Late diagnosis is a critical factor undermining clinical management of patients with biliary tract cancer (BTC). While biliary tumours display extensive inter-patient heterogeneity, the host immune ...response may be comparatively homogenous, providing diagnostic opportunities. Herein, we investigated whether cancer-associated systemic reprogramming could be detected non-invasively to improve diagnosis of BTC.
In this prospective Danish study, whole blood (WB) microRNA (miRNA) profiling was performed in samples from 218 patients with BTC, 99 healthy participants, and 69 patients with differential diagnoses split into discovery (small RNA-sequencing) and validation (RT-qPCR) cohorts. miRNA expression and activity were further investigated in 119 and 660 BTC tissues, respectively.
Four WB miRNAs (let-7a-3p, miR-92b-5p, miR-145-3p, miR-582-3p) were identified and validated as diagnostic of BTC on univariable analysis. Two diagnostic miRNA indexes were subsequently identified that were elevated in patients with BTC and in patients with differential diagnoses, compared to healthy participants. The combination of these miRNA indexes with serum CA 19-9 significantly improved the diagnostic performance of CA 19-9 alone, consistently achieving superior AUC values irrespective of clinical setting (minimum AUC >0.84) or tumour location (minimum AUC >0.87). The diagnostic information captured by miRNA indexes was not recapitulated by routine clinical measurements. Index miRNA expression in BTC tissues was associated with distinct pathobiological and immune features.
WB miRNA profiles are altered in patients with BTC. Quantification of miRNA indexes in combination with serum CA 19-9 has the potential to improve early diagnosis of BTC, pending further validation.
Surgery is currently the only curative intervention for patients with biliary tract cancer (BTC). However, resection is not possible for most patients who are diagnosed with late-stage disease. With the aim of identifying new early diagnostic opportunities, we analysed circulating microRNAs (small non-coding RNAs whose role in cancer is being increasingly recognised) in whole blood samples. We identified a microRNA signature that could distinguish patients with BTC from healthy participants. These miRNAs significantly improved the diagnostic potential of the routinely measured biomarker, CA 19-9, and were implicated in distinct immune processes in tumour tissues.
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•Whole blood miRNA profiles are altered in patients with biliary tract cancer irrespective of tumour location or clinical setting.•Quantification of 4 whole blood miRNAs captures diagnostic information independent of CA 19-9.•Candidate diagnostic miRNA are implicated in tumour immunity in independent resected tissues.
Biliary tract cancer (BTC) is characterized by a desmoplastic extracellular matrix (ECM). We tested the diagnostic and prognostic use of seven circulating biomarkers of ECM remodeling: pro-peptides ...of type III collagen (PRO-C3), VI (PRO-C6) and XI (PRO-C11), matrix metalloprotease (MMP) degraded type III collagen (C3M) and type IV collagen (C4M) fragments, granzyme B degraded type IV collagen fragments (C4G) and MMP degraded and citrullinated vimentin (VICM) a marker of macrophage activation. The study included 269 patients with all stages of BTC and 49 patients with benign biliary tract diseases. Serum samples from BTC patients were collected before surgery, or before first- or second-line chemotherapy. C3M, C4M, PRO-C3, PRO-C6, PRO-C11 and VICM levels were elevated in patients with BTC compared to patients with benign disease. Receiver operating characteristics curve analyses identified PRO-C3 (area under curve AUC = 0.87) as the ECM marker with the best diagnostic performance. The ECM biomarkers correlated with inflammation biomarkers (C-reactive protein CRP, interleukin-6 IL-6 and YKL-40) but not with CA19-9. To investigate prognostic performance, patients were split into three cohorts (first-line, second-line and surgery). Elevated ECM biomarker levels were associated with short overall survival (OS), but only pretreatment PRO-C3 and PRO-C6 were associated with OS in both the first-line and second-line settings when adjusting for CA19-9, performance status and stage in a multivariate Cox-regression analyses. Our results indicate that collagen remodeling is increased in patients with BTC and associated with survival. The collagen pro-peptides (PRO-C3 and PRO-C6) could be used as novel biomarkers in these patients.
