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BACKGROUND The long-term outcomes of diabetic patients presenting with ST-segment elevation myocardial infarction (STEMI) in contemporary practice have received limited study. METHODS We evaluated the clinical characteristics and outcomes of STEMI patients with and without diabetes in a large regional STEMI program designed to facilitate timely primary percutaneous coronary intervention (PCI) (Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, MN). The primary and secondary outcome measures were in-hospital mortality, 1-year major adverse cardiovascular events (MACE) (stroke, myocardial infarction, unplanned PCI or coronary artery bypass graft [CABG] surgery, and all-cause mortality), and 5-year mortality. RESULTS Of the 6292 patients included, 1158 (18.4%) had Diabetes Mellitus (DM) (95.3% Type II, 4.7% Type I). Patients with DM were older (mean age 66 vs. 62.8 years, p < 0.01), had more co-morbidities and were more likely to receive medical therapy without reperfusion (13% vs. 10%, p = 0.003). Patients with DM had higher in-hospital (8% vs. 5%, p = 0.001), 1-year (8% vs. 4%, p < 0.001) and 5-year mortality (16% vs. 9%, p < 0.001) compared to non-diabetics. On Cox proportional hazards analysis, DM was independently associated with worse mortality (hazard ratio: 1.70, 95% confidence interval (CI): 1.32-2.19, p < 0.001) and MACE [HR: 1.63 (95% (CI)): 1.28-2.08, p < 0.001]. CONCLUSIONS Despite advancements in medical therapy and revascularization strategies for STEMI, DM remains independently associated with higher short- and long-term morbidity and mortality in contemporary practice.

PURPOSE To compare clinical outcomes in a cohort of patients with advanced non–small-cell lung cancer (NSCLC) with targetable genomic alterations detected using plasma-based circulating tumor DNA (ctDNA) or tumor-based next-generation sequencing (NGS) assays treated with US Food and Drug Administration–approved therapies at a large academic research cancer center. METHODS A retrospective review from our MD Anderson GEMINI database identified 2,224 blood samples sent for ctDNA NGS testing from 1971 consecutive patients with a diagnosis of advanced NSCLC. Clinical, treatment, and outcome information were collected, reviewed, and analyzed. RESULTS Overall, 27% of the ctDNA tests identified at least one targetable mutation and 73% of targetable mutations were EGFR-sensitizing mutations. Among patients treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapies, there were no significant differences in progression-free survival of 379 days and 352 days ( P value = .41) with treatment based on tissue (n = 40) or ctDNA (n = 40), respectively. Additionally, there were no differences in progression-free survival or objective response rate among those with low (n = 8, 0.01%-0.99%) versus high (n = 16, ≥ 1%) levels of ctDNA of the targetable mutation as measured by variant allele frequency (VAF). Overall, there was excellent testing concordance (n = 217 tests) of > 97%, sensitivity of 91.7%, and specificity of 99.7% between blood-based ctDNA NGS and tissue-based NGS assays. CONCLUSION There were no significant differences in clinical outcomes among patients treated with approved EGFR-TKIs whose mutations were identified using either tumor- or plasma-based comprehensive profiling and those with very low VAF as compared with high VAF, supporting the use of plasma-based profiling to guide initial TKI use in patients with metastatic EGFR-mutant NSCLC.

The outcomes of patients with previous coronary bypass graft surgery (CABG) presenting with ST-segment elevation acute myocardial infarction (STEMI) have received limited study. We compared the clinical and procedural characteristics and outcomes of STEMI patients with and without previous CABG in a contemporary multicenter STEMI registry between 2003 and 2020. The primary outcomes of the study were mortality and major cardiac adverse events (MACE: death, MI or stroke). Survival curves were derived using the Kaplan-Meier method and compared with the log-rank test. Of the 13,893 patients included in the analyses, 7.2% had previous CABG. Mean age was 62.4 ± 13.6 years, most patients (71%) were men and 22% had diabetes. Previous CABG patients were older (69.0 ± 11.7 vs 61.9 ± 13.6 years, p0.001) and more likely to have diabetes (40% vs 21%, p0.001) compared with patients without previous CABG. Previous CABG patients had higher mortality and MACE at 5 years (p0.001). Outcomes were similar with saphenous vein graft vs native coronary culprits. Previous CABG remained associated with mortality from discharge to 18 months (p = 0.044) and from 18 months to 5 years (p0.001) after adjusting for baseline characteristics. Long term outcomes after STEMI were worse among patients with previous CABG compared with patients without previous CABG, even after adjustment for baseline characteristics.

To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.

Background The coronavirus disease 2019 (COVID-19) pandemic has impacted many aspects of ST-segment elevation myocardial infarction (STEMI) care, including timely access to primary percutaneous coronary intervention (PPCI). Objectives The goal of the NACMI (North American COVID-19 and STEMI) registry is to describe demographic characteristics, management strategies, and outcomes of COVID-19 patients with STEMI. Methods A prospective, ongoing observational registry was created under the guidance of 3 cardiology societies. STEMI patients with confirmed COVID+ (group 1) or suspected (person under investigation [PUI]) (group 2) COVID-19 infection were included. A group of age- and sex-matched STEMI patients (matched to COVID+ patients in a 2:1 ratio) treated in the pre-COVID era (2015 to 2019) serves as the control group for comparison of treatment strategies and outcomes (group 3). The primary outcome was a composite of in-hospital death, stroke, recurrent myocardial infarction, or repeat unplanned revascularization. Results As of December 6, 2020, 1,185 patients were included in the NACMI registry (230 COVID+ patients, 495 PUIs, and 460 control patients). COVID+ patients were more likely to have minority ethnicity (Hispanic 23%, Black 24%) and had a higher prevalence of diabetes mellitus (46%) (all p, Central Illustration

This study described the utilisation of telemedicine during the COVID-19 pandemic in June to November 2020. In April 2020, the Centers for Disease Control and Prevention (CDC) and the Health Resources and Services Administration (HRSA) began administering a weekly survey to study the effects of COVID-19 on the testing capacity and operations of health centers. The survey was voluntary and available to 1,382 HRSA-funded centers. Urbanisation and region have been associated with higher rates of telehealth use. Health centers that responded to the COVID-19 surveys were more likely to report multiple visits than those that did not respond. The average percentage of weekly visits for all regions and urbanicity was calculated. The weekly changes were computed based on the number of visits during the first 10 weeks and the second 10 weeks. Week-to-week differences were calculated as the average number of telehealth visits during the first and second weeks of the study. The average percentage of weekly visits that were telehealth-related decreased 25% among the responding health centers during the study period. During the first 10 weeks of the study, the largest absolute change in the number of weekly telehealth visits was reported by health centers in the Northeast. Health centers in the Northeast maintained stable weekly telehealth visits during the second half of the study. Compared with the first 10 weeks, the second half of the study showed a significant change in the percentage of telehealth visits. The average percentage of weekly visits to a telehealth facility differed significantly among various regions. For instance, the South had the lowest percentage of visits. Urban health centers reported significantly higher average percentage of weekly visits for telehealth than rural health centers. The number of cases of COVID-19 in the Northeast also increased during the second quarter. The number of cases of COVID-19 increased in counties where urban health centers are located during the first 10 weeks of the study.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC. Neoadjuvant treatment with nivolumab plus ipilimumab is well tolerated and demonstrates clinical efficacy in patients with early stage lung cancer.

Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.

Aims Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. Methods and results We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. Conclusion Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. Trial registration Clinicaltrials.gov identifier: NCT01458405.

Purpose: Nintedanib enhances the activity of chemotherapy in metastatic non–small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint. Patients and Methods: Eligible patients had stage IB (≥4 cm)–IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%. Results: Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%–32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%–54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%–93%) and 91% (95% CI, 79%–100%), respectively. Most frequent treatment-related grade 3–4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm2, P = 0.048; 142.3 vs. 35.6 cells/mm2, P = 0.018). Conclusions: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies. See related commentary by Blakely and McCoach, p. 3499

Objective To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls. Patients and Methods RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020. Results Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value =1.30×10−23), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P=5.22×10−4), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P=1.66×10−6). Conclusion More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry, this 5-fold increase in ACE2 protein may confer increased risk for COVID-19 manifestations and outcomes in patients with increased ACE2 transcript expression and protein levels in the heart.

Introduction Consolidation durvalumab after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC. We hypothesized that adding immunotherapy concurrently with CRT (cCRT) would increase efficacy without additive toxicity. Methods This phase II study was conducted in two parts. Part 1 (n = 10) involved administration of conventionally fractionated CRT followed by consolidation chemotherapy (atezolizumab [two cycles] and maintenance atezolizumab up to 1 y). Part 2 (n = 30) involved administration of cCRT with atezolizumab followed by the same consolidation and maintenance therapies as in part 1. Programmed cell death ligand-1 staining cutoffs (1% or 50%) using Dako 22C3 immunohistochemistry were correlated with clinical outcomes. Results The overall toxicities for part 1/2 were overall adverse events of grade 3 and above of 80%/80%; immune-related adverse events of grade 3 and above of 30%/20%; and pneumonitis of grade 2 and above of 10%/16%, respectively. In part 1, for preliminary efficacy results, with a median follow-up of 22.5 months, the median progression-free survival was 18.6 months, and the overall survival was 22.8 months. In part 2, with a median follow-up time of 15.1 months, the median progression-free survival was 13.2 months, and the overall survival was not reached. There was no difference in cancer recurrence regardless of programmed cell death ligand-1 status. Conclusions Atezolizumab with cCRT is safe and feasible and has no added toxicities compared with historical rates.

Background Contemporary real‐world data on stroke in patients presenting with ST‐segment–elevation myocardial infarction (STEMI) are scarce. Methods and Results We evaluated the incidence, trends, cause, and predictors of stroke from 2003 to 2019 in 4 large regional STEMI programs in the upper Midwest that use similar transfer and treatment protocols. We also evaluated the long‐term impact of stroke on 5‐year mortality. Multivariate logistic and Cox regression analysis was used to identify variables independently associated with stroke in patients presenting with STEMI and identify variables associated with 5‐year mortality. A total of 12 868 patients presented with STEMI during the study period. Stroke occurred in 98 patients (0.76%). The incidence of stroke remained stable over time (0.5% in 2003, 1.2% in 2019; P ‐trend=0.22). Most (75%) of strokes were ischemic, with a median time to stroke symptoms of 14 hours after primary percutaneous coronary intervention (interquartile range, 4–72 hours), which led to a small minority (3%) receiving endovascular treatment and high in‐hospital mortality (18%). On multivariate regression analysis, age (increment of 10 years) (odds ratio [OR], 1.32; 95% CI, 1.10–1.58; P ‐value=0.003) and preintervention cardiogenic shock (OR, 2.03; (95% CI, 1.03–3.78; P =0.032)) were associated with a higher risk of in‐hospital stroke. In‐hospital stroke was independently associated with increased risk of 5‐year mortality (hazard ratio, 2.01; 95% CI, 1.13–3.57; P =0.02). Conclusions In patients presenting with STEMI, the risk of stroke is low (0.76%). A stroke in patients presenting with STEMI is associated with significantly higher in‐hospital (18%) and long‐term mortality (35% at 5 years). Stroke was associated with double the risk of 5‐year death.

PURPOSE Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a single-arm, open-label, phase II study. PATIENTS AND METHODS Patients with advanced HER2 exon 20 mutant NSCLC were enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The primary end point was objective response rate per RECIST version 1.1. Confirmatory scans were performed at least 28 days from initial radiologic response. RESULTS Thirty patients received poziotinib treatment. At baseline, 90% of patients received prior platinum-based chemotherapy and 53% had two lines or more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed objective response rate was 27% (95% CI, 12 to 46). Responses were observed across HER2 exon 20 mutation subtypes. The median duration of response was 5.0 months (95% CI, 4.0 to not estimable). The median progression-free survival was 5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95% CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse events were skin rash (47%) and diarrhea (20%). There was one possible treatment-related death because of pneumonitis. CONCLUSION Poziotinib showed promising antitumor activity in patients with HER2 exon 20 mutant NSCLC including patients who had previously received platinum-based chemotherapy.

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

Objective: Humans and mice with loss-of-function variants of genes in the TGF-β (transforming growth factor beta) signaling pathway develop aortic aneurysms. These aneurysms could be caused by decreased aortic smooth muscle cell (SMC) contractile-protein levels and impaired aortic SMC contractile-unit function. Accordingly, we investigated whether loss of SMC TGF-β signaling in mice alters aortic contractile-protein levels and aortic contractility. Approach and Results: We used immunoblotting, wire myography, histological analyses, and measurements of aortic nitric oxide and superoxide levels to assess aortic contractile-protein levels and vasomotor function in mice with SMC-specific deletion of the type 2 TGF-β receptor (TBR2 SMΔ mice). Aortic contractile-protein levels were not altered in TBR2 SMΔ mice. Surprisingly, TBR2 SMΔ mice had increased aortic contractility and severe endothelial dysfunction. Endothelial dysfunction was manifested as decreased relaxation to acetylcholine (Emax 37% versus 97%; P P =0.005), decreased endothelial nitric oxide synthase activation (31%; P =0.002), and lower aortic levels of phosphorylated vasodilator-stimulated phosphoprotein (an indicator of nitric oxide bioavailability: 65%; P SMΔ and control aortas with a nitric oxide synthase inhibitor, revealing a significant positive interaction between aortic hypercontractility and absence of endothelium-derived nitric oxide ( P Conclusions: Aortic aneurysms that develop in TBR2 SMΔ mice are not caused by decreased SMC contractility. Loss of physiological SMC TGF-β signaling causes endothelial dysfunction leading to aortic hypercontractility. Endothelial dysfunction may contribute to vascular pathologies associated with abnormal TGF-β signaling.

