Well-characterized Prospective Cohort Research Articles

Efficacy and safety of colistin plus beta-lactams for bone and joint infection caused by fluoroquinolone-resistant gram-negative bacilli: a prospective multicenter study.

The prognosis of bone and joint infections (BJI) caused by Gram-negative bacilli (GNB) worsens significantly in the face of fluoroquinolone-resistance. In this setting, scarce pre-clinical and clinical reports suggest that intravenous beta-lactams plus colistin may improve outcome. Our aim was to assess the efficacy and safety of this treatment in a well-characterized prospective cohort. Observational, prospective, non-comparative, multicenter (14 hospitals) study of adults with BJI caused by fluoroquinolone-resistant GNB treated with surgery and intravenous beta-lactams plus colistin for ≥ 21 days. The primary endpoint was the cure rate. Of the 44 cases included (median age 72 years [IQR 50-81], 22 [50%] women), 32 (73%) had an orthopedic device-related infection, including 17 (39%) prosthetic joints. Enterobacterales were responsible for 27 (61%) episodes, and Pseudomonas spp for 17 (39%), with an overall rate of MDR/XDR GNB infections of 27/44 (61%). Patients were treated with colistin plus intravenous beta-lactam for 28 days (IQR 22-37), followed by intravenous beta-lactam alone for 19 days (IQR 5-35). The cure rate (intention-to-treat analysis; median follow-up = 24 months, IQR 19-30) was 82% (95% CI 68%-90%) and particularly, 80% (95% CI 55%-93%) among patients managed with implant retention. Adverse events (AEs) leading to antimicrobial withdrawal occurred in 10 (23%) cases, all of which were reversible. Colistin AEs were associated with higher plasma drug concentrations (2.8 mg/L vs. 0.9 mg/L, p = 0.0001). Combination therapy with intravenous beta-lactams plus colistin is an effective regimen for BJI caused by fluoroquinolone-resistant GNB. AEs were reversible and potentially preventable by close therapeutic drug monitoring.

Markers of cardiac dysfunction associated with inflammation in a cohort of patients with acute decompensation of cirrhosis.

Inflammation underpinning acute decompensation (AD) of liver disease is an important driver for the development of acute-on-chronic liver failure or death. We aimed to investigate associations between inflammatory biomarkers and impaired cardiac function in patients admitted for AD of cirrhosis. This is a retrospective analysis of a well-characterized prospective cohort of patients with AD of liver disease admitted to a tertiary referral center. All patients had echocardiographic assessment of cardiac function and serum samples at admission. We reclassified patients according to the CLIF-C AD score, measured inflammatory (IL-6, IL-8, TNF-ɑ, CD206) and cardiac-specific (NT-proBNP, troponin T) biomarkers and tested for associations with echocardiographic parameters of cardiac function. We explored the impact on outcome of these factors in multivariate analysis. We included 70 patients (58 ± 10 years, 28 women), with a mean CLIF-C AD score of 47 ± 7. Thirty-nine patients (56%) fulfilled the echocardiographic criteria for cardiac dysfunction. We found associations between parameters of diastolic dysfunction and serum concentrations of IL-6 and CD206. Echocardiographic parameters of cardiac function were not associated with markers of liver dysfunction such as the CLIF-C AD score. In multivariate analysis higher MELD, higher NT-proBNP, and IL-8 concentrations as well as the absence of echocardiographic criteria for cardiac dysfunction significantly associated with death during follow-up. We found evidence in favor of a clinically relevant link between serum biomarkers of inflammation (IL-6, CD206) and echocardiographic signals of cardiac dysfunction in patients with acutely decompensated cirrhosis.

Cumulative Incidence, Predictors, and Outcomes of Transformation to Diffuse Large B-Cell Lymphoma in a Prospective Cohort of Patients with Marginal Zone Lymphoma

