Clinical Impact of Routine Assessment of Patient-Reported Health Status in Heart Failure Clinic.

BACKGROUND: The impact of routine clinic use of patient-reported outcome (PRO) measures on clinical outcomes in patients with heart failure (HF) has not been well-characterized. We tested if clinic-based use of a disease-specific PRO improves patient-reported quality of life at 1 year. METHODS: PRO-HF was an open-label, parallel, patient-level randomized clinical trial of routine PRO assessment or usual care at an academic HF clinic between August 30, 2021, and June 30, 2022, with 1 year of follow-up. In the PRO assessment arm, participants completed the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) at each HF clinic visit and results were shared with their treating clinician. The usual care arm completed the KCCQ-12 at randomization and 1 year later, which was not shared with the treating clinician. The primary outcome was the KCCQ-12 Overall Summary Score (OSS) between 12-15 months post-randomization. Secondary outcomes included domains of the KCCQ-12, hospitalization and emergency department visit rates, HF medication therapy, clinic visit frequency, and testing rates. RESULTS: Across 17 clinicians, 1,248 participants were enrolled and randomized to PRO assessment (n=624) or usual care (n=624). The median age was 63.9 (interquartile range [IQR] 51.8-72.8), 38.9% were women, and the median baseline KCCQ-12 OSS was 82.3 (IQR 58.3-94.8). Final KCCQ-12 (available in 87.9% of the PRO arm and 85.1% in usual care [p=0.16]) median OSS scores were 87.5 (IQR 68.8-96.9) in the PRO arm and 87.6 (IQR 69.7-96.9) in the usual care arm with a baseline-adjusted mean difference of 0.2 (95% CI: -1.7 to 2.0; p=0.85). The results were consistent across pre-specified subgroups. A post hoc analysis demonstrated a significant interaction with greater benefit among participants with baseline KCCQ-12 OSS scores of 60-80 but not in less or more symptomatic participants. No significant differences were found in 1-year mortality, hospitalizations, ED visits, medication therapy, clinic follow-up, or testing rates between arms. CONCLUSIONS: Routine PRO assessment in HF clinic visits did not impact patient-reported quality of life or other clinical outcomes. Alternate strategies and settings for embedding PROs into routine clinical care should be tested.

Palliative care utilization and racial and ethnic disparities among women with de novo metastatic breast cancer in the United States.

PURPOSE: The potential disparities in palliative care delivery for underrepresented minorities with breast cancer are not well known. We sought to determine whether race and ethnicity impact the receipt of palliative care for patients with metastatic breast cancer (MBC). METHODS: We retrospectively reviewed the National Cancer Database for female patients diagnosed with stage IV breast cancer between 2010 and 2017 who received palliative care following diagnosis of MBC to assess the proportion of patients who received palliative care, including non-curative-intent local-regional or systemic therapy. Multivariable logistic regression analysis was performed to identify variables associated with receiving palliative care. RESULTS: 60,685 patients were diagnosed with de novo MBC. Of these, only 21.4% (n = 12,963) received a palliative care service. Overall, there was a positive trend in palliative care receipt from 18.2% in 2010 to 23.0% in 2017 (P < 0.001), which persisted when stratified by race and ethnicity. Relative to non-Hispanic White women, Asian/Pacific Islander women (aOR 0.80, 95% CI 0.71-0.90, P < 0.001), Hispanic women (adjusted odds ratio [aOR] 0.69, 95% CI 0.63-0.76, P < 0.001), and non-Hispanic Black women (aOR 0.94, 95% CI 0.88-0.99, P = 0.03) were less likely to receive palliative care. CONCLUSIONS: Fewer than 25% of women with MBC received palliative care between 2010 and 2017. While palliative care has significantly increased for all racial/ethnic groups, Hispanic White, Black, and Asian/Pacific Islander women with MBC still receive significantly less palliative care than non-Hispanic White women. Further research is needed to identify the socioeconomic and cultural barriers to palliative care utilization.

Association of Body Mass Index With Outcomes Among Patients With Head and Neck Cancer Treated With Chemoradiotherapy.