Background Colorectal cancer is one the most common cancers in the western world with increasing incidence. Approximately 50% of the patients develop liver metastases. Resection of liver metastases is the treatment of choice although almost half of the resected patients get recurrence in the liver. Methods The ASAC trial is a Scandinavian, multicentre, double-blinded, randomized, placebo-controlled study to determine whether adjuvant treatment with low-dose aspirin (acetylsalicylic acid (ASA)) can improve disease-free survival in patients treated for colorectal cancer liver metastases (CRCLM). Up to 800 patients operated for CRCLM will be randomized to Arm#1 ASA 160 mg once daily or Arm#2 Placebo, for a period of 3 years or until disease recurrence. The patients will be recruited at all major hepatobiliary surgical units in Norway, Sweden and Denmark and have follow-up according to standard of care and the National Guidelines. Discussion The ASAC trial will be the first clinical interventional trial to assess the potential beneficial role of ASA in recurrence of CRCLM and survival. ASA is an inexpensive, well-tolerated and easily accessible drug that will be highly potential as adjuvant drug in secondary prevention of CRCLM if the study shows a beneficial effect. We will also determine the effect of ASA as adjuvant treatment on Health-Related Quality of Life and the cost-effectiveness. Trial registration ClinicalTrials.gov NCT03326791. Registered on 31 October 2017.

Background: Integrated care is characterized by evolving heterogeneity in models. Using telepsychiatry to enhance these models can increase access, quality, and efficiencies in care. Intro...

Context Parathyroid carcinoma (PC) is extremely rare. Prognosis is poor, with no known evidence-based systemic therapies. We previously reported complete remission in a patient with metastasized parathyroid carcinoma and high tumor MGMT promoter methylation status who was treated with temozolomide. Objective To study MGMT promoter methylation status in an additional set of aggressive parathyroid tumors. Design/Setting The study included 12 patients: 7 with sporadic and 5 with familial primary hyperparathyroidism (two of the latter carried a CDC73 gross deletion). Patient 9 is the previously described patient with PC and high MGMT methylation status. Her daughter (patient 12) had surgery for severe primary hyperparathyroidism due to atypical parathyroid adenoma during pregnancy. Eleven patients thus had PC and one had atypical parathyroid adenoma. MGMT promoter methylation status was determined from DNA extracted from primary (n = 10) or metastatic (n = 2) tumors. A mean methylation level >20% was considered high. Patient 11 had metastatic PC and received temozolomide cycles. Results Only the previously published patient (patient 9) had high tumor MGMT promoter methylation status. This was not a characteristic of the atypical parathyroid adenoma of the daughter (patient 12). Patient 11 (CDC73 intragenic deletion) has disseminated PC, low MGMT promoter methylation, and stable disease on follow-up after temozolomide treatment. Conclusion High MGMT promoter methylation status seems rare in PC. However, as demonstrated in other neuroendocrine tumors, some patients with disseminated PC might benefit from temozolomide. Demonstration of high methylation status could be a predictor of positive response to temozolomide treatment.

A many-body interferometer is described in which all of its components are treated as quantum objects. It consists of particles reflecting elastically from a “mirror”. Quantum correlation is a consequence of conservation of energy and momentum while interference occurs when the order in which the non-local particles reflect is indeterminate. The resulting superposition exhibits correlated interference with diverse characteristics depending on the structure of the many-body wavegroup. Two non-local microscopic particles reflecting from a mesoscopic “mirror” illustrate unique features of this correlation interferometer. The microscopic momentum exchanged then results in small displacements of the superposed mesoscopic mirror substates, which mitigates experimental difficulties in determining the quantum–classical boundary. Quantum behavior of this mesoscopic mirror, evident in indirect measurements involving correlations between only the reflecting microscopic particles, disappears for a classical mirror which cannot exist in such superposition states.

Purpose BCVI may lead to ischemic stroke, disability, and death, while being often initially clinically silent. Screening criteria for BCVI based on clinical findings and trauma mechanism have improved detection, with Denver criteria being most common. Up to 30% of patients do not meet BCVI screening criteria. The aim of this study was to analyze the effect of augmented Denver criteria on detection, and to determine the relative risk for ischemic stroke. Methods Denver screening criteria were augmented by any high-energy trauma of the cervical spine, thorax, abdomen, or pelvis. All acute blunt trauma WBCT including CT angiography (CTA) over a period of 38 months were reviewed retrospectively by two Fellowship-trained radiologists, as well as any cerebral imaging after the initial trauma. Results 1544 WBCT studies included 374 CTA (m/f = 271/103; mean age 41.5 years). Most common mechanisms of injury were MVA (51.5%) and fall from a height (22.3%). We found 72 BCVI in 56 patients (15.0%), with 13 (23.2%) multiple lesions. The ICA was affected in 49 (68.1%) and the vertebral artery in 23 (31.9%) of cases. The most common injury level was C2, with Biffl grades I and II most common in ICA, and II and IV in VA. Interobserver agreement was substantial (Kappa = 0.674). Of 215 patients imaged, 16.1% with BCVI and 1.9% of the remaining cases had cerebral ischemic stroke (p

The number of patients with heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) is increasing, and for HFpEF, no therapies have clinical benefit. It has been hypothesized that PKG attenuates pathological remodelling, and increasing cGMP would be beneficial for patients with HF. However, neither the RELAX nor NEAT-HFpEF trial showed benefit. But there is still enthusiasm for increasing cGMP in patients with HF, which highlight the need to determine the expression of PDEs in cardiac muscle. This study used immunoblotting to examine the expression of the PDEs that have been suggested to be targets for therapy of HF in both canines (normal and HFpEF) and humans (normal and HFrEF). Our results demonstrate PDE1C and PDE3A are expressed in cardiac muscle, but we could not detect the expression of PDE2A, PDE5A, PDE7A and PDE9A in cardiac tissue lysates from either normal or failing hearts. Thus, one should not expect a clinical benefit for a therapy targeting these PDEs in heart failure, which highlights the importance of rigorous demonstration of the target of therapy prior to undertaking a clinical trial.

