Untargeted metabolomics of COVID-19 patient serum reveals potential prognostic markers of both severity and outcome

Introduction The diagnosis of COVID-19 is normally based on the qualitative detection of viral nucleic acid sequences. Properties of the host response are not measured but are key in determining outcome. Although metabolic profiles are well suited to capture host state, most metabolomics studies are either underpowered, measure only a restricted subset of metabolites, compare infected individuals against uninfected control cohorts that are not suitably matched, or do not provide a compact predictive model. Objectives Here we provide a well-powered, untargeted metabolomics assessment of 120 COVID-19 patient samples acquired at hospital admission. The study aims to predict the patient’s infection severity (i.e., mild or severe) and potential outcome (i.e., discharged or deceased). Methods High resolution untargeted UHPLC-MS/MS analysis was performed on patient serum using both positive and negative ionization modes. A subset of 20 intermediary metabolites predictive of severity or outcome were selected based on univariate statistical significance and a multiple predictor Bayesian logistic regression model was created. Results The predictors were selected for their relevant biological function and include deoxycytidine and ureidopropionate (indirectly reflecting viral load), kynurenine (reflecting host inflammatory response), and multiple short chain acylcarnitines (energy metabolism) among others. Currently, this approach predicts outcome and severity with a Monte Carlo cross validated area under the ROC curve of 0.792 (SD 0.09) and 0.793 (SD 0.08), respectively. A blind validation study on an additional 90 patients predicted outcome and severity at ROC AUC of 0.83 (CI 0.74–0.91) and 0.76 (CI 0.67–0.86). Conclusion Prognostic tests based on the markers discussed in this paper could allow improvement in the planning of COVID-19 patient treatment.

Prognostic Value of Cell-Surface Vimentin-Positive CTCs in Pediatric Sarcomas

BackgroundDespite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety.MethodsHere, for the first time reported in the literature, we have enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients as a possible marker of disease.ResultsWe constructed a ROC with an AUC of 0.831 resulting in a sensitivity of 85.3% and a specificity of 75%. Additionally, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative. We additionally found the use of available molecular testing increased the accuracy of our diagnostic and prognostic tests.ConclusionsOur findings indicate that CSV+ CTCs have prognostic value and can possibly serve as a measure of disease burden.

Impact of the menstrual cycle on commercial prognostic gene signatures in oestrogen receptor-positive primary breast cancer

Purpose Changes occur in the expression of oestrogen-regulated and proliferation-associated genes in oestrogen receptor (ER)-positive breast tumours during the menstrual cycle. We investigated if Oncotype® DX recurrence score (RS), Prosigna® (ROR) and EndoPredict® (EP/EPclin) prognostic tests, which include some of these genes, vary according to the time in the menstrual cycle when they are measured. Methods Pairs of test scores were derived from 30 ER-positive/human epidermal growth factor receptor-2-negative tumours sampled at two different points of the menstrual cycle. Menstrual cycle windows were prospectively defined as either W1 (days 1–6 and 27–35; low oestrogen and low progesterone) or W2 (days 7–26; high oestrogen and high or low progesterone). Results The invasion module score of RS was lower (− 10.9%; p = 0.098), whereas the ER (+ 16.6%; p = 0.046) and proliferation (+ 7.3%; p = 0.13) module scores were higher in W2. PGR expression was significantly increased in W2 (+ 81.4%; p = 0.0029). Despite this, mean scores were not significantly different between W1 and W2 for any of the tests and the two measurements showed high correlation (r = 0.72–0.93). However, variability between the two measurements led to tumours being assigned to different risk categories in the following proportion of cases: RS 22.7%, ROR 27.3%, EP 13.6% and EPclin 13.6%. Conclusion There are significant changes during the menstrual cycle in the expression of some of the genes and gene module scores comprising the RS, ROR and EP/EPclin scores. These did not affect any of the prognostic scores in a systematic fashion, but there was substantial variability in paired measurements.

Randomised controlled trial of a prognostic assessment and management pathway to reduce the length of hospital stay in normotensive patients with acute pulmonary embolism