Background: Although marginal zone lymphoma (MZL) typically exhibits an indolent course, transformation to diffuse large B-cell lymphomas (DLBCL) is associated with a poorer outcome and remains a clinical challenge in managing patients with MZL. The limited existing literature reports various cumulative incidence rates, ranging from 2.5% and 4.7% (Finnish Cancer Registry, 1995-2018) to 6.6% and 8.4% (Florida Cancer Registry, 1995-2016) at 5 and 10-years, respectively, likely in part driven by varying study designs, ascertainment, and study population. Similarly, reported outcomes after transformed MZL (tMZL) have been variable. We evaluated the cumulative incidence of histological transformation (HT) to LBCL in a well-characterized prospective cohort of MZL patients from the upper Midwest, USA, and overall survival (OS) after transformation. Methods: Patients ≥ 18 years old with newly diagnosed MZL were prospectively enrolled in the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) cohort from 2002-2015. Clinical and treatment data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death through 2022. Pathology was classified according to WHO 4/4R, including all transformations. The cumulative incidence of HT to LBCL was determined using death as a competing risk. Time to HT (TTHT) was defined as time from the date of MZL diagnosis to the date of transformation. We evaluated potential predictors of HT using a stepwise approach, and derived hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional hazards models. To assess predictors of OS after HT, patients ≥ 18 years old with newly diagnosed tMZL (into DLBCL) at Mayo Clinic between 1995 and 2002 (N=7) were combined with the MER cases. Results: We identified 524 patients with MZL in the MER cohort: 362 extranodal (EMZL; lung 18%, stomach 16%, orbit 13%, parotid 10%, skin 10%), 84 splenic (SMZL), and 78 nodal (NMZL). The median age at diagnosis was 63 years (range 18-92); 56% were female, and 83% were non-Hispanic white. During a median follow-up of 18.8 years (95% CI 16.7, NA), there were 25 HT (including 8 patients under observation) and 158 deaths. Eight Ten-year OS was 67% and 77% in the groups with and without HT, respectively. The overall cumulative incidence of HT was 1.5% at 2 years after diagnosis, 2.9% at 5 years, 4.5% at 10 years, and 5.7% at 15 years (Panel 1). The cumulative incidence of HT varied by subtype (e.g., at 5 years: 2%, 4% and 6%, in EMZL, NMZL and SMZL, respectively; Panel 2). The median time to HT also varied by subtype: 76 months (interquartile range (IQR) 43, 81) for EMZL, 30 months (IQR 16, 52) for SMZL, and 18 months (IQR 14, 23) for NMZL. In univariable analysis, predictors of HT were Stage III/IV (HR=3.4, 95% CI 1.36-8.53, p=0.009), elevated LDH (HR=2.98, 95% CI 1.25-7.12, p=0.014), and presence of ≥2 extranodal sites (HR=2.69, 95% CI 1.22-5.94, p=0.014). In multivariable analysis, elevated LDH was the only non-composite predictor of HT (HR=2.65, 95% CI 1.08-6.52, p=0.034). MALT-IPI score 2-3 (HR=3.61, 95% CI 1.06-12.25, p=0.040) and FLIPI score 3-5 (HR=2.19, 95% CI 1.22-8.22, p=0.018) also predicted HT. We analyzed OS after HT in 32 cases of tMZL (21 tEMZL, 7 tSMZL, 4 tNMZL). At HT, median age was 68 years (range 39-89); 24 (80%) patients presented with stage III/IV disease, 11 (58%) with elevated LDH, 12 (55%) with hemoglobin <12g/dL, 3 (14%) with platelet count <100x10 9/L and 9 (39%) with biopsy-proven bone marrow involvement. Twenty-six (81%) were treated with a systemic therapy, mainly CHOP-backbone therapy (R-CHOP n=13, CHOP n=4, R-EPOCH n=3, lenalidomide-R-CHOP n=1). Among these patients, the overall response rate was 85% (n=22/26). Three of the 4 non-responders died within 1 year. At last follow-up, 18/32 (56%) patients had died, and 6/13 (46%) alive patients had relapsed (MZL 3/6, DLBCL 3/6). After HT, 2-, 4- and 10-year OS were 76%, 55% and 55%, respectively. In univariable analysis, the only predictor of OS at HT was age ≥70 (HR 3.57 ,95% CI 1.34-9.48, p=0.011). Conclusion: In this North American prospective cohort of mainly non-Hispanic White patients, we found a low cumulative incidence of HT in MZL of 2.9% and 4.5% at 5- and 10-year, which was consistent with the Finnish findings (Kalashnikov et al., 2023). At HT, age was associated with OS and there was a high response rate to CHOP-backbone therapies.

Micronutrient deficiencies and new-onset atrial fibrillation in a community-based cohort: data from PREVEND

AimMalnutrition has been linked to cardiovascular diseases. Both selenium and iron deficiency have been associated with worse prognosis in patients with heart failure (HF). Yet, little is known about the role of micronutrients in the development of atrial fibrillation (AFib). In this study, we aimed to elucidate the association of micronutrient deficiencies with new-onset AFib.MethodsSelenium, magnesium, and iron parameters were measured in a well-characterized prospective cohort study (N = 5452). Selenium deficiency was defined as serum selenium < 70 μg/L, iron deficiency as serum ferritin < 30 μg/L, and magnesium deficiency as plasma magnesium < 0.85 mmol/L. New-onset AFib was the primary outcome. Additionally, we tested for previously reported effect-modifiers where applicable.ResultsSelenium, iron, and magnesium deficiency was observed in 1155 (21.2%), 797 (14.6%), and 3600 (66.0%) participants, respectively. During a mean follow-up of 6.2 years, 136 (2.5%) participants developed new-onset AFib. Smoking status significantly interacted with selenium deficiency on outcome (p = 0.079). After multivariable adjustment for components of the CHARGE-AF model, selenium deficiency was associated with new-onset AFib in non-smokers (HR 1.69, 95% CI 1.09–2.64, p = 0.020), but not in smokers (HR 0.78, 95% CI 0.29–2.08, p = 0.619). Magnesium deficiency (HR 1.40, 95% CI 0.93–2.10, p = 0.110) and iron deficiency (HR 0.62, 95% CI 0.25–1.54, p = 0.307) were not significantly associated with new-onset AFib.ConclusionSelenium deficiency was associated with new-onset AFib in non-smoking participants. Interventional studies that investigate the effects of optimizing micronutrients status in a population at risk are needed to assess causality, especially in those with selenium deficiency.Graphical abstractMicronutrients deficiencies (selenium, iron, and magnesium) have been associated with cardiovascular diseases and mitochondrial dysfunction in human cardiomyocytes. However, it is not known whether these deficiencies are associated with atrial fibrillation. To investigate this question, we measured all three micronutrients in 5452 apparently healthy individuals. After a mean follow-up of 6.2 years, there were 136 participants who developed atrial fibrillation. Participants with selenium deficiency had a significant increased risk to develop atrial fibrillation, as did the participants with two or more deficiencies.