Importance: Combined modality therapy, such as chemoradiotherapy, often results in significant morbidity among patients with head and neck cancer. Although the role of body mass index (BMI) varies based on cancer subtypes, its association with treatment response, tumor recurrence, and survival outcomes among patients with head and neck cancer remains unclear. Objective: To evaluate the role of BMI in treatment response, tumor recurrence, and survival outcomes among patients with head and neck cancer undergoing chemoradiotherapy. Design, Setting, and Participants: This retrospective, observational, single-institution cohort study conducted at a comprehensive cancer center included 445 patients with nonmetastatic head and neck cancer who underwent chemoradiotherapy from January 1, 2005, to January 31, 2021. Exposure: Normal vs overweight or obese BMI. Main Outcomes and Measures: Metabolic response after chemoradiotherapy, locoregional failure (LRF), distant failure (DF), overall survival (OS), and progression-free survival (PFS), with Bonferroni correction used to adjust for multiple comparisons and P < .025 being considered statistically significant. Results: A total of 445 patients (373 men [83.8%]; median age, 61 years [IQR, 55-66 years]; 107 [24.0%] with normal BMI, 179 [40.2%] with overweight BMI, and 159 [35.7%] with obese BMI) were included for analysis. Median follow-up was 48.1 months (IQR, 24.7-74.9 months). On Cox proportional hazards regression multivariable analysis, only overweight BMI was associated with improved OS (5-year OS, 71.5% vs 58.4%; adjusted hazard ratio [AHR], 0.59 [95% CI, 0.39-0.91]; P = .02) and PFS (5-year PFS, 68.3% vs 50.8%; AHR, 0.51 [95% CI, 0.34-0.75]; P < .001). On logistic multivariable analysis, overweight BMI (91.6% vs 73.8%; adjusted odds ratio [AOR], 0.86 [95% CI, 0.80-0.93]; P < .001) and obese BMI (90.6% vs 73.8%; AOR, 0.89 [95% CI, 0.81-0.96]; P = .005) were associated with complete metabolic response on follow-up positron emission tomography-computed tomography after treatments. On Fine-Gray multivariable analysis, overweight BMI was associated with reduction in LRF (5-year LRF, 7.0% vs 25.9%; AHR, 0.30 [95% CI, 0.12-0.71]; P = .01), but not DF (5-year DF, 17.4% vs 21.5%; AHR, 0.92 [95% CI, 0.47-1.77]; P = .79). Obese BMI was not associated with LRF (5-year LRF, 10.4% vs 25.9%; AHR, 0.63 [95% CI, 0.29-1.37]; P = .24) or DF (5-year DF, 15.0% vs 21.5%; AHR, 0.70 [95% CI, 0.35-1.38]; P = .30). Conclusion: In this cohort study of patients with head and neck cancer, when compared with normal BMI, overweight BMI was an independent factor favorably associated with complete response after treatments, OS, PFS, and LRF. Further investigations are warranted to improve understanding on the role of BMI among patients with head and neck cancer.

Association of pre-treatment lymphocyte-monocyte ratio with survival outcome in patients with head and neck cancer treated with chemoradiation.

BACKGROUND: Given the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer. METHODS: A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan-Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias. RESULTS: A total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8-74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82-0.99, p = 0.03) and CSS (aHR 0.83, 95% CI 0.72-0.95, p = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12-2.26, p = 0.009) and CSS (HR 1.68, 95% CI 1.08-2.63, p = 0.02). CONCLUSION: Low LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.

Outcomes in participants with ventilated nosocomial pneumonia and organ failure treated with ceftolozane/tazobactam versus meropenem: a subset analysis of the phase 3, randomized, controlled ASPECT-NP trial.