BackgroundThe length of hospital stay (LOS) for acute pulmonary embolism (PE) varies considerably. Whether the upfront use of a PE prognostic assessment and management pathway is effective in reducing the LOS remains unknown.MethodsWe conducted a randomised, controlled trial of adults hospitalised for acute PE: patients were assigned to a prognostic assessment and management pathway involving risk stratification, followed by predefined criteria for mobilisation and discharge (intervention group), or usual care (control group). The primary end point was LOS. The secondary end points were the cost of prognostic tests and of hospitalisation, and 30-day clinical outcomes.ResultsOf 500 patients who underwent randomisation, 498 were included in the modified intention-to-treat analysis. The median LOS was 4.0 days (interquartile range [IQR], 3.7 to 4.2 days) in the intervention group and 6.1 days (IQR, 5.7 to 6.5 days) in the control group (p<0.001). The mean total cost of prognostic tests was €174.76 in the intervention group, as compared with €233.12 in the control group (mean difference, €−58.37; 95% confidence interval [CI], €−84.34 to €−32.40). The mean total hospitalisation cost per patient was €2085.66 in the intervention group, compared with €3232.97 in the control group (mean difference, €−1147.31; 95% CI, €−1414.97 to €−879.65). No significant differences were observed in 30-day readmissions (4.0% versus 4.8%, respectively), or all-cause (2.4% versus 2.0%) and PE-related mortality rates (0.8% versus 1.2%).ConclusionsThe use of a prognostic assessment and management pathway was effective in reducing the LOS for acute PE.

Diagnostic and Prognostic Value of Cell-Surface Vimentin-Positive Circulating Tumor Cells in Pediatric Sarcoma Patients

Background Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety. Methods Here, for the first time reported in the literature, we have enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients as a possible marker of disease. Results We constructed a ROC with an AUC of 0.831 resulting in a sensitivity of 85.3% and a specificity of 75%. Additionally, patients who were deemed to be CSV + CTC positive were found to have a worse overall survival compared to those who were CSV + CTC negative. We additionally found the use of available molecular testing increased the accuracy of our diagnostic and prognostic tests. Conclusions Our findings indicate that CSV + CTCs have both diagnostic and prognostic value and can possibly serve as a measure of disease burden.

Can we learn from hidden mistakes? Self-fulfilling prophecy and responsible neuroprognostic innovation

A self-fulfilling prophecy (SFP) in neuroprognostication occurs when a patient in coma is predicted to have a poor outcome, and life-sustaining treatment is withdrawn on the basis of that prediction, thus directly bringing about a poor outcome (viz. death) for that patient. In contrast to the predominant emphasis in the bioethics literature, we look beyond the moral issues raised by the possibility that an erroneous prediction might lead to the death of a patient who otherwise would have lived. Instead, we focus on the problematic epistemic consequences of neuroprognostic SFPs in settings where research and practice intersect. When this sort of SFP occurs, the problem is that physicians and researchers are never in a position to notice whether their original prognosis was correct or incorrect, since the patient dies anyway. Thus, SFPs keep us from discerning false positives from true positives, inhibiting proper assessment of novel prognostic tests. This epistemic problem of SFPs thus impedes learning, but ethical obligations of patient care make it difficult to avoid SFPs. We then show how the impediment to catching false positive indicators of poor outcome distorts research on novel techniques for neuroprognostication, allowing biases to persist in prognostic tests. We finally highlight a particular risk that a precautionary bias towards early withdrawal of life-sustaining treatment may be amplified. We conclude with guidelines about how researchers can mitigate the epistemic problems of SFPs, to achieve more responsible innovation of neuroprognostication for patients in coma.

Screening, Diagnostic and Prognostic Tests for COVID-19: A Comprehensive Review

While molecular testing with real-time polymerase chain reaction (RT-PCR) remains the gold-standard test for COVID-19 diagnosis and screening, more rapid or affordable molecular and antigen testing options have been developed. More affordable, point-of-care antigen testing, despite being less sensitive compared to molecular assays, might be preferable for wider screening initiatives. Simple laboratory, imaging and clinical parameters could facilitate prognostication and triage. This comprehensive review summarises current evidence on the diagnostic, screening and prognostic tests for COVID-19.

Cell-surface vimentin positive circulating tumor cells as a diagnostic and prognostic indicator in pediatric sarcoma patients.

e15022 Background: Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains only reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety. Methods: Here, we enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients. Results: We discovered the CSV+CTC could serve as a possible biomarker of disease with sensitivity of 85.3% and specificity of 75%. Significantly, patients who were deemed to be CSV+ CTC positive were found to have a worse overall survival compared to those who were CSV+ CTC negative (773 days vs 2622 days). Addition of readily available genetic analyses improved the sensitivity in both diagnostic and prognostic tests. Conclusions: Our findings indicate that CSV+ CTCs have both diagnostic and prognostic value and can possibly serve as a measure of disease burden.