Purpose/objective(s) Retrospective and prospective studies in patients with oligometastatic non-small-cell lung cancer (NSCLC) suggested clinical benefit after complete metastatic ablation (CMA). So far, no studies have addressed the toxicity and efficacy of CMA to oligometastatic lesions in patients that progressed during immune checkpoint inhibitors (ICIs) therapy. Here, we report results of a single arm- radiotherapy (RT) to oligometastatic lesions from our ongoing phase II trial (NCT02710253). Materials/methods This study enrolled patients that progressed within 6 months of ICI therapy and developed oligo-metastases. Treatment intervention allowed for any dose and fractions of RT per the treating physician to all metastatic sites, with irradiation for up to 6 sites. Primary endpoints of this study are time to new lesion development, and disease control rate (DCR) by RECIST 1.1. Secondary endpoints are toxicity, progression-free survival (PFS), overall survival (OS) and absolute lymphocyte counts (ALC). Results Of the 30 patients initially enrolled in this study, 26 patients (N = 21 NSCLC; N = 5 melanoma) were included in the analysis as they had completed imaging follow-up. A total of 64 lesions were irradiated with a mean of 2.5 lesions per patient. Most frequent location of irradiated was lung (n = 45), followed by adrenal (n = 7), liver (n = 4), bone (n = 4) and others (n = 4); 50% of patients received SBRT. At a median follow-up time of 23.0 months (range, 5.0-44.7 months), 12 patients had no new lesions, while 14 patients developed new lesions in lung (50%), bone (25%), brain (21%). Median time to new lesion development was 14.6 months. DCR was 77% (complete response 19%, partial response 19%, stable disease 38%); median PFS was 10.1 months and median OS was not reached. No toxicities greater than grade 2 was observed. Pre-RT ALC is an independent risk factor for time to new lesion development (P = 0.006, HR = 0.1, 95% CI, 0.02-0.51). Patients without new lesion development had significantly higher baseline ALC (P = 0.011) and more ALC after RT at 1 month (P = 0.025), 3 months (P = 0.006), 6 months (P = 0.002) and 12 months (P = 0.045) compared to patients with new lesions. Other factors including age, gender, SBRT, baseline tumor size, performance status and tumor histology did not affect the time to new lesion development. Conclusion In patients with oligometastatic lesions that progressed on ICI, CMA may be a valid treatment option that generates clinical benefits. By eradicating gross sites of disease by converting area sites into in-situ vaccines, T cells are able to access microscopic metastasis. Larger randomized trials are indicated to further define the role of CMA for ICIs resistance.

The purpose of this study is to examine the incidence, location, and magnetic resonance imaging (MRI) features of spinal epidural hematoma (SEH) and spinal subdural hematoma (SSH) in post-traumatic ankylosing spondylitis (AS) patients. A total of 2256 consecutive referrals for urgent and emergency MRI scans of the spine over a period of eight years and nine months were manually reviewed for any mentions indicating axial ankylosis and post-traumatic spinal hematoma. We found 164 patients with ankylosed spines complicated by spinal fracture, of whom 32 had AS. Of the 132 excluded patients, 80 had diffuse idiopathic skeletal hyperostosis (DISH). The primary outcome was the presence of spinal hematoma, and the secondary outcome was spinal canal narrowing and spinal cord impingement. Two musculoskeletal radiologists and one fellow in musculoskeletal radiology reviewed the images for the presence of spinal hematoma and related signal characteristics, blinded to one another and initial reports. Of 28 post-traumatic AS patients, 19 had SEHs and five had spinal SSHs. There was a statistically significant difference between Frankel grades before and after surgery in respect of neurological improvement (p = 0.008). Patients who had radiologically proven spinal cord impingement showed more severe neurological deficits (p = 0.012). Hematomas with T1 heterogeneity showed a significantly increased delay (p = 0.047) between injury and imaging, while other signal characteristics were only approximate. Both SEH and SSH are common complications in post-traumatic AS patients. Patients benefit from surgery, but the relevance of spinal hematoma as a separate factor causing neurological deficit remains unclear.

People working on behalf of population health, community health, or public health often experience confusion or ambiguity in the meaning of these and other common terms-the similarities and differences and how they bear on the tasks and division of labor for care delivery and public health. Shared language must be clear enough to help, not hinder people working together as they ultimately come to mutual understanding of roles, responsibilities, and actions in their joint work. Based on an iterative lexicon development process, the authors developed and propose a definitional framework as an aid to navigating among related population and community health terms. These terms are defined, similarities and differences clarified, and then organized into 3 categories that reflect goals, realities, and ways to get the job done. Goals include (a) health as well-being for persons, (b) population health as that goal expressed in measurable terms for groups, and (c) community health as population health for particular communities of interest, geography, or other defining characteristic-groups with shared identity and particular systemic influences on health. Realities are social determinants as influences, health disparities as effects, and health equity as both a goal and a design principle. Ways to get the job done include health care delivery systems for enrollees and public health in population-based civic activities-with a broad zone of collaboration where streams of effort converge in partnership with served communities. This map of terms can enable people to move forward together in a broad zone of collaboration for health with less confusion, ambiguity, and conflict.

Aims The present study had two aims: (i) compare echocardiographic parameters in COVID-19 patients with matched controls and (2) assess the prognostic value of measures of left (LV) and right ventricular (RV) function in relation to COVID-19 related death.Methods and results In this prospective multicentre cohort study, 214 consecutive hospitalized COVID-19 patients underwent an echocardiographic examination (by pre-determined research protocol). All participants were successfully matched 1:1 with controls from the general population on age, sex, and hypertension. Mean age of the study sample was 69 years, and 55% were male participants. LV and RV systolic function was significantly reduced in COVID-19 cases as assessed by global longitudinal strain (GLS) (16.4% +/- 4.3 vs. 18.5% +/- 3.0,P Conclusions RV and LV function are significantly impaired in hospitalized COVID-19 patients compared with matched controls. Furthermore, reduced TAPSE and GLS are independently associated with COVID-19-related death.

Introduction: Cell therapy failed to improve global LV ejection fraction (LVEF) in most trials of post-MI LV dysfunction. LVEF does not consider the effect of cell therapy on different segments of the myocardium, which may be heterogeneous across different myocardial regions in patients with regional MI. Hypothesis: Allogeneic cardiosphere-derived cells (CDCs) improve segmental (but not global) myocardial function indexed as circumferential strain by MRI. Methods: In this randomized double-blind trial, 142 post-MI patients with LVEF Results: In total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3(10.8) and 108 (87.1%) males). Segmental Ecc improvement was significantly greater in patients receiving CDC (-0.5%(4.0)) compared to placebo (0.2%(3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of -0.7% (3.5) in patients receiving CDC vs. 0.04% (3.7) in the placebo group, p=0.04). The beneficial effect of CDCs for improving segmental Ecc was greater in patients with LV ejection fraction18.8% or LV end-diastolic volume index>100 [mixed effect regression coefficients of -0.92(p=0.02),-0.78(p=0.03), and -1.16(p=0.004) respectively versus -0.58(p=0.05) for the entire cohort]. Conclusions: In patients with post-MI LV dysfunction, allogeneic CDC administration resulted in improved segmental myocardial function. This CDC induced improvement in segmental myocardial function was greater in patients with severe LV dysfunction, dilated LV and greater infarct size. (clinicaltrials.gov Identifier: NCT01458405).

