lower initial success rates and higher risk of clinical decompensation than in the general population. Recurrence rates at 1 year were higher in AF and atypical AFL ablations and similar for typical AFL and AT ablations when compared to the general population.

Treatment of recurrent mucosal melanoma of the oral cavity with topical imiquimod and pembrolizumab achieves complete histopathologic remission.

Mucosal melanomas constitute a subtype of melanoma with less effective treatments than cutaneous melanomas. We present a case of oral mucosal melanoma that recurred despite multiple resections and adjuvant temozolomide. Treatment with topical imiquimod combined with pembrolizumab achieved remission. A 56-year-old woman presented with a pigmented mass on her left anterior hard palate. Biopsy revealed malignant melanoma. The patient had resection with neck dissection with 3 months of adjuvant temozolomide due to positive margins. Malignant melanoma involving the hard palate recurred 1 year later requiring additional resection. Two years later, two additional pigmented lesions were found; further resections were deferred due to expected morbidity. Following 6 weeks of topical imiquimod treatment, the lesions shrunk significantly. Adjuvant pembrolizumab was added and complete histopathologic remission was observed in 6 months. The patient remained in remission for 4 years before new melanoma in situ was diagnosed, requiring five additional months of imiquimod. As of April 2021, there is no clinical evidence of melanoma. There are limited reports of oral melanoma treated with topical imiquimod. Here, imiquimod administered in combination with pembrolizumab achieved complete pathologic response.

Care Delivery Impact of the COVID-19 Pandemic on Breast Cancer Care.

PURPOSE: COVID-19 has altered healthcare delivery. Previous work has focused on patients with cancer and COVID-19, but little has been reported on healthcare system changes among patients without COVID-19. METHODS: We performed a retrospective study of patients with breast cancer (BC) in New York City between February 1, 2020, and April 30, 2020. New patients were included as were patients scheduled to receive intravenous or injectable therapy. Patients with COVID-19 were excluded. Demographic and treatment information were obtained by chart review. Delays and/or changes in systemic therapy, surgery, radiation, and radiology related to the pandemic were tracked, along with the reasons for delay and/or change. Univariate and multivariable analysis were used to identify factors associated with delay and/or change. RESULTS: We identified 350 eligible patients, of whom 149 (42.6%) experienced a delay and/or change, and practice reduction (51.0%) was the most common reason. The patients who identified as Black or African American, Asian, or Other races were more likely to experience a delay and/or change compared with White patients (Black, 44.4%; Asian, 47.1%; Other, 55.6%; White, 31.4%; P = .001). In multivariable analysis, Medicaid compared with commercial insurance (odds ratio [OR], 3.04; 95% CI, 1.32 to 7.27) was associated with increased odds of a delay and/or change, whereas stage II or III BC compared with stage I (OR, 0.38; 95% CI, 0.15 to 0.95; and OR, 0.28; 95% CI, 0.08 to 0.092, respectively) was associated with decreased odds of a delay and/or change. CONCLUSION: Almost half of the patients with BC without COVID-19 had a delay and/or change. We found racial and socioeconomic disparities in the likelihood of a delay and/or change. Further studies are needed to determine the impact these care alterations have on BC outcomes.

3D Tissue-Engineered Tumor Model for Ewing's Sarcoma That Incorporates Bone-like ECM and Mineralization.

The tumor microenvironment harbors essential components required for cancer progression including biochemical signals and mechanical cues. To study the effects of microenvironmental elements on Ewing's sarcoma (ES) pathogenesis, we tissue-engineered an acellular three-dimensional (3D) bone tumor niche from electrospun poly(ε-caprolactone) (PCL) scaffolds that incorporate bone-like architecture, extracellular matrix (ECM), and mineralization. PCL-ECM constructs were generated by decellularizing PCL scaffolds harboring cultures of osteogenic human mesenchymal stem cells. The PCL-ECM constructs simulated in vivo-like tumor architecture and increased the proliferation of ES cells compared to PCL scaffolds alone. Compared to monolayer controls, 3D environments facilitated the downregulation of the canonical insulin-like growth factor 1 receptor (IGF-1R) signal cascade through mechanistic target of rapamycin (mTOR), both of which are targets of recent clinical trials. In addition to the downregulation of canonical IGF-1R signaling, 3D environments promoted a reduction in the clathrin-dependent nuclear localization and transcriptional activity of IGF-1R. In vitro drug testing revealed that 3D environments generated cell phenotypes that were resistant to mTOR inhibition and chemotherapy. Our versatile PCL-ECM constructs allow for the investigation of the roles of various microenvironmental elements in ES tumor growth, cancer cell morphology, and induction of resistant cell phenotypes.

Mechanically tunable coaxial electrospun models of YAP/TAZ mechanoresponse and IGF-1R activation in osteosarcoma.

Current in vitro methods for assessing cancer biology and therapeutic response rely heavily on monolayer cell culture on hard, plastic surfaces that do not recapitulate essential elements of the tumor microenvironment. While a host of tumor models exist, most are not engineered to control the physical properties of the microenvironment and thus may not reflect the effects of mechanotransduction on tumor biology. Utilizing coaxial electrospinning, we developed three-dimensional (3D) tumor models with tunable mechanical properties in order to elucidate the effects of substrate stiffness and tissue architecture in osteosarcoma. Mechanical properties of coaxial electrospun meshes were characterized with a series of macroscale testing with uniaxial tensile testing and microscale testing utilizing atomic force microscopy on single fibers. Calculated moduli in our models ranged over three orders of magnitude in both macroscale and microscale testing. Osteosarcoma cells responded to decreasing substrate stiffness in 3D environments by increasing nuclear localization of Hippo pathway effectors, YAP and TAZ, while downregulating total YAP. Additionally, a downregulation of the IGF-1R/mTOR axis, the target of recent clinical trials in sarcoma, was observed in 3D models and heralded increased resistance to combination chemotherapy and IGF-1R/mTOR targeted agents compared to monolayer controls. In this study, we highlight the necessity of incorporating mechanical cues in cancer biology investigation and the complexity in mechanotransduction as a confluence of stiffness and culture architecture. Our models provide a versatile, mechanically variable substrate on which to study the effects of physical cues on the pathogenesis of tumors. STATEMENT OF SIGNIFICANCE: The tumor microenvironment plays a critical role in cancer pathogenesis. In this work, we engineered 3D, mechanically tunable, coaxial electrospun environments to determine the roles of the mechanical environment on osteosarcoma cell phenotype, morphology, and therapeutic response. We characterize the effects of varying macroscale and microscale stiffnesses in 3D environments on the localization and expression of the mechanoresponsive proteins, YAP and TAZ, and evaluate IGF-1R/mTOR pathway activation, a target of recent clinical trials in sarcoma. Increased nuclear YAP/TAZ was observed as stiffness in 3D was decreased. Downregulation of the IGF-1R/mTOR cascade in all 3D environments was observed. Our study highlights the complexity of mechanotransduction in 3D culture and represents a step towards controlling microenvironmental elements in in vitro cancer investigations.