BACKGROUND: The pivotal ASPECT-NP trial showed ceftolozane/tazobactam was non-inferior to meropenem for the treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia (vHABP/VABP). Here, we evaluated treatment outcomes by degree of respiratory or cardiovascular dysfunction. METHODS: This was a subset analysis of data from ASPECT-NP, a randomized, double-blind, non-inferiority trial (ClinicalTrials.gov NCT02070757). Adults with vHABP/VABP were randomized 1:1 to 3 g ceftolozane/tazobactam or 1 g meropenem every 8 h for 8-14 days. Outcomes in participants with a baseline respiratory component of the Sequential Organ Failure Assessment (SOFA) score (R-SOFA) ≥ 2 (indicative of severe respiratory failure), cardiovascular component of the SOFA score (CV-SOFA) ≥ 2 (indicative of shock), or R-SOFA ≥ 2 plus CV-SOFA ≥ 2 were compared by treatment arm. The efficacy endpoint of primary interest was 28-day all-cause mortality. Clinical response, time to death, and microbiologic response were also evaluated. RESULTS: There were 726 participants in the intention-to-treat population; 633 with R-SOFA ≥ 2 (312 ceftolozane/tazobactam, 321 meropenem), 183 with CV-SOFA ≥ 2 (84 ceftolozane/tazobactam, 99 meropenem), and 160 with R-SOFA ≥ 2 plus CV-SOFA ≥ 2 (69 ceftolozane/tazobactam, 91 meropenem). Baseline characteristics, including causative pathogens, were generally similar in participants with R-SOFA ≥ 2 or CV-SOFA ≥ 2 across treatment arms. The 28-day all-cause mortality rate was 23.7% and 24.0% [difference: 0.3%, 95% confidence interval (CI) - 6.4, 6.9] for R-SOFA ≥ 2, 33.3% and 30.3% (difference: - 3.0%, 95% CI - 16.4, 10.3) for CV-SOFA ≥ 2, and 34.8% and 30.8% (difference: - 4.0%, 95% CI - 18.6, 10.3), respectively, for R-SOFA ≥ 2 plus CV-SOFA ≥ 2. Clinical cure rates were as follows: 55.8% and 54.2% (difference: 1.6%, 95% CI - 6.2, 9.3) for R-SOFA ≥ 2, 53.6% and 55.6% (difference: - 2.0%, 95% CI - 16.1, 12.2) for CV-SOFA ≥ 2, and 53.6% and 56.0% (difference: - 2.4%, 95% CI - 17.6, 12.8), respectively, for R-SOFA ≥ 2 plus CV-SOFA ≥ 2. Time to death was comparable in all SOFA groups across both treatment arms. A higher rate of microbiologic eradication/presumed eradication was observed for CV-SOFA ≥ 2 and R-SOFA ≥ 2 plus CV-SOFA ≥ 2 with ceftolozane/tazobactam compared to meropenem. CONCLUSIONS: The presence of severe respiratory failure or shock did not affect the relative efficacy of ceftolozane/tazobactam versus meropenem; either agent may be used to treat critically ill patients with vHABP/VABP. TRIAL REGISTRATION: ClinicalTrials.gov NCT02070757. Registered 25 February 2014, https://clinicaltrials.gov/ct2/show/NCT02070757.

Impact of Patient-Reported Outcome Measurement in Heart Failure Clinic on Clinician Health Status Assessment and Patient Experience: A Substudy of the PRO-HF Trial.

BACKGROUND: Clinicians typically estimate heart failure health status using the New York Heart Association Class, which is often discordant with patient-reported health status. It is unknown whether collecting patient-reported health status improves the accuracy of clinician assessments. METHODS: The PRO-HF trial (Patient-Reported Outcomes in Heart Failure Clinic) is a randomized, nonblinded trial evaluating routine Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) collection in heart failure clinic. Patients with a scheduled visit to Stanford heart failure clinic between August 30, 2021 and June 30, 2022 were enrolled and randomized to KCCQ-12 assessment or usual care. In this prespecified substudy, we evaluated whether access to the KCCQ-12 improved the accuracy of clinicians' New York Heart Association assessment or patients' perspectives on their clinician interaction. We surveyed clinicians regarding their patients' New York Heart Association Class, quality of life, and symptom frequency. Clinician responses were compared with patients' KCCQ-12 responses. We surveyed patients regarding their clinician interactions. RESULTS: Of the 1248 enrolled patients, 1051 (84.2%) attended a visit during the substudy. KCCQ-12 results were given to the clinicians treating the 528 patients in the KCCQ-12 arm; the 523 patients in the usual care arm completed the KCCQ-12 without the results being shared. The correlation between New York Heart Association Class and KCCQ-12 Overall Summary Score was stronger when clinicians had access to the KCCQ-12 (r=-0.73 versus r=-0.61, P<0.001). More patients in the KCCQ-12 arm strongly agreed that their clinician understood their symptoms (95.2% versus 89.7% of respondents [odds ratio' 2.27; 95% CI' 1.32-3.87]). However, patients in both arms reported similar quality of clinician communication and therapeutic alliance. CONCLUSIONS: Collecting the KCCQ-12 in heart failure clinic improved clinicians' accuracy of health status assessment; correspondingly, patients believed their clinicians better understood their symptoms. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04164004.