Secreted phospholipase A2 group IIa (sPLA2-IIa) has been shown to promote tumor genesis and cell proliferation. The properties of this group of enzymes are utilized in liposomal drug delivery of ...chemotherapy. sPLA2-IIa is also under investigation as a possible treatment target in itself, and as a prognostic marker. The expression of sPLA2-IIa in breast cancer has not been examined extensively, and never using immunohistochemistry. We sought to investigate the expression of sPLA2-IIa in a cohort of advanced breast cancer patients with correlation to known clinicopathologic risk factors and survival. Material from 525 breast cancer patients (426 primary tumors and 99 metastases or local recurrences) was examined for sPLA2-IIa expression using immunohistochemistry. Out of these, 262 showed expression of sPLA2-IIa. We found that there was no correlation to clinicopathologic characteristics, and no impact of sPLA2-IIa expression on prognosis. However, we found that a large proportion of patients in our study had high levels of sPLA2-IIa expression, and that sPLA2-IIa was equally expressed in primary tumors and metastases. These findings may be significant in the future development of liposomal drug delivery or targeted sPLA2-IIa treatment.
Biliary tract cancer (BTC) is a rare gastrointestinal cancer with a dismal prognosis. Biomarkers with clinical utility are needed. In this study, we investigated the association between survival and ...89 immuno-oncology-related proteins, with the aim of identifying prognostic biomarkers for BTC. The study included patients with BTC (
= 394) treated at three Danish hospitals. Patients were divided into four cohorts: the first-line discovery cohort (
= 202), first-line validation cohort (
= 118), second-line cohort (
= 56), and surgery cohort (
= 41). Plasma protein levels were measured using a proximity extension assay (Olink Proteomics). Twenty-seven proteins were associated with overall survival (OS) in a multivariate analysis in the discovery cohort. In the first-line validation cohort, high levels of interleukin (IL)-6, IL-15, mucin 16, hepatocyte growth factor, programmed cell death ligand 1, and placental growth factor were significantly associated with poor OS in univariate Cox regression analyses. When adjusting for performance status, location, and stage, the association was significant only for IL-6 (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 1.08-1.46) and IL-15 (HR = 2.23, 95% CI 1.48-3.35). Receiver operating characteristic analyses confirmed IL-6 and IL-15 as the strongest predictors of survival. Combining several proteins into signatures further improved the ability to distinguish between patients with short (<6 months) and long survival (>18 months). The study identified several circulating proteins as prognostic biomarkers in patients, with BTC, IL-6, and IL-15 being the most promising markers. Combining proteins in a prognostic signature improved prognostic performance, but future studies are needed to determine the optimal combination and thresholds.
Background Proximity extension assay (PEA) is a novel antibody-based proteomic technology. Sparse data have been published concerning the matrix effect of serum vs. ethylenediamine tetraacetic acid ...(EDTA) plasma and the reproducibility of results obtained using PEA technology. Methods We analyzed samples with the PEA-based 92-plex OlinkR immuno-oncology (I-O) assay. To estimate the matrix effect, we analyzed paired serum and EDTA plasma samples from 12 patients with biliary tract cancer. To evaluate the reproducibility, we used data from 7 studies, where 6-8 serum samples from patients with pancreatic cancer were used as bridging samples on 3 versions of the panel over a 2.5-years period. Results For the study of serum vs. plasma, 80 proteins were evaluable. The mean serum to EDTA plasma ratio ranged from 0.41-3.01. For 36 proteins, the serum and plasma values were not comparable due to high variability of the ratio, poor correlation, or possible concentration effect. For the bridging samples, the mean intra-study inter-assay coefficient of variation (CV) ranged from 11.3% to 26.1%. The mean inter-study CV was 42.0% before normalization and 26.2% after normalization. Inter-study results were well correlated (r greater than or equal to 0.93), especially for studies using the same version of the panel (r greater than or equal to 0.99). Conclusion For 44 of 92 proteins included in the OlinkR I-O panel, the variation between results obtained using serum and EDTA plasma was constant and results were well correlated. Furthermore, samples could be stored for several years and used on different versions of the same PEA panel without it effecting results. Keywords: Olink immuno-oncology, Proximity extension assay, Multiplex Immunoassays, Proteins, Tumor markers, Serum-plasma variability
Biliary tract cancer (BTC) is associated with a dismal prognosis, partly because it is typically diagnosed late, highlighting the need for diagnostic biomarkers. The purpose of this project was to ...identify and validate multiprotein signatures that could differentiate patients with BTC from non-cancer controls.
