Pre-surgery immune profiles of adult glioma patients.

INTRODUCTION: Although immunosuppression is a known characteristic of glioma, no previous large studies have reported peripheral blood immune cell profiles prior to patient surgery and chemoradiation. This report describes blood immune cell characteristics and associated variables prior to surgery among typical glioma patients seen at a large University practice. METHODS: We analyzed pre-surgery blood samples from 139 glioma patients diagnosed with a new or recurrent grade II/III glioma (LrGG, n = 64) or new glioblastoma (GBM, n = 75) and 454 control participants without glioma. Relative cell fractions of CD4, CD8, B-cells, Natural Killer cells, monocytes, and neutrophils, were estimated via a validated deconvolution algorithm from blood DNA methylation measures from Illumina EPIC arrays. RESULTS: Dexamethasone use at time of blood draw varied by glioma type being highest among patients with IDH wild-type (wt) GBM (75%) and lowest for those with oligodendroglioma (14%). Compared to controls, glioma patients showed statistically significant lower cell fractions for all immune cell subsets except for neutrophils which were higher (all p-values < 0.001), in part because of the higher prevalence of dexamethasone use at time of blood draw for IDHwt GBM. Patients who were taking dexamethasone were more likely to have a low CD4 count (< 200, < 500), increased neutrophils, low absolute lymphocyte counts, higher total cell count and higher NLR. CONCLUSION: We show that pre-surgery blood immune profiles vary by glioma subtype, age, and more critically, by use of dexamethasone. Our results highlight the importance of considering dexamethasone exposures in all studies of immune profiles and of obtaining immune measures prior to use of dexamethasone, if possible.

Development and Preliminary Validation of the Lung Transplant Quality of Life (LT-QOL) Survey.

RATIONALE: Although lung transplantation aims to improve health-related quality of life (HRQL), existing instruments fail to include health domains considered important in this population. OBJECTIVES: We aimed to develop a comprehensive lung transplant-specific instrument to address this shortcoming. METHODS: We developed a pool of 126 candidate items addressing domains previously identified as important by lung transplant recipients. Through cognitive interviews conducted in 43 transplant recipients, items deemed irrelevant or redundant were dropped. The 84 remaining items were field tested in lung transplant recipients. Exploratory and confirmatory factor analyses were used to evaluate the factor structure, and scales were evaluated for internal consistency and construct validity. MEASUREMENTS AND MAIN RESULTS: The 84-item preliminary survey was administered to 201 lung transplant recipients with a mean age of 57.9 (±12.7) years; 46% were female. After factor analyses and internal consistency evaluation, we retained 60 items comprising the Lung Transplant Quality of Life (LT-QOL) Survey. The LT-QOL contains 10 scales that measure symptoms, health perceptions, functioning, and well-being. The confirmatory factor analysis model had good approximate fit (comparative fit index = 0.990; standardized root-mean-square residual = 0.062). Cronbach αs for the 10 scales ranged from 0.75 to 0.95. Interscale correlations were consistent with hypothesized relationships. Subjects with severe chronic lung allograft dysfunction (n = 13) reported significantly worse HRQL than subjects without chronic lung allograft dysfunction (n = 168) on 6 of the 10 LT-QOL scales. CONCLUSIONS: The LT-QOL is a new, multidimensional instrument that characterizes and quantifies HRQL in lung transplant recipients.

Suppressed calcineurin-dependent gene expression identifies lung allograft recipients at increased risk of infection.

Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin-dependent genes assesses rejection and infection risk better than does tacrolimus trough. We prospectively followed 44 lung allograft recipients at 2 to 18 months posttransplant and measured changes in whole blood interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE by using generalized-estimating equation-adjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from nontransplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC50 ) was measured in a pretransplant subset. Results showed that MRE did not change with diagnosis of rejection but that airway infection was associated with a 20% absolute decrease (95% confidence interval 11%-29%). MRE increased with time after transplant but was not associated with tacrolimus trough. Interestingly, MRE correlated inversely with corticosteroid dose in the study cohort and ex vivo. Pretransplant tacrolimus IC50 depended on the cytokine measured and varied between individuals, suggesting a range in baseline responses to tacrolimus. We conclude that MRE identifies infection risk in lung allograft recipients, potentially integrating calcineurin inhibitor and steroid effects on lymphocyte effector function.

Frailty phenotypes and mortality after lung transplantation: A prospective cohort study.

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB (n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score-adjusted Cox models. We calculated postestimation marginalized standardized risks for 1-year mortality by frailty status using multivariate logistic regression. SPPB frailty was associated with an increased risk of both 1- and 4-year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6-36.0 and aHR 3.8; 95%CI: 1.8-8.0, respectively). Each 1-point worsening in SPPB was associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08-1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%-21%). In secondary analyses, FFP frailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1-13.2) but not over longer follow-up. Preoperative frailty is associated with an increased risk of death after lung transplantation.

Strategy for Sustaining Cancer Education Services for Underserved Communities.