Introduction: There has been conflicting data regarding the impact of hypertriglyceridemia (HTG) on STEMI outcomes, including reports of a “lipid paradox” defined as lower event rates in patients with HTG. Therefore, the association between HTG and outcomes in STEMI deserves further investigation especially given the results of REDUCE-IT trial. Methods: A prospective, multicenter database of the Midwest STEMI Consortium was examined. The Midwest STEMI Consortium is a unique association of 4 large STEMI systems of care: Iowa Heart Center, Minneapolis Heart Institute Foundation, Prairie Cardiovascular, and The Christ Hospital. We included all consecutive STEMI patients between age of 40 and 75. Those with missing TG levels were excluded (23%). We compared 3 groups of TG levels: normal (500 mg/dl) for MACE (death, MI, or stroke) and all-cause mortality. Results: Of 6492 consecutive STEMI patients from 03/2003 to 01/2020, 3760 (58%) met inclusion criteria. The mean (SD) age was 59.1 ± 9.2 and male gender was predominant (76%). A little over one-third of the study participants had moderate HTG (35%). Patients with higher TG levels had lower HDL levels and increased rates of history of premature CAD, DM, and HTN (Table). Moderate HTG was not a risk factor for MACE or all-cause mortality. Severe HTG was significantly associated with increased in-hospital (p=0.016) but not 1-year all-cause mortality (p=0.21) (Figure). Conclusions: In STEMI patients, higher TG levels were associated with increased in-hospital but not 1-year all-cause mortality.

Introduction: There is limited data regarding the frequency, predictors and impact of repeat, unplanned coronary angiography following successful reperfusion with primary PCI in STEMI pts. Methods: We used the prospective, multicenter Midwest STEMI Consortium database, which was created by unique consolidation of 4 large STEMI systems of care: Iowa Heart Center, Minneapolis Heart Institute Foundation, Prairie Cardiovascular, and The Christ Hospital. Each center has similar, well-established standardized STEMI protocols with collaboration over 100 non-PCI-capable hospitals in Midwest. We included all consecutive STEMI pts who underwent repeat, unplanned coronary angiography within 48-hour of successful primary PCI. We excluded pts who underwent a planned or staged coronary angiography. We compared pts with repeat, unplanned coronary angiography to a propensity-score matched (1:2) pts without repeat coronary angiography within 48-hour. Results: Among 6507 STEMI pts treated with primary PCI from 03/2003 to 01/2020, only 136 (2.1%) underwent repeat, unplanned coronary angiography. These pts had higher rates of LAD culprit, history of prior MI, poor pre-PCI TIMI flow (0 or 1) and lower EF. Nearly half of the repeat, unplanned coronary angiographies revealed patent stent (63/136). There were only 32 (24%) in-stent thrombosis and 30 (22%) new occlusions. Compare to the control group, pts with repeat, unplanned coronary angiography were more likely to have major bleeding and longer LOS (p=(Table). Conclusions: Repeat, unplanned coronary angiography is relatively uncommon after contemporary primary PCI for STEMI pts and is more common with larger, anterior MIs.

Background Tumor and nodal downstaging following neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC) are important markers of therapeutic response associated with favorable prognosis. We studied the impact of four different systemic neoadjuvant therapies on tumor, nodal and overall pathological downstaging of surgically resectable I-IIIA NSCLC (AJCC 7th edition). Methods Our study cohorts consisted of NSCLC patients treated with three cycles of neoadjuvant platinum doublet chemotherapy from 2001–2012 (N=302, 84%), and patients treated on the NEOSTAR study (NCT03158129) who received neoadjuvant nivolumab (N=21,6%), nivolumab plus ipilimumab (N=16, 4%), or platinum doublet chemotherapy plus nivolumab (N=22, 6%). Clinical and pathological (yp) T and N staging were evaluated for downstaging and upstaging; differences were assessed using Fisher’s exact test. Results Following neoadjuvant platinum doublet chemotherapy, nivolumab, nivolumab plus ipilimumab and platinum doublet chemotherapy plus nivolumab, the rates of clinical-to-pathological ypT downstaging were 26% (N=79), 29% (N=6), 38% (N=6) and 59% (N=13), respectively, p =0.012 (table 1). The rates of clinical-to-pathological ypN downstaging in patients with clinical N1 or N2 disease with each therapy were 55% (N=96), 50% (N=3), 50% (N=2), and 42% (N=5) respectively, p =0.862. Overall clinical-to-pathological (ypT and/or ypN) downstaging rates were 38% (N=114), 38% (N=8), 38% (N=6), and 68% (N=15) respectively, p=0.048. The proportions of patients being overall upstaged following each therapy were 28% (N=85), 38% (N=8), 38% (N=6) and 14% (N=3), respectively, p=0.251. These results suggest superior downstaging effect and clinically meaningful lower upstaging probability of combined platinum doublet chemotherapy plus nivolumab as compared to other neoadjuvant regimens. Conclusions The combination of neoadjuvant platinum doublet chemotherapy with nivolumab achieves the most robust tumor and overall pathological downstaging and decreases the probability of upstaging at surgery. Whether the overall downstaging effect results in improved survival will be determined with longer follow-up, in conjunction with results from ongoing phase III neoadjuvant chemo-immunotherapy trials. Trial Registration NCT03158129 Ethics Approval This study was approved by the University of Texas MD Anderson Institutional Review Board with a waiver of informed consent, protocol 2020-0337.

Background Over the past 20 years, the development of regional ST-elevation myocardial infarction (STEMI) care systems has led to remarkable progress in achieving timely coronary reperfusion with attendant improvement in clinical outcomes, including survival. Despite this progress, contemporary STEMI care does not consistently meet the national guideline-recommended goals, which offers an opportunity for further improvement in STEMI outcomes. The lack of single, comprehensive, national STEMI registry complicates our ability to improve STEMI outcomes in particular for high-risk STEMI subsets such as cardiac arrest (CA) and/or cardiogenic shock (CS). Objectives To address this need, the Midwest STEMI Consortium (MSC) was created as a collaboration of 4 large, regional STEMI care systems to provide a comprehensive, multicenter, and prospective STEMI registry without any exclusionary criteria. Methods The MSC is a collaboration of 4 large, regional STEMI care systems: Iowa Heart Center in Des Moines, IA; Minneapolis Heart Institute Foundation in Minneapolis, MN; Prairie Heart Institute in Springfield, IL; and The Christ Hospital in Cincinnati, OH. Each has similar standardized STEMI protocol and together include 6 percutaneous coronary intervention (PCI)-capable hospitals and over 100 non-PCI-capable hospitals. Each center had a prospective database that was transferred to a data coordinating center to create the multicenter database. The comprehensive database includes traditional risk factors, cardiovascular history, medications, time to treatment data, detailed angiographic characteristics, and short- and long-term clinical outcomes up to 5-year for myocardial infarction, stroke, and cardiovascular and all-cause mortality. Ten-year mortality rates were assessed by using national death index. Results Currently, the comprehensive database (03/2003-01/2020) includes 14,911 consecutive STEMI patients with mean age of 62.3 ± 13.6 years, female gender (29%), and left anterior descending artery as the culprit vessel (34%). High risk features included: Age >75 years (19%), left ventricular ejection fraction, Highlights • There is no single, comprehensive, and national STEMI registry. In particular, detailed information regarding high-risk STEMI patients including cardiac arrest (CA) and cardiogenic shock (CS) are frequently missing. • Midwest STEMI Consortium is a unique registry of over 15,000 consecutive patients from 4 large regional STEMI systems. • Unique aspects of the registry include: • Consecutive STEMI activations without exclusions. • Detailed data on high-risk (CA/CS) cohorts. • Detailed angiographic data. • Detailed long-term follow up including mortality to 10 years.