Actigraphy evaluation before and after intravenous ferric carboxymaltose in 3 children with restless sleep disorder.

Restless sleep disorder has been described in the literature as a disorder affecting children and presenting with large muscle movements during sleep with an index of 5 events/h or more, leading to daytime impairment including sleepiness or behavioral problems. Children with restless sleep disorder have been found to have low ferritin levels. Studies with iron supplementation both oral or intravenous have been shown effective in clinically improving both nighttime and daytime symptoms. However objective data of the improvement is lacking. Repeating polysomnography is expensive, and alternative methods of assessing large muscle movements are needed. In this small case series we present actigraphy results in 3 children with restless sleep disorder collected for 1 week, a week before and 8 weeks after intravenous iron supplementation. Although actigraphy parameters were not highly consistent between our 3 patients, improvement in symptoms tend to parallel sleep parameters in actigraphy. CITATION: Chu ZYB, DelRosso LM, Mogavero MP, Ferri R. Actigraphy evaluation before and after intravenous ferric carboxymaltose in 3 children with restless sleep disorder. J Clin Sleep Med. 2023;19(3):633-637.

Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer.

Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype. SIGNIFICANCE: The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.

Outcomes in participants with failure of initial antibacterial therapy for hospital-acquired/ventilator-associated bacterial pneumonia prior to enrollment in the randomized, controlled phase 3 ASPECT-NP trial of ceftolozane/tazobactam versus meropenem.

BACKGROUND: Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and ß-lactamase inhibitor, is approved for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Participants in the ASPECT-NP trial received ceftolozane/tazobactam (3 g [2 g ceftolozane/1 g tazobactam] every 8 h) or meropenem (1 g every 8 h). Participants failing prior antibacterial therapy for the current HABP/VABP episode at study entry had lower 28-day all-cause mortality (ACM) rates with ceftolozane/tazobactam versus meropenem treatment. Here, we report a post hoc analysis examining this result. METHODS: The phase 3, randomized, controlled, double-blind, multicenter, noninferiority trial compared ceftolozane/tazobactam versus meropenem for treatment of adults with ventilated HABP/VABP; eligibility included those failing prior antibacterial therapy for the current HABP/VABP episode at study entry. The primary and key secondary endpoints were 28-day ACM and clinical response at test of cure (TOC), respectively. Participants who were failing prior therapy were a prospectively defined subgroup; however, subgroup analyses were not designed for noninferiority testing. The 95% CIs for treatment differences were calculated as unstratified Newcombe CIs. Post hoc analyses were performed using multivariable logistic regression analysis to determine the impact of baseline characteristics and treatment on clinical outcomes in the subgroup who were failing prior antibacterial therapy. RESULTS: In the ASPECT-NP trial, 12.8% of participants (93/726; ceftolozane/tazobactam, n = 53; meropenem, n = 40) were failing prior antibacterial therapy at study entry. In this subgroup, 28-day ACM was higher in participants who received meropenem versus ceftolozane/tazobactam (18/40 [45.0%] vs 12/53 [22.6%]; percentage difference [95% CI]: 22.4% [3.1 to 40.1]). Rates of clinical response at TOC were 26/53 [49.1%] for ceftolozane/tazobactam versus 15/40 [37.5%] for meropenem (percentage difference [95% CI]: 11.6% [- 8.6 to 30.2]). Multivariable regression analysis determined concomitant vasopressor use and treatment with meropenem were significant factors associated with risk of 28-day ACM. Adjusting for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem. CONCLUSIONS: This post hoc analysis further supports the previously demonstrated lower ACM rate for ceftolozane/tazobactam versus meropenem among participants who were failing prior therapy, despite the lack of significant differences in clinical cure rates. CLINICALTRIALS: gov registration NCT02070757 . Registered February 25, 2014, clinicaltrials.gov/ct2/show/NCT02070757 .

