Phase 2 study of PD-1 blockade following autologous transplantation for patients with AML ineligible for allogeneic transplant.

Allogeneic transplant remains the best postremission therapy for patients with nonfavorable risk acute myeloid leukemia (AML). However, some patients are ineligible because of psychosocial barriers, such as lack of appropriate caregiver support. We hypothesized that immune checkpoint inhibition after autologous transplant might represent effective postremission therapy in such patients. We conducted a phase 2 study of autologous transplantation followed by administration of pembrolizumab (8 cycles starting day +1). Twenty patients with nonfavorable AML in complete remission were treated (median age, 64 years; CR1, 80%); 55% were non-White and adverse-risk AML was present in 40%. Treatment was well tolerated, with only 1 nonrelapse death. Immune-related adverse events occurred in 9 patients. After a median follow-up of 80 months, 14 patients remain alive, with 10 patients in continuous remission. The estimated 2-year LFS was 48.4%, which met the primary end point of 2-year LFS >25%; the 2-year overall survival (OS), nonrelapse mortality, and cumulative incidences of relapse were 68%, 5%, and 46%, respectively. In comparison with a propensity score-matched cohort group of patients with AML receiving allogeneic transplant, the 3-year OS was similar (73% vs 76%). Patients in the study had inferior LFS (51% vs 75%) but superior postrelapse survival (45% vs 14%). In conclusion, programmed cell death protein-1 blockade after autologous transplant is a safe and effective alternative postremission strategy in patients with nonfavorable risk AML who are ineligible for allogeneic transplant, a context in which there is significant unmet need. This trial was registered at www.clinicaltrials.gov as #NCT02771197.

Heterogeneity of Lung Function Phenotypes in Sarcoidosis: Role of Race and Sex Differences.

Rationale: Historically, sarcoidosis was described as a restrictive lung disease, but several alternative phenotypes of pulmonary function have been observed. Pulmonary function phenotypes in sarcoidosis may represent different clinical and/or molecular phenotypes. Objectives: To characterize the prevalence of different pulmonary function phenotypes in a large and diverse sarcoidosis cohort from a tertiary care referral center. Methods: We identified individuals seen between 2005-2015 with a confirmed diagnosis of sarcoidosis. Data were collected from the first pulmonary function test (PFT) performed at our institution which included spirometry and diffusing capacity of the lung for carbon monoxide (DlCO). Demographics and clinical data were collected. Chi-squared analyses and multiple linear regressions were done to assess statistical differences and associations. Global Lung Function Initiative equations were used to calculate percent predicted measurements for spirometry and DlCO. Results: Of 602 individuals with sarcoidosis, 93% (562) had pulmonary involvement, 64% (385) were female, and 57% (341) were Black. Of those with pulmonary involvement, 56% had abnormal pulmonary function. Lung function impairment phenotypes included: 47% restriction, 22% obstruction, 15% isolated reduction in DlCO, and 16% combined obstructive restrictive phenotype. Restriction was the most common PFT phenotype among Black individuals (41%), while no lung impairment was most common among White individuals (66%) (P < 0.001). Males more frequently had obstruction (19%) compared with females (9%) P = 0.001, and females had more restriction (30%) compared with males (21%) P = 0.031. Conclusions: Among individuals with sarcoidosis and pulmonary function impairment, less than half demonstrated a restrictive phenotype. There were significant differences in pulmonary function phenotypes by race and sex.

Resilience Among Small Community-based Organizations During the COVID-19 Pandemic: Insights for Future Public Health Crises.

The coronavirus disease 2019 pandemic has created numerous challenges for many community-based organizations to sustain delivery of services and programs. This paper offers perspectives from leadership of three small community-based organizations serving diverse populations in the Hartford, Connecticut, region on how they were impacted and responded to disruptions during the first year of the coronavirus disease 2019 pandemic. Community-based organizations' commitment to the populations they serve and agility with regard to programming, staffing, and finances were highlighted as key to their resilience, enabling them to serve their clients with stability. The ability to collect information on the impact of the pandemic on clients supported by a well-established, long-term partnership with researchers at the University of Connecticut School of Medicine and Institute for Community Research facilitated their making data-driven decisions on how to best allocate limited resources. The lessons learned about organizational challenges and resilience may be applicable to future public health emergencies.