Allostatic Load and Adverse Pregnancy Outcomes

ABSTRACT Approximately one-fourth of pregnancies experience adverse pregnancy outcomes, such as hypertensive disorders of pregnancy (HDPs), preterm birth, stillbirth, and small-for-gestational age (SGA) neonates. Although an uncertain pathophysiology leading to these outcomes of pregnancy is understood, a major contributing factor may be cumulative stress. Chronic wear and tear on the adaptive system of the body, as well as chronic stress exposure, can be assessed via allostatic load. Chronic stress hailing from circumstances such as food or housing insecurity, racism, unemployment, or a combination of these may contribute to the racial and ethnic disparities observed in pregnancy outcomes. This study aimed to assess the relationship between the allostatic load and adverse pregnancy outcomes, while hypothesizing that higher odds of adverse pregnancy outcomes are directly associated with higher allostatic loads. Second, the authors hypothesized that a significant portion of racial and ethnic disparities in adverse pregnancy outcomes will be accounted for with high allostatic loads. The primary outcome was a composite adverse pregnancy outcome: HDPs, SGA, preterm birth, and stillbirth. Between October 2010 and September 2013, the nuMoM2b study (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be) enrolled 10,038 nulliparous individuals with singleton pregnancies. Eligible individuals were nulliparous, had a viable single gestation with an estimated gestational age of 60/7 and 136/7 weeks, and intended delivery at a participating clinical site. Exclusionary criteria were as follows: unable to provide informed consent, age younger than 13 years, planned termination of pregnancy, 3 or more prior pregnancy losses, fetal malformations or aneuploidy upon enrollment, or having a donor ovum pregnancy. Included within the study were 3 study visits during pregnancy and a final visit at delivery. Baseline clinical assessments, standardized questionnaires by trained chart abstracts, and medical record abstraction were used to ascertain maternal characteristics. Assessment of urine and serum collected between 6 and 14 weeks granted insight into allostatic load biomarkers. A total of 4266 pregnant individuals were included in the primary analysis, with high allostatic load being identified in 35% of the population (≥4 biomarkers in the worst quartile). Some 1171 individuals (27.5%) were identified to have adverse pregnancy outcomes: 386 preterm births (8.6%), 586 HDPs (14.0%), 12 stillbirths (0.3%), and 449 SGA neonates (11%). Adverse pregnancy outcomes occurred in the following numbers: 1 adverse outcome for 967 individuals, 2 for 165, 3 for 38, and 1 for all 4. High allostatic load held significant association with composite adverse pregnancy outcome, whereas HDPs differed by self-reported race. After adjustment for maternal age, gravidity, smoking, bleeding in the first trimester, and health insurance, high allostatic load was associated with the composite adverse pregnancy outcome (adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 1.3–1.7) and hypertensive disorders (aOR, 2.5; 95% CI, 2.0–2.9), but not preterm birth or SGA. High allostatic load only partially mediated the association between self-reported race and adverse pregnancy outcomes. The association between allostatic load and hypertensive disorders differed by self-reported race, but it did not differ for the composite adverse pregnancy outcome, preterm birth, or SGA. Limitations of the study included the small number of stillbirths. Furthermore, the study used the 10-factor allostatic load index and did not assess additional cardiovascular and metabolic indicators in the broader allostatic load index. In addition, the cohort only included nulliparous individuals with tertiary care center access, which is not necessarily generalizable to other populations. Strengths of the study included its use of a large, well-characterized prospective cohort, as well as equal weighing of allostatic load biomarkers and a study population that was racially, ethnically, and geographically diverse. In conclusion, the study indicates that early-pregnancy high allostatic loads are associated with subsequent adverse pregnancy outcomes (HDPs in particular). Allostatic load was also a partial mediator between adverse pregnancy outcomes and race. Further evaluation of components of chronic stress and allostatic load as potentially modifiable risk factors is supported by these findings as a means of improving pregnancy outcomes via these potentially modifiable risk factors.