In this study, we included treatment-naïve patients with BTC, healthy controls, and patients with benign conditions including benign biliary tract disease. Participants were divided into three non-overlapping cohorts: a case-control-based discovery cohort (BTC = 186, controls = 249); a case-control-based validation cohort (validation cohort 1: BTC = 113, controls = 241); and a cohort study-based validation cohort including participants (BTC = 8, controls = 132) referred for diagnostic work-up for suspected cancer (validation cohort 2). Immuno-Oncology (I-O)-related proteins were measured in serum and plasma using a proximity extension assay (Olink Proteomics). Lasso and Ridge regressions were used to generate protein signatures of I-O-related proteins and carbohydrate antigen 19-9 (CA19-9) in the discovery cohort.
Sixteen protein signatures, including 2 to 82 proteins, were generated. All signatures included CA19-9 and chemokine C-C motif ligand 20. Signatures discriminated between patients with BTC vs. controls, with AUCs ranging from 0.95 to 0.99 in the discovery cohort and 0.94 to 0.97 in validation cohort 1. In validation cohort 2, AUCs ranged from 0.84 to 0.94. Nine signatures achieved a specificity of 82% to 84% while keeping a sensitivity of 100% in validation cohort 2. All signatures performed better than CA19-9, and signatures including >15 proteins showed the best performance.
The study demonstrated that it is possible to generate protein signatures that can successfully differentiate patients with BTC from non-cancer controls.
We attempted to find blood sample-based protein profiles that could differentiate patients with biliary tract cancer from those without cancer. Several profiles were found and tested in different groups of patients. The profiles were successful at identifying most patients with biliary tract cancer, pointing towards the utility of multiprotein signatures in this context.
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•Several circulating proteins were associated with biliary tract cancer.•Diagnostic multiprotein signatures were generated and tested.•The signatures discriminated between individuals with biliary tract cancer and controls.•Combining several proteins improved diagnostic ability compared to single markers.
Introduction:
This study aimed to investigate the prevalence of acute kidney injury (AKI) following hip fracture surgery in geriatric patients and to identify predictors for development of AKI with a ...focus on possible preventable risk factors.
Methods:
In this retrospective cohort study, we reviewed electronic medical records of all patients above 65 years of age who underwent hip fracture surgery at Copenhagen University Hospital, Bispebjerg, Denmark, in 2018. Acute kidney injury was assessed according to the Kidney Disease Improving Global Outcomes guidelines. Multivariate logistic regression analyses were used to identify independent risk factors for AKI.
Results:
Postoperative AKI developed in 28.4% of the included patients (85/299). Acute kidney injury was associated with increased length of admission (11.3 vs 8.7 days, P < .001) and 30-day mortality (18/85 vs 16/214, P = .001). In multivariable analysis, higher age (odds ratio OR: 1.05, 95% confidence interval CI: 1.01-1.08, P = .004), heart disease (OR: 1.78, 95% CI: 1.01-3.11, P = .045), and postoperative blood transfusion (OR: 1.84, 95% CI: 1.01-3.36, P = .048) were associated with AKI. Moreover, a higher postoperative C-reactive protein (199.0 ± 99.9 in patients with AKI, 161.3 ± 75.2 in patients without AKI) and lower postoperative diastolic blood pressure were observed in patients developing AKI.