A shift in lung macrophage composition is associated with COVID-19 severity and recovery.

Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue-resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.

Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function.

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).

Mesenchymal stromal cell therapy for acute respiratory distress syndrome due to coronavirus disease 2019.

BACKGROUND AIMS: The acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications. METHODS: Patients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48-120 h apart. RESULTS: Remestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59-100%) patients were extubated, nine (82%, 95% CI, 48-97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2-52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34-100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion. CONCLUSIONS: The authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes.

High-Dose Bendamustine, Etoposide, Cytarabine, and Melphalan (BeEAM) Conditioning Before Autologous Transplantation for Patients With Multiple Myeloma.

Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM), and efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed. Bendamustine combines both alkylating and antimetabolite properties, can induce responses in MM resistant to other alkylators and represents a promising agent to combine with Mel prior to ASCT. We performed a phase II study to test the safety and efficacy of the high-dose chemotherapy combination of bendamustine, etoposide, cytarabine, and melphalan (BeEAM) in newly diagnosed MM patients up to 70 years of age. The primary study endpoint was the day 100 complete response rate. Sixty-five patients with a median (range) age of 59 (40-69) years underwent transplantation from 2015 to 2020. Other characteristics included Karnofsky performance status <80%, hematopoietic cell transplantation-comorbidity index ≥3, International Staging System III, and high-risk fluorescein in situ hybridization (FISH) in 35%, 46%, 26%, and 44%, respectively. ASCT after BeEAM was well tolerated, and there were no non-relapse deaths through 1 year after transplantation. Although at least 1 nonhematologic grade 3 toxicity was reported in 58 (89%) patients (including grade 3 febrile neutropenia in 48% and stomatitis/esophagitis in 28%), there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. The day 100 response rate was ≥CR1 and ≥ very good partial response (VGPR1) in 40% and 89%, respectively. With a median follow-up of 44 (13-70) months, the 3-year overall survival was 92%, 96%, and 90% for all patients and those with standard- and high-risk FISH, respectively. The corresponding values for 3-year progression-free survival was 57%, 72%, and 40%, respectively. When BeEAM-conditioned patients were compared to historical Mel-conditioned cohort, no significant differences were noted in relapse or survival outcomes in univariate or multivariable analysis. In summary, BeEAM was shown to be a safe and effective conditioning regimen before up-front autologous transplant for MM. Although the BeEAM regimen does not appear to offer a significant advantage over single-agent Mel, further studies combining bendamustine and melphalan in the front-line setting may be warranted.

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery.

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoMΦ). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

Lung Cancer Risk among Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Rationale: Chronic obstructive pulmonary disease (COPD) is a well-established independent risk factor for lung cancer; however, the literature on the association between asthma and lung cancer is mixed. Whether asthma-COPD overlap (ACO) is associated with lung cancer has not been studied. Objectives: We aimed to compare lung cancer risk among patients with ACO versus COPD and other conditions associated with airway obstruction. Methods: We studied 13,939 smokers from the National Lung Cancer Screening Trial who had baseline spirometry and used spirometric indices and history of childhood asthma to categorize participants into five specific airway disease subgroups. We used Poisson regression to compare unadjusted and adjusted lung cancer risk. Results: The incidence rate of lung cancer per 1,000 person-years was as follows: ACO, 13.2 (95% confidence interval [CI], 8.1-21.5); COPD, 11.7 (95% CI, 10.5-13.1); asthmatic smokers, 1.8 (95% CI, 0.6-5.4); Global Initiative for Chronic Obstructive Lung Disease-Unclassified, 7.7 (95% CI, 6.4-9.2); and normal spirometry smokers, 4.1 (95% CI, 3.5-4.8). Patients with ACO had increased adjusted risk of lung cancer compared with patients with asthma (incidence rate ratio [IRR], 4.5; 95% CI, 1.3-15.8) and normal spirometry smokers (IRR, 2.3; 95% CI, 1.3-4.2) in models adjusting for other risk factors. Adjusted lung cancer incidence in patients with ACO and COPD were not found to be different (IRR, 1.2; 95% CI, 0.7-2.1). Conclusions: The risk of lung cancer among patients with ACO is similar to those with COPD and higher than other groups of smokers. These results provide further evidence that COPD, with or without a history of childhood asthma, is an independent risk factor for lung cancer.

Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake.

TUG tethering proteins bind and sequester GLUT4 glucose transporters intracellularly, and insulin stimulates TUG cleavage to translocate GLUT4 to the cell surface and increase glucose uptake. This effect of insulin is independent of phosphatidylinositol 3-kinase, and its physiological relevance remains uncertain. Here we show that this TUG cleavage pathway regulates both insulin-stimulated glucose uptake in muscle and organism-level energy expenditure. Using mice with muscle-specific Tug (Aspscr1)-knockout and muscle-specific constitutive TUG cleavage, we show that, after GLUT4 release, the TUG C-terminal cleavage product enters the nucleus, binds peroxisome proliferator-activated receptor (PPAR)γ and its coactivator PGC-1α and regulates gene expression to promote lipid oxidation and thermogenesis. This pathway acts in muscle and adipose cells to upregulate sarcolipin and uncoupling protein 1 (UCP1), respectively. The PPARγ2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The ATE1 arginyltransferase, which mediates a specific protein degradation pathway and controls thermogenesis, regulates the stability of the TUG product. We conclude that insulin-stimulated TUG cleavage coordinates whole-body energy expenditure with glucose uptake, that this mechanism might contribute to the thermic effect of food and that its attenuation could promote obesity.

Monitoring of Farm-Level Antimicrobial Use to Guide Stewardship: Overview of Existing Systems and Analysis of Key Components and Processes.

The acknowledgment of antimicrobial resistance (AMR) as a major health challenge in humans, animals and plants, has led to increased efforts to reduce antimicrobial use (AMU). To better understand factors influencing AMR and implement and evaluate stewardship measures for reducing AMU, it is important to have sufficiently detailed information on the quantity of AMU, preferably at the level of the user (farmer, veterinarian) and/or prescriber or provider (veterinarian, feed mill). Recently, several countries have established or are developing systems for monitoring AMU in animals. The aim of this publication is to provide an overview of known systems for monitoring AMU at farm-level, with a descriptive analysis of their key components and processes. As of March 2020, 38 active farm-level AMU monitoring systems from 16 countries were identified. These systems differ in many ways, including which data are collected, the type of analyses conducted and their respective output. At the same time, they share key components (data collection, analysis, benchmarking, and reporting), resulting in similar challenges to be faced with similar decisions to be made. Suggestions are provided with respect to the different components and important aspects of various data types and methods are discussed. This overview should provide support for establishing or working with such a system and could lead to a better implementation of stewardship actions and a more uniform communication about and understanding of AMU data at farm-level. Harmonization of methods and processes could lead to an improved comparability of outcomes and less confusion when interpreting results across systems. However, it is important to note that the development of systems also depends on specific local needs, resources and aims.

Prospective phase 2 trial of ixazomib after nonmyeloablative haploidentical peripheral blood stem cell transplant.