Association of Pack-Years of Cigarette Smoking With Survival and Tumor Progression Among Patients Treated With Chemoradiation for Head and Neck Cancer.

Importance: After 10 pack-years of smoking was initially established as a threshold for risk stratification, subsequent clinical trials incorporated it to identify candidates for treatment deintensification. However, several recent studies were unable to validate this threshold externally, and the threshold for smoking exposure remains unclear. Objective: To estimate the threshold of pack-years of smoking associated with survival and tumor recurrence among patients with head and neck cancer. Design, Setting, and Participants: This single-institution, cohort study included patients with nonmetastatic head and neck cancer receiving chemoradiation from January 2005 to April 2021. Data were analyzed from January to April 2022. Exposures: Heavy vs light smoking using 22 pack-years as a threshold based on maximizing log-rank test statistic. Main Outcomes and Measures: Overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF). Results: A total of 518 patients (427 male [82.4%]; median [IQR] age, 61 [55-66] years) were included. Median (IQR) follow-up was 44.1 (22.3-72.8) months. A nonlinear Cox regression model using restricted cubic splines showed continuous worsening of OS and PFS outcomes as pack-years of smoking increased. The threshold of pack-years to estimate OS and PFS was 22. Cox multivariable analysis (MVA) showed that more than 22 pack-years was associated with worse OS (adjusted hazard ratio [aHR] 1.57; 95% CI, 1.11-2.22; P = .01) and PFS (aHR, 1.38; 95% CI, 1.00-1.89; P = .048). On Fine-Gray MVA, heavy smokers were associated with DF (aHR, 1.71; 95% CI, 1.02-2.88; P = .04), but not LRF (aHR, 1.07; 95% CI, 0.61-1.87; P = .82). When 10 pack-years of smoking were used as a threshold, there was no association for OS (aHR, 1.23; 95% CI, 0.83-1.81; P = .30), PFS (aHR, 1.11; 95% CI, 0.78-1.57; P = .56), LRF (aHR, 1.19; 95% CI, 0.64-2.21; P = .58), and DF (aHR, 1.45; 95% CI, 0.82-2.56; P = .20). Current smoking was associated with worse OS and PFS only among human papillomavirus (HPV)-positive tumors (OS: aHR, 2.81; 95% CI, 1.26-6.29; P = .01; PFS: aHR, 2.51; 95% CI, 1.22-5.14; P = .01). Conclusions and Relevance: In this cohort study of patients treated with definitive chemoradiation, 22 pack-years of smoking was associated with survival and distant metastasis outcomes. Current smoking status was associated with adverse outcomes only among patients with HPV-associated head and neck cancer.

Quality of Life After Stereotactic Body Radiation Therapy or Surgery for Early-Stage NSCLC: A Systematic Review.

Quality of life (QOL) is a key consideration for patients with early-stage NSCLC choosing between treatment options. Currently, it is not well established whether stereotactic body radiation therapy (SBRT) or surgery offers superior QOL in early-stage NSCLC. The objective of this systematic review is to summarize the prospective literature on QOL in patients with early-stage NSCLC after treatment with SBRT or surgery. A comprehensive literature review using PubMed and EMBASE was performed in April 2022. Prospective studies evaluating QOL data across multiple time points in patients with early-stage NSCLC after SBRT or surgery were included. A total of 25 studies involving 1597 SBRT patients and 1652 surgery patients met the inclusion criteria. Across most studies, QOL remained stable after treatment with SBRT. After surgery, QOL initially decreased; however, it often returned to baseline in the next 6 to 12 months. Utilization of video-assisted thoracoscopic surgery and sublobar resection reduced the magnitude of the initial decrease in QOL after surgery and led to faster recovery to baseline. Owing to the heterogeneity of patient populations between studies evaluating SBRT versus surgery, direct comparisons between the two treatments remain difficult to make. Clinicians should appropriately counsel patients with this information to help guide patient-centered discussions on choosing the optimal treatment modality.