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Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation.

RATIONALE: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation. OBJECTIVES: To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates. METHODS: In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively. MEASUREMENTS AND MAIN RESULTS: Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB. CONCLUSIONS: Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

A retrospective observational study of benign anthracotic lymphadenitis and its association with PET avid lymph nodes in patients undergoing cancer evaluation.

BACKGROUND: Accurate staging of newly diagnosed or recurrent malignancy is essential for effective treatment. An important first step in staging involves the use of PET/CT to identify areas of FDG avidity. PET/CT however has limitations, including false positive FDG uptake from benign causes. In this paper we characterize an uncommon yet clinically important cause of false positive PET/CTs, that of benign anthracotic lymphadenitis (BAL). We examine the clinical, radiographic and histologic characteristics of BAL in patients referred for endobronchial ultrasound (EBUS) guided biopsies and discuss its context in relation to existing literature. METHODS: We performed a retrospective observational case series of 20 patients who were referred for EBUS guided biopsies of PET positive mediastinal and hilar lymph nodes during the work-up or treatment of suspected malignancy. RESULTS: To be included, all patients received PET imaging as well as an EBUS guided biopsy of FDG avid lymph nodes which demonstrated anthracotic pigment as the only histologic abnormality. The key findings were that 90% of patients in this cohort were born outside of the US, 90% had bilateral FDG avid lymph nodes with an average standardized uptake value (SUV) of 7.9±2.2. Most patients, based on their history, had a likely exposure to biomass fuel or urban pollution. CONCLUSIONS: BAL may be an underrecognized cause for PET positive lymph nodes in patients undergoing work-up for malignancy. These findings support the importance of sampling mediastinal and hilar lymph nodes even when SUVs are highly suggestive of malignancy.

Frailty trajectories in adult lung transplantation: A cohort study.

BACKGROUND: Frailty is common in adults with advanced lung disease and is associated with death before and after lung transplantation. We aimed to determine whether frailty changes from before to after the lung transplant. METHODS: In a single-center, prospective cohort study among adults undergoing lung transplantation from 2010 to 2017, we assessed frailty by the Short Physical Performance Battery (SPPB; higher scores reflect less frailty) and Fried Frailty Phenotype (FFP; higher scores reflect greater frailty) before and repeatedly up to 36 months after transplant. We tested for changes in frailty scores over time using segmented mixed effects models, adjusting for age, sex, and diagnosis. We quantified the proportion of subjects transitioning between frailty states (frail vs not frail) from before to after the transplant. RESULTS: In 246 subjects, changes in frailty occurred within the first 6 post-operative months and remained stable thereafter. The overall change in frailty was attributable to improvements among those subjects who were frail before transplant. They experienced a 5.1-point improvement in SPPB (95% confidence interval [CI] 4.6-5.7) and a 1.8-point improvement in FFP (95% CI -2.1 to -1.6) during the early period. Frailty by SPPB and FFP did not change in those who were not frail before transplant. Approximately 84% of survivors who were frail before transplant became not frail after transplant. CONCLUSIONS: Pre-operative frailty resolves in many patients after lung transplantation. Because a large proportion of frailty may be attributable to advanced lung disease, frailty alone should not be an absolute contraindication to transplantation.

Improvement in patient-reported outcomes after lung transplantation is not impacted by the use of extracorporeal membrane oxygenation as a bridge to transplantation.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is increasingly used as a bridge to lung transplantation. The impact of preoperative ECMO on health-related quality of life (HRQL) and depressive symptoms after lung transplantation remains unknown, however. METHODS: In a single-center prospective cohort study, we assessed HRQL and depressive symptoms before and at 3, 6, and 12 months after lung transplantation using the Short Form 12 Physical and Mental Component Scores (SF12-PCS and SF12-MCS), Airway Questionnaire 20-Revised (AQ20R), EuroQol 5D (EQ5D), and Geriatric Depression Scale (GDS). Changes in HRQL were quantified by segmented linear mixed-effects models controlling for age, sex, diagnosis, preoperative forced expiratory volume in 1 second, 6-minute walk distance, and Lung Allocation Score. We compared changes in HRQL among subjects bridged with ECMO, subjects hospitalized but not on ECMO, and subjects called in for transplantation as outpatients. RESULTS: Out of 189 subjects, 17 were bridged to transplantation with ECMO. In all groups, improvements in HRQL following lung transplantation exceeded the minimally clinically important difference using the SF12-PCS, AQ20R, EQ5D, and GDS. HRQL defined by SF12-MCS did not change after transplantation. Improvements were generally similar among the groups, except for EQ5D, which showed a trend toward less benefit in the outpatients, possibly due to their better HRQL before lung transplantation. CONCLUSIONS: Subjects ill enough to require ECMO as a bridge to lung transplantation appear to achieve similar improvements in HRQL and depressive symptoms as those who do not. It is reassuring to both providers and patients that lung transplantation provides substantial improvements in HRQL, even for those patients who are critically ill in the run up to transplantation.