Proteasome inhibition results in extensive immunomodulatory effects that augment natural killer cell cytotoxicity and inhibit aspects of T-cell, B-cell, and dendritic cell function. We performed a phase 2 study that examined the effects of ixazomib for graft-versus-host disease (GVHD) prophylaxis (up to 12 cycles) with posttransplant cyclophosphamide and tacrolimus after standard nonmyeloablative haploidentical donor transplantation (HIDT). Ixazomib was started on day +5 (4 mg on days 1, 8, and 15 of a 28-day cycle), with dose reductions allowed in future cycles for toxicity. All patients received peripheral blood stem cells. Twenty-five patients were enrolled with a median age of 62 years (range, 35-77 years) who had acute leukemia (4), myelodysplastic syndrome (7), non-Hodgkin lymphoma/Hodgkin lymphoma/chronic lymphocytic leukemia (8), and myeloma (6). The hematopoietic cell transplant comorbidity index was ≥3 in 68% of the patients. After a median follow-up of 33.5 months, the cumulative incidence of relapse/progression at 1 year was 24% and 44% at 3 years, which failed to meet the statistically predefined goal of decreasing 1-year risk of relapse. Engraftment occurred in all patients with no secondary graft failure, and 3-year nonrelapse mortality (NRM) was 12%. Cumulative incidence of grade 3 to 4 acute GVHD was 8%, whereas moderate-to-severe chronic GVHD occurred in 19%. Nineteen patients survive with an estimated 1-year overall survival (OS) of 84% and 3-year OS of 74%. Hematologic and cutaneous toxicities were common but manageable. The substitution of ixazomib for mycophenolate mofetil (MMF) post-HIDT results in reliable engraftment, comparable rates of clinically significant GVHD, relapse and NRM, and favorable OS. This trial was registered at www.clinicaltrials.gov as # NCT02169791.

Recent Advances in the Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease is a chronic, irreversible obstructive lung disease that results from exposure to noxious stimuli. Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) usually result from viral or bacterial respiratory infections, but may also result from exposure to environmental pollution. AECOPD are associated with functional decline, increased risk of subsequent exacerbations, and death. Despite the poor prognosis of AECOPD, patients are empowered through self-management programs in their battle against this lethal disease. Morbidity and mortality of chronic obstructive pulmonary disease hospitalizations are reduced by implementing standardized treatment modalities outlined in this article throughout the hospitalization and beyond.

Creating a Comprehensive Approach to Exposing Underrepresented Pre-health Professions Students to Clinical Medicine and Health Research.

BACKGROUND/PURPOSE: With the urgency to create more equitable health care, increased research and early exposure to health interventions and clinical medicine are imperative. Health disparities continue to persist nationwide, particularly in underserved areas and among traditionally disadvantaged populations. In addition to the need to eliminate health disparities, increasing the diversity among health professionals to more accurately reflect the US population is essential. METHODS: The health professions partnership at the School of Medicine and the School of Dental Medicine is a comprehensive pipeline designed to increase the preparation of underrepresented students for health careers. Through this health professions pipeline's Health Disparities Clinical Summer Research Fellowship Program (HDCSRFP), undergraduate students are exposed to health disparities research and clinical skills over seven weeks. Over the course of the program, participants conducted a research project, gained clinical exposure by shadowing community physicians and other health professionals, and received mentoring by health professional faculty and students. At the conclusion of the program, participants presented their research projects during a poster symposium. RESULTS: A total of 121 program participants between 2008 and 2018 each conducted a research project focused on reducing health inequities within specific populations, particularly in urban settings. The health professions pipeline has been instrumental in increasing the aptitude and competitiveness of these students pursuing health careers through participation in research, clinical medicine, and enrichment activities. Specifically, 92% of the 79 program participants identified who completed undergraduate studies before the end of the 2018 fall semester pursued a career or further studies within a health profession. Forty-six percent of these college graduates were accepted or matriculated in medical school by the end of 2018. CONCLUSION: The HDCSRFP, like the other health professions partnership pipeline programs, serves as a model for other educational programs to expose students to the field of medicine and health research, and to increase diversity within health professions.

Comparative Effectiveness of Robotic-Assisted Surgery for Resectable Lung Cancer in Older Patients.