Effects of prenatal opioid and alcohol exposures on immune and serotonin factors in human placenta

PurposeOpioids and alcohol impact critical serotonin (5-HT) function in the developing placenta and fetus through the actions of immune proinflammatory factors. Yet, possible convergent effects of opioids and alcohol on human placental toll-like receptor 4 (TLR4) activation and subsequent 5-HT homeostasis remain entirely unknown. The purpose of this study was to examine the effect of prenatal exposure to opioids with or without prenatal alcohol exposure (PAE) on the expression of key placental immune and serotonin signaling factors in human placental tissue obtained from a well-characterized prospective cohort. MethodsData were collected from a subset of participants enrolled in the prospective pre-birth Ethanol, Neurodevelopment, Infant, and Child Health (ENRICH-1) cohort. Women were recruited and classified into four study groups: 1) PAE (n = 20); 2) those taking medications for opioid use disorder (MOUD; n = 28), 3) concurrent PAE and MOUD (n = 20); and 4) controls (HC; n = 20) based on prospective, repeated self-report, and biomarker analysis. Placenta samples underwent tissue processing to identify mRNA for TLR4, nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), serotonin transporter (SERT), tryptophan hydroxylase (TPH1), indoleamine 2,3-Dioxygenase 1 (IDO) as well as protein concentrations of TLR4, IL-1β, TNF-α, SERT. To consider the association between study group and mRNA/protein expression of our targets, multivariable regression models were developed with inclusion of a priori selected covariates. ResultsThere was a significant negative association between PAE and SERT mRNA (β = −0.01; p < 0.01) and a positive association with TPH1 mRNA expression (β = 0.78; p < 0.05). In addition, there was a negative association between MOUD and TNF-α protein expression (β = −0.12; p < 0.05). ConclusionsThis study provides the first evidence that PAE may inhibit SERT expression while simultaneously promoting increased TPH1 protein expression in human placenta. This may result in increased 5-HT in fetal circulation known to affect neurodevelopment. Our data suggest that opioids and alcohol may disturb the bidirectional, dynamic interaction between the placental immune and serotonin system. Given the implication for brain development and health across the life-span further investigation of these critical mechanisms in well-defined cohorts is required.

Maternal plasma lipids are involved in the pathogenesis of preterm birth.

BackgroundPreterm birth is defined by the onset of labor at a gestational age shorter than 37 weeks, and it can lead to premature birth and impose a threat to newborns’ health. The Puerto Rico PROTECT cohort is a well-characterized prospective birth cohort that was designed to investigate environmental and social contributors to preterm birth in Puerto Rico, where preterm birth rates have been elevated in recent decades. To elucidate possible relationships between metabolites and preterm birth in this cohort, we conducted a nested case-control study to conduct untargeted metabolomic characterization of maternal plasma of 31 women who experienced preterm birth and 69 controls who underwent full-term labor at 24–28 gestational weeks.ResultsA total of 333 metabolites were identified and annotated with liquid chromatography/mass spectrometry. Subsequent weighted gene correlation network analysis shows that the fatty acid and carene-enriched module has a significant positive association (P = 8e−04, FDR = 0.006) with preterm birth. After controlling for potential clinical confounders, a total of 38 metabolites demonstrated significant changes uniquely associated with preterm birth, where 17 of them were preterm biomarkers. Among 7 machine-learning classifiers, the application of random forest achieved a highly accurate and specific prediction (AUC = 0.92) for preterm birth in testing data, demonstrating their strong potential as biomarkers for preterm births. The 17 preterm biomarkers are involved in cell signaling, lipid metabolism, and lipid peroxidation functions. Additional modeling using only the 19 spontaneous preterm births (sPTB) and controls identifies 16 sPTB markers, with an AUC of 0.89 in testing data. Half of the sPTB overlap with those markers for preterm births. Further causality analysis infers that suberic acid upregulates several fatty acids to promote preterm birth.ConclusionsAltogether, this study demonstrates the involvement of lipids, particularly fatty acids, in the pathogenesis of preterm birth.

Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial

PurposeTo explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib.MethodsA subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response.ResultsForty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9–8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2–4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22–7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02–4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011).ConclusionIL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.

Non-memory subjective cognitive concerns predict incident motoric cognitive risk syndrome.

Motoric cognitive risk syndrome (MCR) is a predementia condition that combines slow gait and subjective cognitive concerns. As the earliest markers of MCR are relatively unknown, the role of subjective cognitive concerns was investigated to predict incident MCR in a well-characterized prospective cohort of non-demented older adults. Non-demented MCR-free older adults (n=476) from the Central Control of Mobility in Aging cohort completed gait, subjective cognition and neuropsychological assessment at baseline and follow-up. Subjective concerns were analyzed via responses to 12 items from three validated measures, the Late-Life Function and Disability Instrument - Disability Component, the Activities of Daily Living Prevention Instrument and the Geriatric Depression Scale, and were independent of items utilized to diagnose MCR. Cox proportional hazard models examined the association between cognitive concerns and incident MCR. After 2.36±1.4years, 28 participants developed MCR. Executive functioning (adjusted hazard ratio 2.458, 95% confidence interval 1.094-5.524, P=0.029) and mental clarity concerns (adjusted hazard ratio 3.917, 95% confidence interval 1.690-9.077, P=0.001) were associated with incident MCR, controlling for age, sex, education and gait speed. Subjective cognitive concerns in non-memory cognitive domains predict incident MCR. Although most MCR studies assess cognitive concerns about memory, our findings suggest the need to broaden the scope of subjective cognitive assessment to enhance the accuracy of diagnosis and prediction of future cognitive decline.

Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy.

Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT01307605) of 154 treatment-naïve FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4- to CD8-positive T cells (P=0·009) and increased amounts of PD1+ tumour-infiltrating T cells (P=0·007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1+ T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R2 . In the latter group, high amounts of GATA3+ T helper (Th2) equivalents were associated with better progression-free survival (P<0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4+ and, particularly, PD1+ T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents. [Correction added on 11 February 2020, after online publication: The NCT-trial number was previously incorrect and has been updated in this version].

Clinical Utility of an Increase in Magnetic Resonance Elastography in Predicting Fibrosis Progression in Nonalcoholic Fatty Liver Disease.

Cross-sectional studies have shown that magnetic resonance elastography (MRE) is accurate in the noninvasive detection of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD). However, there are limited data on the longitudinal association between an increase in liver stiffness on MRE and fibrosis progression in NAFLD. Therefore, using a well-characterized prospective cohort of patients with biopsy-proven NAFLD, we aimed to examine the longitudinal association between a 15% increase in liver stiffness on MRE and fibrosis progression in NAFLD. This prospective cohort study included 102 patients (62.7% women) with biopsy-proven NAFLD who underwent contemporaneous MRE and liver biopsy at baseline followed by a repeat paired liver biopsy and MRE assessment. The primary outcome was odds of fibrosis progression by one or more stage as assessed by the Nonalcoholic Steatohepatitis Clinical Research Network histologic scoring system. The mean (±SD) of age and body mass index (BMI) were 52 (±14) years and 32.6 (±5.3) kg/m2 , respectively. The median time interval between the two paired assessments was 1.4years (interquartile range 2.15years). The number of patients with fibrosis stages 0, 1, 2, 3, and 4 was 27, 36, 12, 17, and 10, respectively. In unadjusted analysis, a 15% increase in MRE was associated with increased odds of histologic fibrosis progression (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.17-10.76; P=0.0248). These findings remained clinically and statistically significant even after multivariable adjustment for age, sex, and BMI (adjusted OR, 3.36; 95% CI, 1.10-10.31; P=0.0339). A 15% increase in MRE was the strongest predictor of progression to advanced fibrosis (OR, 4.90; 95% CI, 1.35-17.84; P=0.0159). A 15% increase in liver stiffness on MRE may be associated with histologic fibrosis progression and progression from early fibrosis to advanced fibrosis.

Metabolic impact of pheochromocytoma/paraganglioma: targeted metabolomics in patients before and after tumor removal.

Excess catecholamine release by pheochromocytomas and paragangliomas (PPGL) leads to characteristic clinical features and increased morbidity and mortality. The influence of PPGLs on metabolism is ill described but may impact diagnosis and management. The objective of this study was to systematically and quantitatively study PPGL-induced metabolic changes at a systems level. Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens in a clinically well-characterized prospective cohort study. Analyses of metabolic profiles of plasma specimens from 56 prospectively enrolled and clinically well-characterized patients (23 males, 33 females) with catecholamine-producing PPGL before and after surgery, as well as measurement of 24-h urinary catecholamine using LC-MS/MS. From 127 analyzed metabolites, 15 were identified with significant changes before and after surgery: five amino acids/biogenic amines (creatinine, histidine, ornithine, sarcosine, tyrosine) and one glycerophospholipid (PCaeC34:2) with increased concentrations and six glycerophospholipids (PCaaC38:1, PCaaC42:0, PCaeC40:2, PCaeC42:5, PCaeC44:5, PCaeC44:6), two sphingomyelins (SMC24:1, SMC26:1) and hexose with decreased levels after surgery. Patients with a noradrenergic tumor phenotype had more pronounced alterations compared to those with an adrenergic tumor phenotype. Weak, but significant correlations for 8 of these 15 metabolites with total urine catecholamine levels were identified. This first large prospective metabolomics analysis of PPGL patients demonstrates broad metabolic consequences of catecholamine excess. Robust impact on lipid and amino acid metabolism may contribute to increased morbidity of PPGL patients.

