Blood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to ...everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort.
All patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 p-tau181, glial fibrillary acidic protein GFAP, neurofilament light chain NfL, total tau t-tau, and ubiquitin C-terminal hydrolase L1 UCH-L1) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included.
Three hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value.
Plasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics.
This study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.
Plasma biomarkers have emerged as promising tools for identifying amyloid beta (Aβ) pathology. Before implementation in routine clinical practice, confounding factors modifying their concentration ...beyond neurodegenerative diseases should be identified. We studied the association of a comprehensive list of demographics, comorbidities, medication and laboratory parameters with plasma p-tau181, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) on a prospective memory clinic cohort and studied their impact on diagnostic accuracy for discriminating CSF/amyloid PET-defined Aβ status. Three hundred sixty patients (mean age 66.5 years, 55% females, 53% Aβ positive) were included. Sex, age and Aβ status-adjusted models showed that only estimated glomerular filtration rate (eGFR, standardized β −0.115 −0.192 to −0.035,
p
= 0.005) was associated with p-tau181 levels, although with a much smaller effect than Aβ status (0.685 0.607–0.763,
p
< 0.001). Age, sex, body mass index (BMI), Charlson comorbidity index (CCI) and eGFR significantly modified GFAP concentration. Age, blood volume (BV) and eGFR were associated with NfL levels. p-tau181 predicted Aβ status with 87% sensitivity and specificity with no relevant increase in diagnostic performance by adding any of the confounding factors. Using two cut-offs, plasma p-tau181 could have spared 62% of amyloid-PET/CSF testing. Excluding patients with chronic kidney disease did not change the proposed cut-offs nor the diagnostic performance. In conclusion, in a memory clinic cohort, age, sex, eGFR, BMI, BV and CCI slightly modified plasma p-tau181, GFAP and NfL concentrations but their impact on the diagnostic accuracy of plasma biomarkers for Aβ status discrimination was minimal.
Gerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such ...as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS.
We evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain 18F-FDG-PET.
Two patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed.
In contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS.
•Gerstmann-Sträussler-Scheinker shows normal sleep stages•Sleep alterations in Gerstmann-Sträussler-Scheinker are non-specific•Further description of sleep findings and correlation with neuropathology are warranted
Approximately 10% of patients are unable to synthesize CA 19.9 (Lewis-negative), and these results are erroneously considered false-negatives. The aim of this study was to confirm that CA 19.9 cannot ...be detected by immunoassays in Lewis-negative patients.
CA 19.9 levels were measured by immunological assays and Lewis phenotype was determined by the haemagglutination reaction.
Patients with Lewis phenotype (a+b-) or (a-b+) had significantly higher CA 19.9 levels than Lewis-negative patients with active cancer (p<0.001), no-evidence of disease (NED) patients (p<0.001) or patients with benign disease (p<0.001). Ninenty-four percent of patients (33/35) with undetectable CA 19.9 had a Lewis-negative phenotype. Additionally, 94.7% (34/36) of patients with Lewis-negative phenotypes had undetectable CA 19.9 serum levels.
Patients with undetectable CA 19.9 serum levels tend to be Lewis-negative, and CA 19.9 is not useful in diagnosis or follow-up.
Abstract
Background and study aims
Colorectal cancer (CRC) risk after a positive fecal immunochemical test (FIT) and negative colonoscopy is unknown. We aimed to ascertain the cumulative incidence ...of post-colonoscopy colorectal cancer (PCCRC) and the manifestation of other lesions that could explain the test positivity in individuals with a negative colonoscopy in a population screening program.
Patients and method
Observational study in participants from the first round of a CRC screening program (2010 – 2012) with positive-FIT (≥ 20 μg/g of feces) and negative colonoscopy (without neoplasia). A 42- to 76-month follow-up was performed searching in the National Health Service database and by a brief structured telephonic interview.
Results
Of 2659 FIT-positive individuals who underwent colonoscopy, 811 (30.5 %) had a negative colonoscopy. Three PCCRC (0.4 %) were detected within 11 – 28 months and accelerated carcinogenesis was ruled out. Among those with normal colonoscopy, 32 (5 %) relevant lesions were detected at follow-up. One-third of them (11/32) were significant neoplasias: a gastric cancer, a small-bowel lymphoma, six advanced colorectal adenomas, and the three PCCRC. The 21 remaining lesions were inflammatory, vascular disorders, or non-advanced colorectal adenomas.
Conclusions
The vast majority (95 %) of individuals did not present any subsequent lesion that could explain the FIT positivity. The very low incidence (0.4 %) and characteristics of PCCRC observed in our cohort reinforce the concept that, although a positive FIT preselects high risk individuals, a high quality colonoscopy is the paramount factor in preventing PCCRC. Improving quality standards of colonoscopy are required to strengthen the current CRC screening strategies.
We have previously identified six serum tumor markers (TMs) (carcinoembryonic antigen, carbohydrate antigen 15.3, squamous cell carcinoma-associated antigen, cytokeratin-19 fragment, neuron-specific ...enolase, and pro-gastrin-releasing peptide) related to the presence of lung cancer (LC).
To validate their individual performance in an independent cohort, and to explore if their combined assessment (≥1 abnormal TM value) is a more accurate marker for LC presence.
We determined these six TMs in 3,144 consecutive individuals referred to our institution by their primary care physician because of the clinical suspicion of LC.