BACKGROUND: Robotic-assisted surgery (RAS) is a novel surgical approach increasingly used for patients with non-small cell lung cancer (NSCLC). However, data comparing the effectiveness and costs of RAS vs open thoracotomy and video-assisted thoracoscopic surgery (VATS) for NSCLC are limited. METHODS: Patients > 65 years old with stage I to IIIA NSCLC treated with RAS, VATS, or open thoracotomy were identified from the Surveillance, Epidemiology, and End Results-Medicare database and matched according to age, sex, stage, and extent of resection. Propensity score methods were used to compare adjusted rates of postoperative complications, adequate lymph node staging, survival, and treatment-related costs. RESULTS: In this matched study cohort of 2,766 patients with resected NSCLC, RAS was associated with lower complication rates (OR, 0.57; 95% CI, 0.42-0.79) compared with open thoracotomy, and similar complication rates (OR, 1.02; 95% CI, 0.76-1.37) compared with VATS. Patients undergoing RAS were as likely to have adequate lymph node sampling as those undergoing open thoracotomy (OR, 1.28; 95% CI, 0.94-1.74) or VATS (OR, 0.88; 95% CI, 0.66-1.18). There was no significant difference in overall survival after RAS vs open thoracotomy (hazard ratio, 0.81; 95% CI, 0.63-1.04) or VATS (hazard ratio, 0.91; 95% CI, 0.70-1.18). Costs were similar for RAS ($54,702) vs open thoracotomy ($57,104; P = .08), and higher compared with VATS ($48,729; P = .02). CONCLUSIONS: RAS led to improved operative outcomes compared with open thoracotomy but may not offer an advantage over VATS. The comparative effectiveness of RAS should be further evaluated prior to widespread adoption.

Interactions of the DASH Diet with the Renin-Angiotensin-Aldosterone System.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet is widely recommended to lower blood pressure, but its mechanisms of action are unclear. Lines of evidence suggest an interaction with the renin-angiotensin-aldosterone system (RAAS). OBJECTIVE: We conducted a randomized, controlled, cross-over feeding trial to test RAAS-related mechanisms underlying the DASH diet in patients with isolated systolic hypertension. METHODS: Participants entered a 1-wk run-in period on a control (CON) diet and then consumed the DASH or CON diets for 4 wk each in randomized sequence. Calorie content was controlled to maintain weight, and sodium intake was set at 3 g daily. After each diet, participants had hormonal and hemodynamic assessments obtained at baseline, in response to RAAS inhibition with captopril (CAP) 25 mg, and to graded angiotensin II (AngII) infusions (1 ng/kg and 3 ng/kg × 45 min). Primary outcomes were mean arterial pressure (MAP) and renal blood flow (RBF), and secondary outcomes were diastolic function, pulse wave velocity (PWV), plasma renin activity (PRA), and aldosterone (ALDO) responses by diet. RESULTS: In total, 44 (19 female) participants completed the study. DASH + CAP significantly lowered MAP compared with CON + CAP (83 ± 11 mmHg compared with 88 ± 14 mmHg, P <0.01). RBF was increased with DASH + CAP compared with CON + CAP (486 ± 149 cc/min compared with 451 ± 171 cc/min, P <0.001). Study diet did not change PWV but CAP reduced diastolic function on the DASH diet (P <0.05). DASH + CAP significantly increased PRA compared with CON + CAP (1.52 ± 1.78 ng/mL/min compared with 0.89 ± 1.17 ng/mL/min; P <0.001). ALDO sensitivity to AngII infusion was greater with DASH when compared to CON (17.4 ± 7.7 ng/mL compared with 13.8 ± 6.2 ng/dL, P <0.05) as was DASH + CAP compared with CON + CAP (15.1 ± 5.3 ng/dL compared with 13.1 ± 5.9 ng/mL, P <0.05). CONCLUSIONS: The DASH diet interacts with the RAAS resulting in vascular and hormonal responses similar to a natriuretic effect, which appears to augment the hypotensive effect of angiotensin-converting enzyme (ACE) inhibition in individuals with isolated systolic hypertension. This trial was registered at clinicaltrials.gov as NCT00123006.

Interstitial Lung Abnormalities and Lung Cancer Risk in the National Lung Screening Trial.