Abstract 605: Association of blood lipid profile and lung cancer risk: Results from the Southern Community Cohort Study

Abstract Lung cancer is the second most common cancer and the leading cause of cancer death in the U.S. African Americans (AAs) have a higher incidence rate than any other racial group. Lipid metabolism and homeostasis play important roles in the growth of cancer cells and the regulation of membrane proteins. Some previous epidemiological studies have evaluated the association between blood lipid levels and lung cancer risk; however, the results were inconsistent, and few explored patterns among AAs. To investigate the association of blood lipid levels and lung cancer risk, particularly in a low socioeconomic population and AAs, we conducted a nested case-control study using resources from the Southern Community Cohort Study, a well-characterized prospective cohort study of approximately 86,000 adult men and women, two-thirds of whom are AAs. Blood lipid profiles, including total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TRIG), and lipoprotein-a (Lp-a), were measured in 372 lung cancer cases and 721 matched controls. AAs had lower median levels of TRIG, and higher levels of HDL and Lp-a than European Americans (EAs). Conditional logistic regression analysis revealed an inverse association between TC and lung cancer risk, with an adjusted OR for the highest vs. lowest tertiles of 0.67 (95% CI: 0.45-0.99). This association was observed in both AAs and EAs, but was only statistically significant in EAs. Further stratified analysis found that this association was only significant in cases that were diagnosed within 2 years of blood collection. No significant associations of other lipid markers with lung cancer risk were observed. The findings from our study suggest that the inverse associations between TC and lung cancer risk more likely resulted from cancerous occurrence and progression and associated lifestyle changes rather than being indicative of causal markers. Citation Format: Yan Sun, Jie Wu, Hyung-Suk Yoon, Wei Zheng, William J. Blot, Qiuyin Cai. Association of blood lipid profile and lung cancer risk: Results from the Southern Community Cohort Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 605.

Collagen Formation Assessed by N-Terminal Propeptide of Type 3 Procollagen Is a Heritable Trait and Is Associated With Liver Fibrosis Assessed by Magnetic Resonance Elastography.

N-terminal propeptide of type 3 procollagen (PRO-C3) is a biomarker of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). This study examines the association between PRO-C3 concentration and liver fibrosis assessed by magnetic resonance elastography (MRE)-measured stiffness (MRE-stiffness) and the heritability of PRO-C3 concentration in a cohort of twins and families with and without NAFLD. We performed a cross-sectional analysis of a well-characterized prospective cohort of 306 participants, including 44 probands with NAFLD-cirrhosis and their 72 first-degree relatives, 24 probands with NAFLD without advanced fibrosis and their 24 first-degree relatives, and 72 controls without NAFLD and their 72 first-degree relatives. Liver steatosis was assessed by magnetic resonance imaging proton density fat fraction, and liver fibrosis was assessed by MRE-stiffness. Serum PRO-C3 was assessed by competitive, enzyme-linked immunosorbent assay. We assessed the familial correlation of PRO-C3 concentration, the shared gene effects between PRO-C3 concentration and liver steatosis and fibrosis, and the association between PRO-C3 concentration and genetic variants in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing (MBOAT), and glucokinase regulator (CGKR) genes. In multivariable-adjusted models including age, sex, body mass index, and ethnicity, serum PRO-C3 correlated strongly with liver fibrosis (r2 =0.50, P<0.001) and demonstrated robust heritability (h2 , 0.36; 95% confidence interval [CI], 0.07, 0.59; P=0.016). PRO-C3 concentration and steatosis had a strong genetic correlation (shared genetic determination: 0.62; 95% CI, 0.236, 1.001; P=0.002), whereas PRO-C3 concentration and fibrosis had a strong environmental correlation (shared environmental determination: 0.55; 95% CI, 0.317, 0.717; P<0.001). PRO-C3 concentrations were higher in carriers of the TM6SF2 rs58542926-T allele compared with noncarriers: 15.7 (±10.5) versus 10.8 (±5.7) ng/L (P=0.047). Conclusion: Serum PRO-C3 correlates with MRE-assessed fibrosis, is heritable, shares genetic correlation with liver steatosis and shares environmental correlation with liver fibrosis. PRO-C3 concentration appears to be linked to both fibrosis and steatosis and increased in carriers of the TM6SF2 rs58542926 risk allele.

Lack of Association Between Select Circulating miRNAs and Bone Mass, Turnover, and Fractures: Data From the OFELY Cohort.

Postmenopausal osteoporosis is characterized by the occurrence of fragility fracture with an increase in morbidity and mortality. Recently, microRNAs (miRNAs) have raised interest as regulators of translational repression, mediating a number of key processes, including bone tissue in both physiological and diseased states. The aim of this study was to examine the serum levels of 32 preselected miRNAs with reported function in bone and their association with osteoporotic fracture. We performed cross-sectional and longitudinal analyses from the OFELY Cohort. Serum levels of the miRNAs were quantified by qRT-PCR in 682 women: 99 premenopausal and 583 postmenopausal women, with 1 and 122 women with prevalent fragility fractures in each group, respectively. We have collected clinical variables (such as age, prevalent, and incident fractures), bone turnover markers (BTMs), BMD by dual X-ray absorptiometry, and bone microarchitecture with HRpQCT. We observed a number of miRNAs to be associated with fragility fractures (prevalent or incident), BTMs, BMD, and microarchitecture. This effect, however, was negated after age adjustment. This may be because age was also strongly associated with the serum levels of the 32 miRNAs (correlation coefficient up to 0.49), confirming previous findings. In conclusion, in a well-characterized prospective cohort with a sizeable sample size, we found no evidence that these 32 preselected miRNAs were not associated with BTMs, BMD, microarchitecture, and or fragility fractures. © 2019 American Society for Bone and Mineral Research.