Objective To evaluate the impact of COVID‐19 pandemic migitation measures on of ST‐elevation myocardial infarction (STEMI) care. Background We previously reported a 38% decline in cardiac catheterization activations during the early phase of the COVID‐19 pandemic mitigation measures. This study extends our early observations using a larger sample of STEMI programs representative of different US regions with the inclusion of more contemporary data. Methods Data from 18 hospitals or healthcare systems in the US from January 2019 to April 2020 were collecting including number activations for STEMI, the number of activations leading to angiography and primary percutaneous coronary intervention (PPCI), and average door to balloon (D2B) times. Two periods, January 2019–February 2020 and March–April 2020, were defined to represent periods before (BC) and after (AC) initiation of pandemic mitigation measures, respectively. A generalized estimating equations approach was used to estimate the change in response variables at AC from BC. Results Compared to BC, the AC period was characterized by a marked reduction in the number of activations for STEMI (29%, 95% CI:18–38, p

Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m(2) IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4(+)PD-1(+)ICOS(+)), and proliferating B cells (CD20(+)Ki67(+)) in the lymph nodes. Interestingly, regulatory T cell (CD4(+)CD25(+)CD127(lo)) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7(+)CD45RA(+)) and naïve B cells (IgD(+)CD27(−)CD20(+)) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p

Objective To examine the clinicopathological features of periocular sebaceous carcinoma and describe the differences in T category between the seventh and eighth editions of the American Joint Committee on Cancer (AJCC) staging system for eyelid carcinoma in a Canadian population. Methods This study is a single-centre retrospective review of consecutive patients diagnosed with periocular sebaceous carcinoma at Vancouver General Hospital over a 24-year period. Medical records and pathological slides were reviewed. Clinicopathological features, management, and outcomes were recorded. Each carcinoma was staged as per both the seventh and eighth editions AJCC staging system for eyelid carcinoma. Results Forty-five patients (25 women, 20 men) were identified with a median age of 74 years (range 42–91 years). Tumour size was with a median of 4 mm (range 1–30 mm) and a mean of 6.7 mm. Using the seventh edition, patients were assigned the following T categories: Tis = 10, T1 = 9, T2 = 11, T3 = 8, T4 = 0. Under the eighth edition, 18 of 45 patients (40%) were restaged, with the majority of these (15 patients, 33%) being downstaged. The eighth edition categories were as follows: Tis = 10, T1 = 22, T2 = 3, T3 = 0, T4 = 3. Three patients developed disease recurrence, 2 of whom (staged T2c and T4b) died of disease. Conclusions There were substantial differences in the seventh and eighth editions of AJCC for the staging of periocular sebaceous carcinoma. Our series had small tumours at presentation with infrequent recurrences or metastases. We found a high number of patients with in-situ-only disease.

BackgroundCheckpoint inhibitor (CPI) immunotherapy has revolutionized cancer treatment. However, immune-related adverse events and the risk of infections are not well studied. To assess the infectious risk of CPIs, we evaluated the incidence of infections in lung cancer patients treated with CPIs plus conventional chemotherapy (CC) vs CC alone.MethodsWe performed a retrospective comparative study of patients with advanced non–small cell lung cancer who received CPIs combined with CC and those treated with CC alone at our institution during January 2016 to February 2019. We compared clinical characteristics, treatments, and outcomes including infection rate and mortality between the groups.ResultsWe identified 123 patients for the CPI group and 147 patients for the control (CC) group. Eighteen patients (15%) in the CPI group and 33 patients (22%) in the control group developed infections (P = .1). Pneumonia was the most common infection encountered in both groups. Urinary tract infection was higher in the CC group (40%) than in the CPI group (9%) (P = .01). On multivariable analysis, chronic obstructive pulmonary disease (P = .024), prior use of corticosteroids (P = .021), and neutropenia (P ConclusionsLung cancer patients treated with CPIs combined with CC have a comparable risk of infection to those treated with CC alone, although there is a trend towards fewer infections in those given CPIs, particularly when it comes to urinary tract infections.

Background Patients with mental illness are frequently treated in primary care, where Primary Care Providers (PCPs) report feeling ill-equipped to manage their care. Team-based models of care improve outcomes for patients with mental illness, but multiple barriers limit adoption. Barriers include practical issues and psychosocial factors associated with the reorganization of care. Practice facilitation can improve implementation, but does not directly address the psychosocial factors or gaps in PCP skills in managing mental illness. To address these gaps, we developed Relational Team Development (RELATED). Methods RELATED is an implementation strategy combining practice facilitation and psychology clinical supervision methodologies to improve implementation of team-based care. It includes PCP-level clinical coaching and a team-level practice change activity. We performed a preliminary assessment of RELATED with a convergent parallel mixed method study in 2 primary care clinics in an urban Federally Qualified Health Center in Southwest, USA, 2017-2018. Study participants included PCPs, clinic staff, and patient representatives. Clinic staff and patients were recruited for the practice change activity only. Primary outcomes were feasibility and acceptability. Feasibility was assessed as ease of recruitment and implementation. Acceptability was measured in surveys of PCPs and staff and focus groups. We conducted semi-structured focus groups with 3 participant groups in each clinic: PCPs; staff and patients; and leadership. Secondary outcomes were change in pre- post- intervention PCP self-efficacy in mental illness management and team-based care. We conducted qualitative observations to better understand clinic climate. Results We recruited 18 PCPs, 17 staff members, and 3 patient representatives. We ended recruitment early due to over recruitment. Both clinics developed and implemented practice change activities. The mean acceptability score was 3.7 (SD=0.3) on a 4-point Likert scale. PCPs had a statistically significant increase in their mental illness management self-efficacy [change = 0.9, p-value= Conclusions RELATED was feasible and highly acceptable. It led to positive changes in PCP self-efficacy in Mental Illness Management. If confirmed as an effective implementation strategy, RELATED has the potential to significantly impact implementation of evidence-based interventions for patients with mental illness in primary care.

