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Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection
Various recent studies have focused on analyzing tumor genetic material released into the blood stream, known as circulating tumor DNA (ctDNA). Herein, we describe current research on the application of ctDNA to cancer management, including prognosis determination, monitoring for treatment efficacy/relapse, treatment selection, and quantification of tumor size and disease burden. Specifically, we examine the utility of ctDNA for early cancer diagnostics focusing on the development of a blood test to detect cancer in asymptomatic individuals by sequencing and analyzing mutations in ctDNA. Next, we discuss the prospect of using ctDNA to test for cancer, and present our calculations based on previously published empirical findings in cancer and prenatal diagnostics. We show that very early stage (asymptomatic) tumors are not likely to release enough ctDNA to be detectable in a typical blood draw of 10 mL. Data are also presented showing that mutations in circulating free DNA can be found in healthy individuals and will likely be very difficult to distinguish from those associated with cancer.We conclude that the ctDNA test, in addition to its high cost and complexity, will likely suffer from the same issues of low sensitivity and specificity as traditional biomarkers when applied to population screening and early (asymptomatic) cancer diagnosis.
Journal Article
The unique characteristics of COVID-19 coagulopathy
Thrombotic complications and coagulopathy frequently occur in COVID-19. However, the characteristics of COVID-19-associated coagulopathy (CAC) are distinct from those seen with bacterial sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC), with CAC usually showing increased D-dimer and fibrinogen levels but initially minimal abnormalities in prothrombin time and platelet count. Venous thromboembolism and arterial thrombosis are more frequent in CAC compared to SIC/DIC. Clinical and laboratory features of CAC overlap somewhat with a hemophagocytic syndrome, antiphospholipid syndrome, and thrombotic microangiopathy. We summarize the key characteristics of representative coagulopathies, discussing similarities and differences so as to define the unique character of CAC.
Journal Article
Next generation viscoelasticity assays in cardiothoracic surgery: Feasibility of the TEG6s system
Viscoelastic near-patient assays of global hemostasis have been found useful and cost-effective in perioperative settings. Shortcomings of current systems include substantial laboratory intensity, user-dependent reproducibility, relatively large sample volumes, sensitivity to ambient vibration and limited comparability between techniques and devices. The aim of this study was to assess feasibility of a new, resonance-based viscoelastic whole blood methodology (TEG6s) in cardiac surgery with cardiopulmonary bypass (CPB) and to compare the parameters this system produces with the ROTEM delta system and standard coagulation tests.
In a prospective evaluation study, twenty-three consecutive cardiac surgery patients underwent hemostasis management according to current guidelines, using the ROTEM delta system and standard coagulation tests. Blood samples were collected prior to CPB before anesthetic induction (pre-CPB), during CPB on rewarming (CPB), and 10 minutes after heparin reversal with protamine (post-CPB). ROTEM and standard coagulation test results were compared with TEG6s parameters, which were concurrently determined using its multi-channel microfluidic cartridge system.
TEG6s provided quantifiable results pre-CPB and post-CPB, but only R (clotting time) of CKH (kaolin with heparinase) was measurable during CPB (full heparinization). Spearman's correlation coefficient (rs) was 0.78 for fibrinogen levels and MA CFF (functional fibrinogen). Correlation of several TEG6s parameters was good (0.77 to 0.91) with MCF FIBTEM, and poor (<0.56) with prothrombin time and activated partial thromboplastin time (<0.44). Rs with platelet count was moderate (0.70, MA CK; 0.73, MA CRT). Accuracy of MA CFF for detection of fibrinogen deficiency < 1.5 g/L was high (ROC-AUC 0.93).
The TEG6s system, which is based on resonance viscoelastic methodology, appears to be feasible for POC hemostasis assessment in cardiac surgery. Its correlations with standard coagulation parameters are quite similar to those of ROTEM and there is good diagnostic accuracy for fibrinogen levels lower than 1.5 g/L. During full heparinization, TEG6s testing is limited to R measurement. Larger studies are needed to assess superiority over other POC systems.
Journal Article
Can we predict the prognosis of COPD with a routine blood test?
The major characteristic of COPD is systemic inflammation. The parameters such as neutrophil-to-lymphocyte ratio (NLR) and eosinophil-to-basophil ratio (EBR) in routine blood test (RBT) are considered to be the underlying biomarkers of inflammation. We hypothesized that the prognosis of patients with COPD can be predicted with RBT.