LC was excluded in 1,316 individuals and confirmed in 1,828 patients (1,563 with non-small cell LC and 265 with small cell LC). This study validated the previously reported performance of each individual TM. We also showed that their combined assessment (≥1 abnormal TM) had a better sensitivity, specificity, negative predictive value, and positive predictive value (88.5, 82, 83.7, and 87.3%, respectively) than each TM considered individually and that it increased the diagnostic performance (area under the curve) of a clinical model that included tumor size, age, and smoking status. In patients with radiographic nodules less than 3 cm, the negative predictive value of the TM panel was 71.8%, hence providing some support for a more conservative diagnostic approach. Finally we identified two TMs (neuron-specific enolase and pro-gastrin-releasing peptide) that differentiate the risk of non-small cell LC from that of small cell LC.
The combined assessment of a panel of six serum TMs is a more accurate marker for LC presence than these same TMs considered individually. The potential of these TMs in the diagnostic and screening settings deserves further research.
Serrated polyposis syndrome (SPS) is a high risk condition for colorectal cancer (CRC). Surveillance strategies for patients with serrated lesions remain controversial. We aimed to evaluate a ...diagnostic strategy to detect SPS consistently during reassessment colonoscopy in patients with proximal serrated lesions.
This was a retrospective study of all individuals from a fecal immunochemical test (FIT)-based CRC screening program (2010 - 2013) with one or more serrated lesions of ≥ 5 mm proximal to the sigmoid colon on baseline colonoscopy. We analyzed all individuals empirically scheduled for a reassessment colonoscopy aimed at diagnosing SPS within 1 year. Reassessment colonoscopy was performed with standard white-light or chromoendoscopy ± high definition endoscopy depending on availability. SPS diagnosis was based on the cumulative number of polyps in both the baseline and reassessment colonoscopies. Factors associated with SPS diagnosis were analyzed.
From 3444 screening colonoscopies, 196 patients met the study entry criteria, of whom 11 patients (0.32 %) met the criteria for SPS on baseline colonoscopy. Reassessment colonoscopies were performed in 71 patients at 11.9 ± 1.7 months and detected 20 additional patients with SPS, a tripling of the rate of SPS up to 0.90 %. Independent factors associated with SPS diagnosis were: having five or more proximal serrated lesions (odds ratio OR 4.01 95 % confidence interval 1.20 - 13.45;
0.02) or two or more sessile serrated polyps ≥ 10 mm (OR 6.35 1.40 - 28.81;
0.02) on baseline colonoscopy and the use of chromoendoscopy ± high definition endoscopy during reassessment colonoscopy (OR 4.99 1.11 - 22.36;
0.04).
A 1-year reassessment colonoscopy using chromoendoscopy and high definition endoscopes substantially improves SPS detection in individuals from a FIT-based screening program with proximal serrated lesions. Five or more proximal serrated lesions or two or more sessile serrated polyps ≥ 10 mm could be thresholds for requiring a reassessment colonoscopy. Prospective studies are required to validate these results and adjust surveillance recommendations in patients with serrated lesions.
Prostate health index (phi), a measure calculated as p2PSA/fPSA×√tPSA, has shown valuable results in the detection of prostate cancer (PCa), improving the prediction of the aggressiveness of the ...tumor. The aim of our study was to test whether prostate volume influences phi performance using univariate and multivariate models. 220 patients with PSA<10μg/L (102 with negative biopsy and 118 with PCa) were included in the study. Serum concentrations of tPSA, fPSA and p2PSA were measured on Access2 analyzer. The higher accuracy was found for phi, obtaining an AUC of 0.748. Bigger AUCs were obtained for phi, %p2PSA, %fPSA and tPSA in patients with small prostate volume (≤35cc); meanwhile, the lowest AUCs were found in patients with large prostate volume (>50cc). Including phi and %p2PSA in a multivariable analysis based on patient age, prostate volume, tPSA, and %fPSA accuracy increased from 0.762 to 0.802 (logistic regression model) or 0.815 (artificial neural network). Accuracy excluding prostate volume in these models was 0.762 and 0.775, respectively. The inclusion of phi and %p2PSA in a multivariate model identifies better men with PCa. Prostate volume remains a key factor in the interpretation of biomarkers used to detect PCa.
•Accuracy of prostate health index is higher than the accuracy of total PSA.•Phi is an accurate test for the detection of prostate cancer, specially when prostate volume is small.•Prostate volume is a key factor in the interpretation of prostate health index.
A new approach to prostate cancer screening Filella, Xavier; González, Álvaro; Augé, Josep Maria ...
Advances in laboratory medicine,
09/2023, Letnik:
4, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Prostate cancer screening based on prostate-specific antigen (PSA) testing has been a matter of controversy. Although screening for prostate cancer was effective in reducing mortality, it resulted in ...overdiagnosis, which translated into unnecessary treatments and numerous adverse effects. As a result, recommendations from scientific societies became increasingly restrictive. In the recent years, new approaches to prostate cancer screening have been proposed. These new approaches are aimed at solving the controversy between widespread screening vs. no screening, and reconsidering PSA testing as a screening tool with a good benefit/risk balance. In this context, the European Association of Urology submitted a proposal to the European Commission for prostate cancer screening to be performed as a function of baseline PSA concentrations. The European Commission recently recommended the implementation of organized prostate cancer screening programs for men aged ≤70 years based on PSA values in combination with follow-up magnetic resonance imaging.