BACKGROUND: Some interstitial lung diseases are associated with lung cancer. However, it is unclear whether asymptomatic interstitial lung abnormalities convey an independent risk. OBJECTIVES: The goal of this study was to assess whether interstitial lung abnormalities are associated with an increased risk of lung cancer. METHODS: Data from all participants in the National Lung Cancer Trial were analyzed, except for subjects with preexisting interstitial lung disease or prevalent lung cancers. The primary analysis included those who underwent low-dose CT imaging; those undergoing chest radiography were included in a confirmatory analysis. Participants with evidence of reticular/reticulonodular opacities, honeycombing, fibrosis, or scarring were classified as having interstitial lung abnormalities. Lung cancer incidence and mortality in participants with and without interstitial lung abnormalities were compared by using Poisson and Cox regression, respectively. RESULTS: Of the 25,041 participants undergoing low-dose CT imaging included in the primary analysis, 20.2% had interstitial lung abnormalities. Participants with interstitial lung abnormalities had a higher incidence of lung cancer (incidence rate ratio, 1.61; 95% CI, 1.30-1.99). Interstitial lung abnormalities were associated with higher lung cancer incidence on adjusted analyses (incidence rate ratio, 1.33; 95% CI, 1.07-1.65). Lung cancer-specific mortality was also greater in participants with interstitial lung abnormalities. Similar findings were obtained in the analysis of participants undergoing chest radiography. CONCLUSIONS: Asymptomatic interstitial lung abnormalities are an independent risk factor for lung cancer that can be incorporated into risk score models.

Outcomes of Older Patients with Pulmonary Fibrosis and Non-Small Cell Lung Cancer.

Rationale: Characteristics and outcomes of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) in the United States remain understudied.Objectives: To determine the tumor characteristics and survival of patients with IPF with non-small cell lung cancer (NSCLC) using U.S. population-based data.Methods: We selected Medicare beneficiaries from the Surveillance, Epidemiology, and End Results registry with histologically confirmed NSCLC diagnosed between 2007 and 2011. IPF was identified using two validated claims-based algorithms. We compared tumor characteristics and used logistic and Cox regression to compare rates of stage-appropriate therapy and of overall and lung cancer-specific survival in those with IPF and without IPF.Results: A total of 54,453 patients with NSCLC were included. Those with IPF were more likely to be diagnosed at an earlier stage (P < 0.01) and to have squamous histology (46% vs. 35%; P < 0.01) and lower-lobe tumors (38% vs. 28%; P < 0.01) than those without IPF. Patients with IPF and stages I-II disease had odds of receiving stage-appropriate therapy similar to patients without IPF who had stages I-II disease (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.89-1.43); however, those with advanced disease were less likely to be treated (OR, 0.82; 95% CI, 0.68-0.99). Overall and lung cancer-specific survival were worse in patients with IPF (respectively, hazard ratio [HR], 1.35; 95% CI, 1.26-1.45; and HR, 1.21; 95% CI, 1.10-1.32).Conclusions: NSCLC has a unique presentation in patients with IPF and is associated with poorer prognosis. Further research is needed to identify optimal treatment strategies in this population.

Idiopathic Pulmonary Fibrosis and Lung Cancer. A Systematic Review and Meta-analysis.

Rationale: The association between idiopathic pulmonary fibrosis (IPF) and lung cancer has been previously reported. However, there is the potential for significant confounding by age and smoking, and an accurate summary risk estimate has not been previously ascertained.Objectives: To determine the risk and burden of lung cancer in patients with IPF, accounting for known confounders.Methods: We conducted a comprehensive literature search of MEDLINE, EMBASE, and SCOPUS databases and used the Newcastle Ottawa criteria to assess study quality. We then assessed the quality of ascertainment of IPF cases based on modern consensus criteria. Data that relied on administrative claims or autopsies were excluded. We calculated summary risk estimates using a random effects model.Results: Twenty-five cohort studies were included in the final analysis. The estimated adjusted incidence rate ratio from two studies was 6.42 (95% confidence interval [CI], 3.21-9.62) and accounted for age, sex, and smoking. The summary incidence rate from 11 studies was 2.07 per 100 person-years (95% CI, 1.46-2.67), and the summary mortality rate was 1.06 per 100 person-years (95% CI, 0.62-1.51) obtained from three studies. The summary prevalence from 11 studies was 13.74% (95% CI, 10.17-17.30), and the proportion of deaths attributable to lung cancer was 10.20 (95% CI, 8.52-11.87) and was obtained from nine studies.Conclusions: IPF is an increased independent risk factor for lung cancer, even after accounting for smoking. Further well-designed studies using modern consensus criteria are needed to explore mechanisms of this association.