Ultra-deep Sequencing of Hadza Hunter-Gatherers Recovers Vanishing Gut Microbes.

The gut microbiome is a key modulator of immune and metabolic health. Human microbiome data is biased towards industrialized populations, providing limited understanding of the distinct and diverse non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing and strain cultivation on 351 fecal samples from the Hadza, hunter-gatherers in Tanzania, and comparative populations in Nepal and California. We recover 94,971 total genomes of bacteria, archaea, bacteriophages, and eukaryotes, 43% of which are absent from existing unified datasets. Analysis of in situ growth rates, genetic pN/pS signatures, high-resolution strain tracking, and 124 gut-resident species vanishing in industrialized populations reveals differentiating dynamics of the Hadza gut microbiome. Industrialized gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource that expands our understanding of microbes capable of colonizing the human gut and clarifies the extensive perturbation brought on by the industrialized lifestyle.

Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity.

Background: Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph+) leukemia. Objectives: We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK). Methods: Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs. Results: Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. Conclusions: Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.

Trends in Postoperative Intensity-Modulated Radiation Therapy Use and Its Association With Survival Among Patients With Incompletely Resected Non-Small Cell Lung Cancer.

Importance: National guidelines allow consideration of postoperative radiation therapy (PORT) among patients with incompletely resected non-small cell lung cancer (NSCLC). However, there is a paucity of prospective data because recently completed trials excluded patients with positive surgical margins. In addition, unlike for locally advanced NSCLC, the role of intensity-modulated radiation therapy (IMRT) for PORT remains unclear. Objective: To evaluate trends of IMRT use for PORT in the US and the association of IMRT with survival outcomes among patients with incompletely resected NSCLC. Design, Setting, and Participants: This retrospective cohort study used data from the National Cancer Database for patients diagnosed between January 2004 and December 2019 with incompletely resected NSCLC who underwent upfront surgery with positive surgical margins followed by PORT. Exposures: IMRT vs 3D conformal radiation therapy (3DCRT) for PORT. Main Outcomes and Measures: The main outcome was overall survival. Multivariable Cox proportional hazards regression assessed the association of IMRT vs 3DCRT with overall survival. Multivariable logistic regression identified variables associated with IMRT. Propensity score matching (1:1) was performed based on variables of interest. Results: A total of 4483 patients (2439 men [54.4%]; median age, 67 years [IQR, 60-73 years]) were included in the analysis. Of those, 2116 (47.2%) underwent 3DCRT and 2367 (52.8%) underwent IMRT. Median follow-up was 48.5 months (IQR, 31.1-77.2 months). The proportion of patients who underwent IMRT increased from 14.3% (13 of 91 patients) in 2004 to 70.7% (33 of 471 patients) in 2019 (P < .001). IMRT was associated with improved overall survival compared with 3DCRT (adjusted hazard ratio, 0.84; 95% CI, 0.78-0.91; P < .001). Similar findings were observed for 1463 propensity score-matched pairs; IMRT was associated with improved 5-year overall survival compared with 3DCRT (37.3% vs 32.2%; hazard ratio, 0.88; 95% CI, 0.80-0.96; P = .003). IMRT use was associated with receipt of treatment at an academic facility (adjusted odds ratio [aOR], 1.15; 95% CI, 1.00-1.33; P = .049), having T4 stage tumors (aOR, 1.50; 95% CI, 1.13-1.99; P = .005) or N2 or N3 stage tumors (aOR, 1.25; 95% CI, 1.04-1.51; P = .02), and receipt of pneumonectomy (aOR, 1.35; 95% CI, 1.02-1.80; P = .04). Conclusion and Relevance: This cohort study found that use of IMRT for PORT among patients with incompletely resected NSCLC increased in the US from 2004 to 2019 and was associated with improved survival compared with 3DCRT. Further studies are warranted to investigate the role of different radiation therapy techniques for PORT.