Antenatal Vitamin D Status Is Not Associated with Standard Neurodevelopmental Assessments at Age 5 Years in a Well-Characterized Prospective Maternal-Infant Cohort

Although animal studies show evidence for a role of vitamin D during brain development, data from human studies show conflicting signals. We aimed to explore associations between maternal and neonatal vitamin D status with childhood neurodevelopmental outcomes. Comprehensive clinical, demographic, and lifestyle data were collected prospectively in 734 maternal-infant dyads from the Cork BASELINE Birth Cohort Study. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were quantified at 15 weeks of gestation and in umbilical cord sera at birth via a CDC-accredited liquid chromatography-tandem mass spectrometry method. Children were assessed at age 5 y through the use of the Kaufman Brief Intelligence Test (2nd Edition, KBIT-2) and the Child Behaviour Checklist (CBCL). Linear regression was used to explore associations between 25(OH)D and neurodevelopmental outcomes. 25(OH)D concentrations were <30 nmol/L in 15% of maternal and 45% of umbilical cord sera and <50 nmol/L in 42% of mothers and 80% of cords. At age 5 y, the mean±SD KBIT-2 intelligence quotient (IQ) composite score was 104.6±8.6; scores were 107.2±10.0 in verbal and 99.8±8.8 in nonverbal tasks. Developmental delay (scores <85) was seen in <3% of children across all domains. The mean±SD CBCL total problem score was 21.3±17.5; scores in the abnormal/clinical range for internal, external, and total problem scales were present in 12%, 4%, and 6% of participants, respectively. KBIT-2 and CBCL subscale scores at 5 y were not different between children exposed to low antenatal vitamin D status, either at 30 or 50 nmol/L 25(OH)D thresholds. Neither maternal nor cord 25(OH)D (per 10 nmol/L) were associated with KBIT-2 IQ composite scores [adjusted β (95% CI): maternal -0.01 (-0.03, 0.02); cord 0.01 (-0.03, 0.04] or CBCL total problem scores [maternal 0.01 (-0.04, 0.05); cord 0.01 (-0.07, 0.09)]. In this well-characterized prospective maternal-infant cohort, we found no evidence that antenatal 25(OH)D concentrations are associated with neurodevelopmental outcomes at 5 y. The BASELINE Study was registered at www.clinicaltrials.gov as NCT01498965; the SCOPE Study was registered at http://www.anzctr.org.au as ACTRN12607000551493.

Cortical Thinning and Neuropsychiatric Outcomes in Children Exposed to Prenatal Adversity: A Role for Placental CRH?

The authors sought to assess associations among early-life exposure to adversity, the development and maturation of neurons and brain circuits, and neurodevelopmental outcomes. Specifically, they examined whether fetal exposure to placental corticotropin-releasing hormone (CRH), a molecule conveying maternal signals to the fetus, predicts brain growth and neuropsychiatric outcomes in school-age children. In a large, well-characterized prospective cohort, concentrations of placental CRH (pCRH) in maternal plasma were determined during five intervals during gestation. When the children reached school age, their brain structures were examined using MRI, and emotional and cognitive tests assessing internalizing and externalizing behaviors and attention were administered (N=97, 49 of them girls). Levels of pCRH during gestation predicted structural and functional brain outcomes in children. Specifically, fetal exposure to elevated pCRH levels was associated with thinning of selective cortical regions and with commensurate cognitive and emotional deficits. The relations among fetal exposure to pCRH, cortical thinning, and childhood function were sex specific. In view of the established effects of CRH on maturation and arborization of cortical neurons, and the major contribution of dendrites to cortical volume, these findings position pCRH as an important mediator of the consequences of early-life adversity on neuropsychiatric outcomes.