Patients with COPD in stable stage were enrolled. The RBT, pulmonary function testing (PFT), BODE index, C-reactive protein (CRP), procalcitonin, and erythrocyte sedimentation rate (ESR) were performed at enrollment and every follow-up once in every 3 months during the 24-month follow-up period. Meanwhile, exacerbation count and mortality incidence were recorded. The correlation between the prognostic biomarkers and the prognosis of patients was analyzed.
The NLR and EBR in RBT have a significant correlation with the severity of patients with COPD. The NLR is an independent predictor for mortality and the EBR is an independent predictor for exacerbation.
As an inexpensive, accessible, and convenient assay, RBT may be used as a practical means in the prediction of prognosis of patients with COPD in future clinical settings.
Journal Article
The Association between Blood Test Trends and Undiagnosed Cancer: A Systematic Review and Critical Appraisal
Clinical guidelines include monitoring blood test abnormalities to identify patients at increased risk of undiagnosed cancer. Noting blood test changes over time may improve cancer risk stratification by considering a patient's individual baseline and important changes within the normal range. We aimed to review the published literature to understand the association between blood test trends and undiagnosed cancer. MEDLINE and EMBASE were searched until 15 May 2023 for studies assessing the association between blood test trends and undiagnosed cancer. We used descriptive summaries and narratively synthesised studies. We included 29 articles. Common blood tests were haemoglobin (24%, n = 7), C-reactive protein (17%, n = 5), and fasting blood glucose (17%, n = 5), and common cancers were pancreatic (29%, n = 8) and colorectal (17%, n = 5). Of the 30 blood tests studied, an increasing trend in eight (27%) was associated with eight cancer types, and a decreasing trend in 17 (57%) with 10 cancer types. No association was reported between trends in 11 (37%) tests and breast, bile duct, glioma, haematological combined, liver, prostate, or thyroid cancers. Our review highlights trends in blood tests that could facilitate the identification of individuals at increased risk of undiagnosed cancer. For most possible combinations of tests and cancers, there was limited or no evidence.
Journal Article
Epidemiology of diabetes mellitus, pre-diabetes, undiagnosed and uncontrolled diabetes in Central Iran: results from Yazd health study
Over the past few decades, the prevalence of Diabetes Mellitus (DM) has risen rapidly in Iran and other low and middle-income countries. We investigated the prevalence of DM, pre-diabetes, undiagnosed and uncontrolled diabetes and its relationship with some associated socioeconomic factors in the Yazd Greater Area in Iran.
Yazd Health Study is a longitudinal study conducted to determine the prevalence of non-communicable disease and related risk factors. In a two-step cluster sampling, 10,000 adults aged 20-69 years (200 clusters) were selected. In the recruitment phase, DM was considered if the patients had been either diagnosed DM by a physician or had fasting blood glucose ≥ 126 mg/dL. Chi square test was used for categorical variables to evaluate the differences and logistic regression model was applied to determine the predictors of diabetes.. P-value < 0.05 considered statistically significant.
Of the 9965 individuals recruited, the crude self-reported prevalence of DM was 14.1% (95% CI: 13.4-14.7). The prevalence was higher in women than men (15.6 vs.12.4%), significantly. The age-standardized prevalence of DM was 8%. The prevalence was 14.9% in Yazd local people and 8.6% in those residents migrated from other provinces (P < 0.0001). We showed a significant association between DM prevalence and age, education, marital status, unemployment, insurance status, and positive family history (P < 0.0001). The prevalence of DM diagnosed by phycisians was 16.1% in participants (age-standardized prevalence: 8.3%). The subset analysis showed that 4.8% of patients were not aware of their disease. The prevalence of pre-diabetes was 25.8%. Of those with diabetes, 58.3% were not adequately controlled, which is not statistically significant with socio-economic status.
The current study showed a high prevalence of DM in Yazd Greater Area which is closely related to some socio-demographic factors. The high prevalence of pre-diabetes is alarming. Effective strategies for DM prevention should be introduced. The majority of people with diabetes are aware, but half of them are not controlled. The ineffective care plan currently in use, should be reviewed. Patients needs to be encouraged to improve their lifestyle. Active follow-up of patients is recommended to ensure continuity of care.
