Prospective Study Of Biomarkers Research Articles

Triple combination of vemurafenib, cobimetinib, and atezolizumab in real clinical practice in the Russian Federation: results of the A1 cohort of the ISABELLA study.

Among several treatment options for BRAF-mutant metastatic melanoma, a combination of BRAF inhibitor, MEK inhibitor, and anti-PDL1 antibody seems to be a new emergent approach recently registered in the Russian Federation. It is still not clear which patient population benefits more from this simultaneous use of three drugs instead of its sequencing. This study aimed to evaluate patients' characteristics treated in real practice in 14 Russian regions by triple combination and to analyze their outcomes depending on biomarkers (PD-L1 expression). This was a part (cohort A1) of a prospective non-interventional study of clinical outcomes and biomarkers in patients with skin melanoma. Patients were included in cohort A1 if combination treatment with vemurafenib (vem) + cobimetinib (cobi) + atezolizumab (atezo) was initiated no earlier than 12 weeks (84 days) prior to written informed consent to participate in this study. The index event was the initiation of therapy with all three drugs vem + cobi + atezo (i.e., triple combination). The primary efficacy endpoint of the study was the 24-month overall survival (OS), defined as the time from the index date to the date of death from any cause. If the patient did not experience an event, the OS will be censored at the date of the last contact. Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in the Intention to treat (ITT) population, in biomarker positive population, and in population with brain metastases were also evaluated. Quality of life questionnaires were pre-planned by protocol if it was a part of routine practice. Adverse events were also collected. Between March 2021 and May 2023, 59 patients were enrolled in 19 centers from 14 regions of Russia. Thirty-one of 59 (52.4%) patients had central nervous system metastases, and 18 of 31 (58.4%) were symptomatic. Forty of 59 patients (68%) received the triple combination as the first-line treatment. The median follow-up period was 16.83 [95% confidence interval (CI) 13.8-19.8] months. The mean duration of therapy with this regimen was 9.95 months (95% CI 7.48-13.8). ORR was 55.1%; progression as the best outcome was seen in 16.3%. The median DoR was 12.95 months (95% CI 11.0-14.8 months), with a median of 20.3 months (95% CI 9.1-31.5 months) when triple therapy was administered in the first-line treatment. In patients with brain metastases (N = 31), ORR was 45.1%; the median DoR was 12.95 (95% CI 11.0-14.8 months). The median PFS in the entire population was 13.6 months (95% CI 8.6-18.6); the 24-month PFS was 22%. The estimated median OS in the entire population was 15.8 months (95% CI NA); 24-month OS was 45% (95% CI 0.32-0.64). In multivariate Cox regression model, biomarkers of interest [lactate dehydrogenase, Programmed cell death ligand-1 (PD-L1)] did not have statistically significant impact on PFS, OS, or DoR probably due to high data missing rate. No unexpected adverse events were reported. Grades 3-4 AEs were seen in 23 of 59 patients (38%) with most common were skin and liver toxicity. Triple combination of atezolizumab, vemurafenib, and cobimetinib had proven its efficacy and tolerability in real settings. No impact of potential predictive biomarkers was seen (NCT05402059).

A prospective study of MRI biomarkers in the brain and lower limb muscles for prediction of lower limb motor recovery following stroke.

The aim of this prospective observational longitudinal study was to explore and decipher the predictive value of prospective MRI biomarkers in the brain and lower limb muscles for 3-month lower limb motor recovery following stroke. In the brain, we measured the integrity of the corticospinal tract (fractional anisotropy/"FA"). In the muscles, we measured volume, fatty replacement (fat fraction analysis and proton spectroscopy) and oedema. Measurements were taken at two time points: (1) within 4 weeks of stroke (baseline measurement, clinical and imaging) and (2) 3 months following stroke (follow up measurement, clinical only). Clinical measurements consisted of assessments of functional ability and strength (Fugl-Meyer score, motor NIHSS, Functional Ambulation Category/"FAC", and muscle dynamometry). Twenty-three patients completed imaging and clinical assessments at baseline and follow-up; five patients had partial imaging assessment. The results provided some evidence that damage to the corticospinal tract would result in less motor recovery: recovery of the Fugl-Meyer score and dynamometric ankle plantarflexion, ankle dorsiflexion, and knee extension correlated positively and significantly with fractional anisotropy (0.406-0.457; p = 0.034-p = 0.016). However, fractional anisotropy demonstrated a negative correlation with recovery of the Functional Ambulation Category (-0.359, p = 0.046). For the muscle imaging, significant inverse correlation was observed between vastus lateralis fat fraction vs. NIHSS recovery (-0.401, p = 0.04), and a strong positive correlation was observed between ratio of intra- to extra-myocellular lipid concentrations and the recovery of knee flexion (0.709, p = 0.007). This study supports previous literature indicating a positive correlation between the integrity of the corticospinal tract and motor recovery post-stroke, expanding the limited available literature describing this relationship specifically for the lower limb. However, recovery of functional ambulation behaved differently to other clinical recovery markers by demonstrating an inverse relationship with corticospinal tract integrity. The study also introduces some muscle imaging biomarkers as potentially valuable in the prediction of 3-month lower limb motor recovery following stroke.