Discussion and Conclusion:
Acute kidney injury was common following hip fracture surgery and associated with longer admissions and increased mortality. Patients developing AKI were older and showed several postoperative similarities, including higher C-reactive protein, lower postoperative diastolic pressure, and the need for blood transfusion.
Departments of 1 Clinical Physiology and
Nuclear Medicine, 4 Anaesthesia
and Intensive Care, and
5 Endocrinology, Herlev Hospital,
2 Department of Anaesthesia,
Gentofte Hospital, 3 Institute
of ...Medical Physiology, and 6 Institute of
Pharmacology, University of Copenhagen, DK-2730 Herlev, Denmark
This study measured the pressor and plasma
catecholamine response to local hypothermia during adaptation to
hypobaric hypoxia. Eight healthy men were studied at rest and after 10 and 45 min of local cooling of one hand and forearm as well as after 30 min of rewarming at sea level and again 24 h and 5 days after rapid, passive transport to high altitude (4,559 m). Acute mountain sickness scores ranged from 5 to 16 (maximal attainable score: 20) on the first
day but were reduced to 0-8 by the fifth day. Systolic blood pressure, heart rate, and plasma epinephrine increased on
day 1 at altitude compared with sea
level but declined again on day 5 ,
whereas diastolic and mean blood pressures continued to rise in
parallel with plasma norepinephrine. With local cooling, an increased
vasoactive response was seen on the fifth day at altitude. Very high
pressures were obtained, and the pressure elevation was prolonged.
Heart rate increased twice as much on day
5 compared with the other two occasions. Thoracic fluid
index increased with cooling on day 5 ,
suggesting an increase in pulmonary vascular resistance. In conclusion,
prolonged hypoxia seems to elicit an augmented pressor response to
local cooling in the systemic and most likely also the pulmonary circulation.
acute mountain sickness; bioimpedance; healthy subjects; pulmonary
vascular resistance; thoracic fluid index
Depression represents the second leading cause of years lived with disability worldwide.1 However, 30 % of patients do not achieve remission after treatment with anti-depressants.2 Effective and ...fast-acting treatments are needed.
Our meta-analysis of placebo-controlled randomized controlled trials measuring effects of anti-inflammatory compounds on depressive symptoms showed that glucocorticoids – although the current evidence is weak – displayed the largest effect size (SMD = 0.90; 95 % CI: 0.36 to 1.44), equivalent to more than double the effect of current anti-depressants, in as little as 1-14 days.3 However, the included studies had only a limited number of patients (nTotal=59) and inadequate reporting of safety outcomes.4,5
The DEXA-PSYCH Study will investigate the acute effect and safety of oral dexamethasone compared to placebo as augmentation in treatment of moderate to severe depression.
Investigator-initiated, double-blind, parallel-group, superiority, randomized, placebo-controlled clinical trial.
300 patients from the Mental Health Services in The Capital Region of Denmark will be randomized. Patient from diagnosed with non-psychotic, recurrent or single episode moderate to severe depression are eligible. Exclusion criteria include, but are not limited to, diagnosis of a psychotic disorder, personality disorder, bipolar disorder (or a family history thereof) or disorders that are relative contraindications for treatment with glucocorticoids, including diabetes.
Orally administered dexamethasone at 4 mg/day for 4 days and subsequently 2 mg/day for 3 days as add-on to treatment as usual (TAU).
The primary outcome is change from baseline (day 0) on the Montgomery-Asberg Depression Rating Scale (MADRS10) at day 7. Key secondary outcomes include effects on remission rates, quality of life, suicidal ideation and psychiatric hospitalizations as well as suicide attempts. Safety outcomes and all-cause discontinuation will be reported.
The primary outcome will be analyzed through a Mixed Model for Repeated Measurements (MMRM) in an intention-to-treat analysis.
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