Association of Serum Level of Vitamin D at Diagnosis With Breast Cancer Survival

There are long-standing interests in the potential benefits of vitamin D for preventing breast cancer recurrence and mortality, yet data from prospective cohort studies are limited. To investigate a serum biomarker of vitamin D status, 25-hydroxyvitamin D (25OHD) measured at the time of breast cancer diagnosis, to determine the association with prognosis. The Pathways Study is a prospective cohort study of breast cancer survivors established in 2006. Enrollment was completed in 2013; follow-up is ongoing. The cohort was established in Kaiser Permanente Northern California, a large integrated health care delivery system in northern California. Women with a diagnosis of incident invasive breast cancer were typically consented and enrolled within 2 months of diagnosis. The overall enrollment rate was 46% (4505 of 9820). Participants are followed for health outcomes and comorbidities at 12, 24, 48, 72, and 96 months after baseline interview. A case-cohort design was used for efficiency assay of 25OHD, selecting 1666 cohort members with serum samples and ensuring representation in the subcohort of races and clinical subtypes. The data analysis was performed from January 5, 2014, to March 15, 2015. Primary outcomes are breast cancer recurrence, second primary cancer, and death. Mean (SD) age was 58.7 (12.4) years. Serum 25OHD concentrations were lower in women with advanced-stage tumors, and the lowest in premenopausal women with triple-negative cancer. Levels were also inversely associated with hazards of disease progression and death. Compared with the lowest tertile, women with the highest tertile of 25OHD levels had superior overall survival (OS). This association remained after adjustment for clinical prognostic factors (hazard ratio [HR], 0.72; 95% CI, 0.54-0.98). Among premenopausal women, the association with OS was stronger, and there were also associations with breast cancer-specific survival and invasive disease-free survival (OS: HR, 0.45; 95% CI, 0.21-0.96; breast cancer-specific survival: HR, 0.37; 95% CI, 0.15-0.93; invasive disease-free survival: HR, 0.58; 95% CI, 0.34-1.01; all after full adjustment). Serum 25OHD levels were independently associated with breast cancer prognostic characteristics and patient prognosis, most prominently among premenopausal women. Our findings from a large, well-characterized prospective cohort provide compelling observational evidence on associations of vitamin D with lower risk of breast cancer morbidity and mortality.

Abstract 3455: Association of oral microbiome with lung cancer risk: Results from the Southern Community Cohort Study

Abstract Lung cancer is the leading cause of cancer death in the United States. The lungs are inhabited by diverse microbial communities. Bacterial infection in the lungs, such as a history of pneumonia and tuberculosis, has been associated with increased risk of lung cancer. Recent studies have found that the oral microbiome is the primary source of the bacterial microbiota in the lungs and that the bacterial species detected in the lungs overlap those found in the mouth. Therefore, readily-accessible oral samples may be used to investigate the role of bacteria in lung cancer etiology. In this study, we evaluated the association of the oral microbiome with subsequent risk of developing lung cancer. We conducted a nested case-control study using resources of the Southern Community Cohort Study, a well-characterized prospective cohort study of approximately 86,000 adult men and women, two-thirds of whom are African American. DNA was isolated from pre-diagnostic mouth rinse samples of 177 lung cancer cases and 177 controls matched on age, race, sex, smoking, and date of sample collection. The V4 domain of microbial 16S rRNA gene was sequenced. Sequencing libraries were prepared using the NEXTflex 16S V4 Amplicon-Seq Kit and sequenced with paired-end 150 bp using Illumina MiSeq. Sequencing data were processed using QIIME, and sequence reads were clustered into Operational Taxonomic Units (OTUs). On average, 82,254 sequencing reads were obtained for each sample. Duplicated quality control samples (n = 18; 2 samples each repeated for 9 times) showed very similar microbiome compositions, indicating high data quality. A total of 693 OTUs were observed and classified to 11 phyla. The observed composition was similar to the oral microbiome data from other studies, including the Human Microbiome Project. Multiple oral bacteria differed between lung cancer cases and controls. For example, Order CW040 was associated with increased lung cancer risk with OR of 3.64 (P = 0.0098). Family Tissierellaceae and Genus Parvimonas were associated with decreased risk of lung cancer with ORs of 0.42 (P = 0.0025) and 0.41 (P = 0.0014), respectively. Some of the associations differed by race. Among the lung cancer-associated oral bacteria, Family Fusobacteriaceae, Family Neisseriaceae, and Order Bacteroidales were among the most abundant bacteria found in the lungs. In summary, our study suggests that certain bacteria in the mouth are associated with substantial development of lung cancer and that the oral microbiome plays an important role in lung cancer etiology. Further studies with a larger sample size and with more comprehensive investigation are needed to confirm these findings. Citation Format: Qiuyin Cai, Jirong Long, Hua Xie, Xiaofei Wang, Jie Wu, Regina Courtney, Xiao Ou Shu, Wei Zheng, William J. Blot. Association of oral microbiome with lung cancer risk: Results from the Southern Community Cohort Study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3455.

Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis

The biological and molecular events that underlie bone marrow fibrosis in patients with myelodysplastic syndromes are poorly understood, and its prognostic role in the era of the Revised International Prognostic Scoring System (IPSS-R) is not yet fully determined. We have evaluated the clinical and biological events that underlie bone marrow fibrotic changes, as well as its prognostic role, in a well-characterized prospective patient cohort (n=77) of primary MDS patients. The degree of marrow fibrosis was linked to parameters of erythropoietic failure, marrow cellularity, p53 protein accumulation, WT1 gene expression, and serum levels of CXCL9 and CXCL10, but not to other covariates including the IPSS-R score. The presence of bone marrow fibrosis grade 2 or higher was associated with the presence of mutations in cohesin complex genes (31.5% vs. 5.4%, p=0.006). By contrast, mutations in CALR, JAK2, PDGFRA, PDGFRB, and TP53 were very rare. Survival analysis showed that marrow fibrosis grade 2 or higher was a relevant significant predictor for of overall survival, and independent of age, performance status, and IPSS-R score in multivariate analysis.