A better understanding of clinician and patient characteristics that are associated with referral for palliative care in a real‐world context may help to overcome barriers to timely palliative care access. This article reports patterns of outpatient palliative care referral among thoracic medical oncologists and identifies oncologist characteristics associated with greater referral., Background. There is significant variation in access to palliative care. We examined the pattern of outpatient palliative care referral among thoracic medical oncologists and identified oncologist characteristics associated with greater referral. Materials and Methods. We retrieved data on all patients who died of advanced thoracic malignancies at our institution between January 1, 2007, and December 31, 2012. Using median as a cutoff, we defined two groups (high‐referring and low‐referring oncologists) based on their frequency of referral. We examined various oncologist‐ and patient‐related characteristics associated with outpatient referral. Results. Of 1,642 decedents, 444 (27%) had an outpatient palliative care referral. The median proportion of referral among 26 thoracic oncologists was 30% (range 9%–45%; median proportion of high‐referring 37% vs. low‐referring 24% when divided into two groups at median). High‐referring oncologists were significantly younger (age 45 vs. 56) than low‐referring oncologists; they were also significantly more likely to refer patients earlier (median interval between oncology consultation and palliative care consultation 90 days vs. 170 days) and to refer those without metastatic disease (7% vs. 2%). In multivariable mixed‐effect logistic regression, younger oncologists (odds ratio [OR] = 0.97 per year increase, 95% confidence interval [CI] 0.95–0.995), younger patients (OR = 0.98 per year increase, 95% CI 0.97–0.99), and nonmetastatic disease status (OR = 0.48, 95% CI 0.29–0.78) were significantly associated with outpatient palliative care referral. Conclusion. The pattern of referral to outpatient palliative care varied widely among thoracic oncologists. Younger oncologists were not only referring a higher proportion of patients, but also referring patients earlier in the disease trajectory. Implications for Practice. This retrospective cohort study found that younger thoracic medical oncologists were significantly more likely to refer patients to outpatient palliative care and to do so earlier in the disease trajectory compared with older oncologists, even after adjusting for other known predictors such as patient demographics. The findings highlight the role of education to standardize palliative care access and imply that outpatient palliative care referral is likely to continue to increase with a shifting oncology workforce.

Purpose To establish, in the phase 1 portion of a prospective phase 1/2 study, the maximum tolerated dose of image guided intensity modulated radiation therapy (IMRT) or proton therapy (IMPT), both with a simultaneous integrated boost (SIB), for patients with stage II to IIIB non-small cell lung cancer receiving concurrent chemoradiation therapy. Methods and Materials Patients had pathologically proven non-small cell lung cancer, either unresectable stage II to IIIB disease or recurrent disease after surgical resection, and could tolerate concurrent chemoradiation. Radiation doses were selectively escalated to the SIB volume (internal gross tumor volume + 5-mm margin), and the dose to the planning target volume (internal gross tumor volume + 8-mm margin for clinical target volume + 5 mm) was kept at 60 Gy [cobalt gray equivalent (CGE)] over 30 fractions. Patients were randomized between the IMRT and IMPT groups if slots were available on the treatment machines for both groups. Otherwise, patients were allocated to IMRT or IMPT, whichever had an open treatment slot on the machine without randomization. Results Fifteen patients (6 IMRT, 9 IMPT) were enrolled. The highest doses to the SIB were 72 Gy in the IMRT group and 78 Gy(CGE) in the IMPT group. Nine patients (6 IMRT, 3 IMPT) received an SIB dose of 72 Gy(CGE) [biologically effective dose = 89.3 Gy(CGE)], and 6 patients (IMPT) received an SIB dose of 78 Gy(CGE) [biologically effective dose = 98.3 Gy(CGE)]. Dose-limiting (grade ≥3) toxicity (esophagitis) developed in 1 of the 9 patients given 72 Gy(CGE) SIB. Grade ≥3 pneumonitis developed in 2 of the 6 patients treated to 78 Gy(CGE) IMPT SIB: 1 (grade 3) at 3 months after treatment and the other (grade 5, possibly related to treatment) at 2 months after treatment. Only 1 patient developed a marginal tumor recurrence with a median follow-up of 25 months (range, 4.3-47.4 months). Conclusions We recommend that an SIB dose of 72 Gy(CGE) be used as the highest SIB dose for the planned randomized phase 2 study.

Background Data from meta-analyses support the use of induction or adjuvant platinum-based chemotherapy for locally advanced non-small cell lung cancers (NSCLCs). This phase 2 study assessed the role of induction cisplatin and docetaxel followed by surgery in patients with resectable stage I to III NSCLCs, followed by 12 months of adjuvant erlotinib. Methods Patients with resectable stage I to III NSCLCs received cisplatin 80 mg/m 2 , docetaxel 75 mg/m 2 every 21 days for 3 cycles, followed by surgery, followed by adjuvant erlotinib for 12 months. The primary endpoint included safety. Long-term efficacy outcomes and exploratory analysis of intermediary endpoints are also reported (NCT00254384). Results Forty-seven eligible patients received a median of 3 cycles of induction treatment, 37 underwent surgical resection, and only 21 received adjuvant erlotinib. Two patients died in the perioperative period (1 sepsis during chemotherapy, 1 acute respiratory distress syndrome postoperatively). Most common grade 3 to 5 toxicities during chemotherapy included hypokalemia (8%), infection (7%), and granulocytopenia (25%). During adjuvant erlotinib, 14% of patients experienced grade 2 rash. Median overall survival was 3.4 years. Major pathologic responses in the primary tumor were observed in 19% (7 of 37) of patients and correlated with improved long-term overall survival. Complete pathologic response in mediastinal/hilar nodes also correlated with superior survival. Conclusions Induction cisplatin and docetaxel was well tolerated. Adjuvant erlotinib did not improve outcomes compared with historical controls. Major pathologic response predicted for improved long-term survival and is a suitable intermediary endpoint for future phase 2 studies.

The use of satellite systems and manned aircraft surveys for remote data collection has been shown to be transformative for sea turtle conservation and research by enabling the collection of data on turtles and their habitats over larger areas than can be achieved by surveys on foot or by boat. Unmanned aerial vehicles (UAVs) or drones are increasingly being adopted to gather data, at previously unprecedented spatial and temporal resolutions in diverse geographic locations. This easily accessible, low-cost tool is improving existing research methods and enabling novel approaches in marine turtle ecology and conservation. Here we review the diverse ways in which incorporating inexpensive UAVs may reduce costs and field time while improving safety and data quality and quantity over existing methods for studies on turtle nesting, at-sea distribution and behaviour surveys, as well as expanding into new avenues such as surveillance against illegal take. Furthermore, we highlight the impact that high-quality aerial imagery captured by UAVs can have for public outreach and engagement. This technology does not come without challenges. We discuss the potential constraints of these systems within the ethical and legal frameworks which researchers must operate and the difficulties that can result with regard to storage and analysis of large amounts of imagery. We then suggest areas where technological development could further expand the utility of UAVs as data-gathering tools; for example, functioning as downloading nodes for data collected by sensors placed on turtles. Development of methods for the use of UAVs in sea turtle research will serve as case studies for use with other marine and terrestrial taxa.