Moderate dose serial therapy for aged and resistant patients with cholangiocarcinomas.

e16160 Background: Advanced (Adv) intrahepatic IH Cholangiocarcinoma BD trials found multi-drug, sequences (GFLIO) safely expand eligibility (El) for patients (pts) of all ages -/+ resistant Ca (R). Two series had response/survival (S) of 80% / > 2 years (yr) (Bruckner et al Anti Ca Res 16). Therapy reverses R to key drugs, improves the pts' many immune functions and exposure to neoantigens, (Caraglia RT et al Front Oncol 19.) A.L.A.N.(AS) blood tests (Ts) predict chances of S (Salati et al EuJCa 18). Methods: Kaplan-Meier analyses examine prognostic Ts as El criteria for real-world pts. El included poor risk pts: any adult age, +/- R (-/+ prior test drugs). El: Intent to treat; consent; adv measurable IHBD; active progression (pg); Performance 0-2 and expected 6 wks S. The inE have 2ary CNS, require IVs; are unable to reach office, or have gr3-4 toxicity. GFLIO every 2 wks in mg/M2: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hrs; Leucovovorin 180 Irinotecan 80 and day (D)2, Oxaliplatin 40. On pg, drugs are added, none are discontinued: D2 docetaxel 20-25, -/+ Mitomycin C 4-6; on 2nd pg, D1 Cetuximab is added (KRAS wild), wkly, and replaced on 3rd pg with D1 bevacizumab 10 mg/kg every 2 wks. Baseline A.L.A.N. assays (AS) are in Salati ibid. Results: Survival of the 35 pts, 19 R, is: 84% at 1 yr and 64% (CI 50-78%) at 2 yrs, median S CI 22.5 - > 24 mos; S at 12, 18 and 24 mos: with no unfavorable (UF) AS0 Ts (12 pts), is 100, 100, and 90%; with 1-2 UF Ts (15pts), is 76, 66 and 66% (CI > 56%). With 3-4 UF Ts (8 pts) S is 67, 34, and 13%. The old, 14 > 70, and young S similarly (̃); 4/4 > 75 S in remission for > 2 yr. p. 0.36, HR 1.68. Pts, 19R/16 - prior therapy, S similarlỹ, p 0.96, HR 1.03; both groups have similar ̃ Ts AS. Females, 17, and males, in spite of a cluster with UF AS 3-4, have similar ̃ S, p 0.6, HR 1.4. GFLIO induction produced neither hospitalizations, neutropenic fevers nor severe neuropathy and no initial need for prophylactic or high dose granulocyte factors. Favorable (Fav) Ts include: low < 3.1 neutrophile-lymphocyte ratio, 57%of pts, 81% S 2yr, p 0.005 HR 9.4; 2-4/4 fav ALAN Ts, 77% of pts,78% S 2 yr, p 0.007, hr 6.3; low < 300,000 platelets 71%, 80% S 2 yr, p 0.01, HR 1.7, and high > 3.5 albumin,74% of pts,72% S 2yr, p 0.03, HR 3.9. Groups defined by single UF Ts (except low albumin, 33% S 2 yr) S > ̃ 50% at 2 yr. Conclusions: A real world, safe, survival of > 2yr, is confirmed in this 3rd series. This meets NCI criteria for: selective use, and development of GFLIO's elements (lowest effective dosages and sequential regimens), and prognostic tests (criteria and models). Therapy can, in theory, correct UF T's - pathology. When matched for AScore, GFLIO is ̃ effective, -/+, R and at all ages. Tests and GFLIO can change practice, improve El and survival for under treated pts, some half of all pts, the aged and the Resistant, told they have "only 6 or 12 mos to live." Clinical trial information: NCT01905150.

Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction

Worldwide, colorectal cancer (CRC) is a deadly disease whose death rate ranks second among cancers though its incidence ranks third. Early CRC detection is key and is associated with improved survival outcomes. However, existing tests for CRC diagnosis have several weaknesses thus rendering them inefficient. Moreover, reliable prognostic tests that can predict the overall cancer outcome and recurrence of the disease as well as predictive markers that can assess effectiveness of therapy are still lacking. Thus, shifting to noninvasive liquid biopsy or blood-based biomarkers is vital to improving CRC diagnosis, prognosis, and prediction. Methylated circulating tumor DNA (ctDNA) has gained increased attention as a type of liquid biopsy that is tumor-derived fragmented DNA with epigenetic alterations. Methylated ctDNA are more consistently present in blood of cancer patients as compared to mutated ctDNA. Hence, methylated ctDNA serves as a potential biomarker for CRC that is worth investigating. In this review, we explore what has been reported about methylated ctDNA as a biomarker for CRC diagnosis that can distinguish between CRC patients or those having adenoma and healthy controls as validated specifically through ROC curves. We also examine methylated ctDNA as a biomarker for CRC prognosis and prediction as confirmed through robust statistical analyses. Finally, we discuss the major technical challenges that limits the use of methylated ctDNA for clinical application and suggest possible recommendations to enhance its usage.