Journal Article
Analysis of Thrombophilia Test Ordering Practices at an Academic Center: A Proposal for Appropriate Testing to Reduce Harm and Cost
Ideally, thrombophilia testing should be tailored to the type of thrombotic event without the influence of anticoagulation therapy or acute phase effects which can give false positive results that may result in long term anticoagulation. However, thrombophilia testing is often performed routinely in unselected patients. We analyzed all consecutive thrombophilia testing orders during the months of October and November 2009 at an academic teaching institution. Information was extracted from electronic medical records for the following: indication, timing, comprehensiveness of tests, anticoagulation therapy at the time of testing, and confirmatory repeat testing, if any. Based on the findings of this analysis, we established local guidelines in May 2013 for appropriate thrombophilia testing, primarily to prevent testing during the acute thrombotic event or while the patient is on anticoagulation. We then evaluated ordering practices 22 months after guideline implementation. One hundred seventy-three patients were included in the study. Only 34% (58/173) had appropriate indications (unprovoked venous or arterial thrombosis or pregnancy losses). 51% (61/119) with an index clinical event were tested within one week of the event. Although 46% (79/173) were found to have abnormal results, only 46% of these had the abnormal tests repeated for confirmation with 54% potentially carrying a wrong diagnosis with long term anticoagulation. Twenty-two months after guideline implementation, there was an 84% reduction in ordered tests. Thus, this study revealed that a significant proportion of thrombophilia testing was inappropriately performed. We implemented local guidelines for thrombophilia testing for clinicians, resulting in a reduction in healthcare costs and improved patient care.
Journal Article
The influence of blood on the human gut microbiome
Colorectal cancer (CRC) is one of the prevailing causes of cancer mortality in the world. A common screening test for CRC is based on the human hemoglobin immunochemical based fecal occult blood test (iFOBT), which consists in the detection of blood in the patient's stool. In addition to iFOBT, recent studies support the use of the gut microbiome as a biomarker for CRC prediction. However, these studies did not take into account the effect of blood itself on the microbiome composition, independently of CRC. Therefore, we investigated the microbiome of patients undergoing the iFOBT screening in order to determine the effect of blood alone. Our cohort consisted of patients who had no blood in their stools (n = 265) or did have blood but no underlying precancerous or cancerous lesions (n = 235). We also identified bacterial taxa specifically associated with the presence of blood in stools.
We observed significant differences in the intestinal bacterial composition that could be solely caused by the presence of blood in stools. More precisely, we identified 12 bacterial species showing significant differences in abundance between both our study groups. These species, Bacteroides uniformis, Collinsella aerofaciens, Eggerthella lenta and Clostridium symbiosum demonstrated increased abundance in the presence of blood. In contrast, the species Prevotella copri, Coprococcus eutactus and catus, Faecalibacterium prausnitzii, Roseburia faecis, Blautia obeum, Gemmiger formicilis and Clostridium celatum showed decreased abundance in patients with blood in their stools. Notably, we found multiple taxa that were reported in previous studies linking microbiome composition and diseases.
We show that, in the absence of disease, blood in the stools has a major influence on the composition of the microbiome. Our data suggest that blood itself should be taken into consideration when investigating the microbiome signatures of intestinal diseases.
Journal Article
Are Type and Screen Samples Routinely Necessary Before Laparoscopic Cholecystectomy?
Aims
Type and screen (T&S) samples are routinely requested before all laparoscopic cholecystectomies (LCs) at our centre despite the low reported risk of major vascular injury and peri-operative transfusion. Our retrospective case series aimed to identify local transfusion need to inform policy.
Methods
Emergency and elective LC performed at a single tertiary centre between March 2014 and October 2016 (30 months) were analysed. This included all patients aged ≥ 16, and procedures converted to open where LC was the primary procedure. Peri-operative complications and transfusion data were obtained from electronic records.
Results
In total, 1002 consecutive patients met inclusion criteria; 12 patients were transfused during index admission (1.20%). No patients required emergency transfusion or had major vascular injuries. Despite local policy, 106 patients (10.6%) did not have a valid T&S sample prior to their procedure. Transfused patients were more likely to be emergency admissions (
n
= 10/12). The most common indications for transfusion were pre-operative anaemia (
n
= 7/12) and septic coagulopathy (
n
= 2/12).
Conclusions
Peri-operative transfusions at our centre were low. No patients required intra-operative blood transfusions dependent on a pre-operative T&S sample. Patients requiring transfusion were predictable from their pre-operative clinical status. We propose that a highly selective T&S policy is safe and can reduce costs.
Journal Article