Purpose To assess the incidence of costal cartilage (CC) fractures in whole-body computed tomographic (CT) examinations for blunt trauma and to evaluate distribution of CC fractures, concomitant injuries, mechanism of injury, accuracy of reporting, and the effect on 30-day mortality. Materials and Methods Institutional review board approval was obtained for this retrospective study. All whole-body CT examinations for blunt trauma over 36 months were reviewed retrospectively and chest trauma CT studies were evaluated by a second reader. Of 1461 patients who underwent a whole-body CT examination, 39% (574 of 1461) had signs of thoracic injuries (men, 74.0% [425 of 574]; mean age, 46.6 years; women, 26.0% [149 of 574]; mean age, 48.9 years). χ2 and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Interobserver agreement was calculated by using Cohen kappa values. Results A total of 114 patients (men, 86.8% [99 of 114]; mean age, 48.6 years; women, 13.2% [15 of 114]; mean age, 45.1 years) had 221 CC fractures. The incidence was 7.8% (114 of 1461) in all whole-body CT examinations and 19.9% (114 of 574) in patients with thoracic trauma. Cartilage of rib 7 (21.3%, 47 of 221) was most commonly injured. Bilateral multiple consecutive rib fractures occurred in 36% (41 of 114) versus 14% (64 of 460) in other patients with chest trauma (OR, 3.48; 95% CI: 2.18, 5.53; P < .0001). Hepatic injuries were more common in patients with chest trauma with CC fractures (13%, 15 of 114) versus patients with chest trauma without CC fractures (4%, 18 of 460) (OR, 3.72; 95% CI: 1.81, 7.64; P = .0001), as well as aortic injuries (n = 4 vs n = 0; P = .0015; OR, unavailable). Kappa value for interobserver agreement in detecting CC fractures was 0.65 (substantial agreement). CC fractures were documented in 39.5% (45 of 114) of primary reports. The 30-day mortality of patients with CC fractures was 7.02% (eight of 114) versus 4.78% (22 of 460) of other patients with chest trauma (OR, 1.50; 95% CI: 0.65, 3.47; P = .3371). Conclusion CC fractures are common in high-energy blunt chest trauma and often occur with multiple consecutive rib fractures. Aortic and hepatic injuries were more common in patients with CC fractures than in patients without CC fractures. © RSNA, 2017.

PURPOSE/OBJECTIVE(S) To report updated findings from a prospective phase II trial of salvage high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer (NCT02710253). MATERIALS/METHODS Eligible patients had metastatic disease that progressed on immunotherapy within the prior 6 months. Patients were given either HD-RT (20-70Gy total; 3-12.5Gy/fraction), or HD-RT and LD-RT to separate lesions (LD-RT comprised of < 2Gy/fraction up to 10Gy total), with continued immunotherapy. Radiographic response was assessed per RECIST1.1 and Immune-Related Response Criteria (irRC). Primary endpoints were 1) 4-month disease control (complete/partial response [CR/PR] or stable disease [SD]) or an overall response (CR/PR) at any point in ≥10% of patients, and 2) dose-limiting toxicity within 3 months not exceeding 30%. Also, where applicable, biopsies pre- and post- low-dose RT were collected, FFPE slides were prepared and analyzed by Multiplex Immunofluorescence (Multi-IF) microscopy for immune-cell infiltration. RESULTS Seventy-four patients were analyzed (39 in HD-RT group and 35 in HD-RT+LD-RT group), mostly with non-small cell lung cancer (n = 38) or melanoma (n = 21). Patients received immunotherapy for a median of 7.1 months (3.7-10.6 months) before RT, and 95% maintained the same therapy after RT. The median follow-up time was 13.8 months. The site most commonly treated with HD- or LD-RT was lung/mediastinum. The primary endpoint was met for the 72 evaluable patients, with a 4-month overall disease control rate of 42% (RECIST1.1, 47% [16/34] for the HD-RT+LD-RT group and 37% [14/38] for the HD-RT only group). Three (4.2%) patients experienced grade ≥3 toxicity. LD-RT treated lesion response rates (irRC, 53%) was improved compared to nonirradiated lesions in the HD-RT+LD-RT (23%, P = 0.002) and HD-RT only (11%, P < 0.001) group. The median PFS was 7.0 months vs. 5.8 months, while median OS was 15.9 months vs. 10.5 months for the HD-RT+LD-RT group vs. HD-RT only group respectively; however, statistical significance was not reached. Furthermore, the addition of LD-RT did not significantly affect the absolute lymphocyte counts (ALC), with ALC reduction after treatment recorded as 420/μL vs. 340/μL in the HD-RT only vs. HD-RT+LD-RT groups (P = 0.44). The Multi-IF data for 3 analyzed biopsies of LD-RT lesions showed strong correlation between T cell and NK cell infiltration and clinical response rate. Lesion 1 for example (24% SD), had CD56+ NK cell numbers increase from 67 to 1837 n/mm2 post LD-RT. Lesion 2 (-80% PR) had its CD3+CD4+ T cells increase from 287 to 1233 n/mm2 and NK cells increase from 0 to 187 n/mm2; while lesion 3 (-8% SD) showed an increase from 79 to 131 n/mm2 and 3.6 to 7.3 n/mm2 in the T cell and NK cell compartments respectively. CONCLUSION Low-dose RT is an effective and safe way to enhance individual lesion-specific response rates among progressing patients with solid tumors, with the ability to improve the infiltration of effector immune cells into the tumor microenvironment.

Introduction Exploratory analysis of clinical trials in various tumor types have demonstrated potential improvements in overall response rate (ORR) to chemotherapy after exposure to vaccine-based immunotherapy. The objective of this retrospective study was to determine if single-agent chemotherapy (3rd-line or beyond) would yield improved ORR when given after exposure to programmed death-(ligand)1 inhibitors (anti-PD1) in metastatic non-small cell lung cancer (NSCLC). Materials and methods We queried the Thoracic GEMINI database of MD Anderson Cancer Center for patients treated between 06/12 and 11/16 who received at least one single-agent chemotherapy as 3rd-line or beyond, following progression after platinum-based chemotherapy and anti-PD1. We evaluated efficacy outcomes to each therapy, including ORR by RECIST version 1.1, progression-free survival (PFS), and overall survival (OS). Results Out of 306 anti-PD1-treated patients registered in the database, 28 met eligibility criteria − 54% were male, median age was 66 years, 82% had adenocarcinoma, and 71% were former/current smokers. The anti-PD1 and single-agent chemotherapy most commonly used were nivolumab (86%) and docetaxel (50%), respectively. ORR to single-agent chemotherapy after exposure to anti-PD1 was 39% (11/28 patients, 8 confirmed). In contrast, ORR to first-line chemotherapy in this cohort was 37%. Liver metastasis was the only factor associated with response to single-agent chemotherapy on univariate analysis (p Conclusion In NSCLC patients, the confirmed ORR to single-agent chemotherapy after immunotherapy exposure was higher as compared to historical data from the pre-anti-PD1 era, and approached ORR to first-line platinum-based chemotherapy. Further investigation of a possible immunotherapy-induced chemosensitization effect is warranted.