Defining the optimal threshold and prognostic utility of pre-treatment hemoglobin level as a biomarker for survival outcomes in head and neck cancer patients receiving chemoradiation.

OBJECTIVES: We sought to define the optimal threshold for anemia in North American head and neck cancer patients and evaluate its role as a prognostic biomarker. MATERIALS AND METHODS: A single-institution database was queried for patients with head and neck cancer who underwent chemoradiation from January 2005 to April 2021. An optimal threshold of hemoglobin (Hgb) level was defined based on maximum log-rank test statistic. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate treatment outcomes. RESULTS: A total of 496 patients were identified. Threshold for Hgb was determined to be 11.4 for both overall survival (OS) and progression-free survival (PFS). Low Hgb was associated with worse OS (adjusted hazards ratio [aHR] 2.41, 95 % confidence interval [CI] 1.53-3.80, p < 0.001) and PFS (aHR 2.01, 95 % CI 1.30-3.11, p = 0.002). Similar findings were observed among 39 matched pairs for OS (5-year OS 22.3 % vs 49.0 %; HR 2.22, 95 % CI 1.23-4.03, p = 0.008) and PFS (5-year PFS 24.3 % vs 39.1 %; HR 1.78, 95 % CI 1.02-3.12, p = 0.04). Among those with HPV-negative tumors, low Hgb was associated with worse OS (aHR 13.90, 95 % CI 4.66-41.44, p < 0.001) and PFS (aHR 5.24, 95 % CI 2.09-13.18, p < 0.001). However, among those with HPV-positive tumors, low Hgb was not associated with both OS (aHR 1.75, 95 % CI 0.60-5.09, p = 0.31) and PFS (aHR 1.13, 95 % CI 0.41-3.14, p = 0.82). CONCLUSION AND RELEVANCE: Low Hgb below 11.4 was an independent adverse prognostic factor for worse survival. It was also prognostic among patients with HPV-negative tumors, but not for HPV-positive tumors.

Ceftolozane/tazobactam for hospital-acquired/ventilator-associated bacterial pneumonia due to ESBL-producing Enterobacterales: a subgroup analysis of the ASPECT-NP clinical trial.

BACKGROUND: After the MERINO trial with piperacillin/tazobactam, the efficacy of ß-lactam/tazobactam combinations in serious infections involving extended-spectrum ß-lactamase (ESBL)-producing pathogens merits special evaluation. OBJECTIVES: To further confirm the efficacy of ceftolozane/tazobactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) involving ESBL-positive and/or AmpC-producing Enterobacterales. METHODS: Retrospective subgroup analysis of the ASPECT-NP trial comparing ceftolozane/tazobactam with meropenem for treating HABP/VABP in mechanically ventilated adults (ClinicalTrials.gov NCT02070757). ESBLs were identified using whole genome sequencing. Chromosomal AmpC production was quantified employing a high-sensitivity mRNA transcription assay. RESULTS: Overall, 61/726 (8.4%) participants had all baseline lower respiratory tract (LRT) isolates susceptible to both study treatments and ≥1 baseline ESBL-positive/AmpC-overproducing Enterobacterales isolate. In this subgroup (ceftolozane/tazobactam n = 30, meropenem n = 31), baseline characteristics were generally comparable between treatment arms. The most frequent ESBL-positive and/or AmpC-overproducing Enterobacterales isolates (ceftolozane/tazobactam n = 31, meropenem n = 35) overall were Klebsiella pneumoniae (50.0%), Escherichia coli (22.7%), and Proteus mirabilis (7.6%). The most prevalent ESBLs were CTX-M-15 (75.8%), other CTX-M (19.7%), and SHV (4.5%); 10.6% of isolates overproduced chromosomal AmpC. Overall, 28 day all-cause mortality was 6.7% (2/30) with ceftolozane/tazobactam and 32.3% (10/31) with meropenem (25.6% difference, 95% CI: 5.54 to 43.84). Clinical cure rate at test-of-cure, 7-14 days after end of therapy, was 73.3% (22/30) with ceftolozane/tazobactam and 61.3% (19/31) with meropenem (12.0% difference, 95% CI: -11.21 to +33.51). Per-isolate microbiological response at test-of-cure was 64.5% (20/31) with ceftolozane/tazobactam and 74.3% (26/35) with meropenem (-9.8% difference, 95% CI: -30.80 to +12.00). CONCLUSIONS: These data confirm ceftolozane/tazobactam as an effective treatment option for HABP/VABP involving ceftolozane/tazobactam-susceptible ESBL-positive and/or AmpC-producing Enterobacterales.

Deconvoluting the Cells of the Human Heart with iPSC Technology: Cell Types, Protocols, and Uses.

PURPOSE OF REVIEW: Induced pluripotent stem cells (iPSCs) have become widely adopted tools in cardiovascular biology due to their ability to differentiate into patient-specific cell types. Here, we describe the current protocols, important discoveries, and experimental limitations from the iPSC-derived cell types of the human heart: cardiomyocytes, cardiac fibroblasts, vascular smooth muscle cells, endothelial cells, and pericytes. In addition, we also examine the progress of 3D-based cell culture systems. RECENT FINDINGS: There has been rapid advancement in methods to generate cardiac iPSC-derived cell types. These advancements have led to improved cardiovascular disease modeling, elucidation of interactions among different cell types, and the creation of 3D-based cell culture systems able to provide more physiologically relevant insights into cardiovascular diseases. iPSCs have become an instrumental model system in the toolbox of cardiovascular biologists. Ongoing research continues to advance the use of iPSCs in (1) disease modeling, (2) drug screening, and (3) clinical trials in a dish.

Racial/Ethnic Differences and Trends in Pathologic Complete Response Following Neoadjuvant Chemotherapy for Breast Cancer.

The purpose of this study was to evaluate nationwide trends in pathologic complete response (pCR) and its racial variations for breast cancer. The National Cancer Database was queried for women from 2010 to 2017 with non-metastatic breast cancer who underwent neoadjuvant chemotherapy. The primary endpoints, pCR and overall survival, were evaluated using Cochran-Armitage test, logistic, and Cox regression multivariable analyses. A total of 104,161 women were analyzed. Overall, pCR improved from 2010 to 2017 (15.1% to 27.2%, trend p < 0.001). Compared to non-Hispanic White (NHW) women, Hispanic White (HW) women were more likely to have pCR for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-positive tumors (adjusted odds ratio (aOR) 1.29, 95% confidence interval (CI) 1.08-1.53, p = 0.005). Black women were less likely to have pCR for HR-HER2+ tumors (aOR 0.81, 95% CI 0.73-0.89, p < 0.001) and triple negative (aOR 0.82, 95% CI 0.77-0.87, p < 0.001) tumors, but more likely for HR+HER2- tumors (aOR 1.13, 95% CI 1.03-1.24, p = 0.009). Among patients who achieved pCR, Asian or Pacific Islander (API) women were associated with better survival (adjusted hazards ratio (aHR) 0.52, 95% CI 0.33-0.82, p = 0.005) than NHW women. Despite positive trends in pCR rates, the likelihood of pCR and survival outcomes may be intricately dependent on racial/ethnic groups and tumor receptor subtypes.

Clinical and microbiological outcomes, by causative pathogen, in the ASPECT-NP randomized, controlled, Phase 3 trial comparing ceftolozane/tazobactam and meropenem for treatment of hospital-acquired/ventilator-associated bacterial pneumonia.

OBJECTIVES: In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated. METHODS: Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7-14 days after the end of therapy) in the microbiological ITT (mITT) population. RESULTS: The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: -4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: -18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: -4.51 to 19.38], respectively, were also comparable. CONCLUSIONS: In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response.

Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial.

BACKGROUND: The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. METHODS: Baseline renal function was categorized as normal renal function (creatinine clearance 80-130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. RESULTS: A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [- 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; - 2.6 [- 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; - 2.1 [- 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [- 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [- 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [- 8.7 to 19.0]). CONCLUSIONS: C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.