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy

Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

Acute pancreatitis after pancreatoduodenectomy: A prospective study of diffusion-weighted magnetic resonance imaging, serum biomarkers, and clinical features

BackgroundPostpancreatectomy acute pancreatitis is challenging to diagnose and poorly characterized in its early phases. However, it represents the ideal target for novel therapeutic opportunities possibly gleaned from medical acute pancreatitis. This study aims to systematically investigate early radiologic, biochemical, and clinical features of postpancreatectomy acute pancreatitis. MethodsThis was a prospective observational study of patients undergoing pancreatoduodenectomy from September 2019 to January 2021. Diffusion-weighted magnetic resonance imaging was performed on postoperative day 3. Serum pancreatic amylase and lipase were assessed daily until postoperative day 5. Postoperative serum hyperamylasemia and postpancreatectomy acute pancreatitis were defined based on the International Study Group for Pancreatic Surgery definition. ResultsA total of 65 patients were enrolled according to the sample size calculation. Patients with postoperative serum hyperamylasemia and postpancreatectomy acute pancreatitis had significantly lower apparent diffusion coefficient values at diffusion-weighted magnetic resonance imaging but no macroscopic features consistent with acute pancreatitis. Subsequently, 21 patients (32.3%) underwent computed tomography imaging for clinical worsening, and 6 had radiologic features of acute pancreatitis. All these latter patients had postoperative serum hyperamylasemia and worse outcomes, characterized by local (postoperative pancreatic fistula: 83%) and systemic morbidity (sepsis: 66.7%). The postoperative serum hyperamylasemia incidence was 21.5% (n = 14), and postpancreatectomy acute pancreatitis occurred in 6 patients (9.2%), with 4 grade B (6.1%) and 2 grade C (3%). ConclusionPostpancreatectomy acute pancreatitis is characterized by early serum hyperamylasemia and hyperlipasemia. Although pancreatic changes may appear at postoperative day 3 diffusion-weighted magnetic resonance imaging, its standard use has no impact on postoperative management. Macroscopic radiologic features appear later and correlate with worse clinical scenarios. This paper paves the ground for including postpancreatectomy acute pancreatitis in the spectrum of acute pancreatitis, promoting the transfer of treatment strategies for acute pancreatitis into managing postpancreatectomy acute pancreatitis.

Acute pancreatitis following Pancreaticoduodenectomy: A prospective study of diffusion-weighted magnetic resonance imaging, serum biomarkers, and clinical features

Acute pancreatitis following Pancreaticoduodenectomy: A prospective study of diffusion-weighted magnetic resonance imaging, serum biomarkers, and clinical features

EP05.01-012 Avoiding Cardiac Toxicity in Lung Cancer Radiotherapy (ACcoLade) Trial - Initial Results

Increasing cardiac radiation dose is associated with worse survival and cardiac events following thoracic radiotherapy however, the mechanism of injury is unknown. High sensitivity cardiac troponin I (hsTnI) and N-terminal pro-B-type natriuretic peptide (NT pro-BNP) are established blood biomarkers of cardiac injury. Cardiac CT (CCT) is a non-invasive method of assessing coronary artery disease and echocardiography assesses cardiac structure and function. We present initial results of a prospective cohort study of cardiac blood and imaging biomarkers in patients undergoing lung cancer radiotherapy.

Menopausal Transition: Prospective Study of Estrogen Status, Circulating MicroRNAs, and Biomarkers of Bone Metabolism.

ObjectiveOsteoporosis is associated with an impaired balance between bone resorption and formation, which in turn leads to bone loss and fractures. Many recent studies have underlined the regulatory role of microRNAs (miRNAs) in bone remodeling processes and their potential as biomarkers of osteoporosis. The purpose of this study was to prospectively examine the association of circulating miRNAs and bone biomarkers with estrogen status in women before and after oophorectomy, as well as in oophorectomized women on estrogen therapy.MethodsIn this prospective study, we included 11 women before oophorectomy and hysterectomy and at 201 ± 24 days after the surgery. Another 11 women were evaluated 508 ± 127 days after oophorectomy and hysterectomy and after an additional 203 ± 71 days of estradiol treatment. Serum miRNAs were profiled by sequencing. Estrogen status and biomarkers of bone metabolism were quantified. Bone mineral density was assessed in the lumbar spine.ResultsOur analysis revealed 17 miRNAs associated with estrogen levels. Of those miRNAs that were upregulated with estrogen deficiency and downregulated after estrogen therapy, miR-422a correlated with serum beta-carboxy-terminal type I collagen crosslinks (β-CTX) and procollagen 1 N-terminal propeptide (P1NP); and miR-1278 correlated with serum β-CTX, P1NP, osteocalcin, sclerostin, and Dickkopf-1(Dkk1). In contrast, we found an inverse association of miR-24-1-5p with estrogen status and a negative correlation with serum β-CTX, P1NP, osteoprotegerin, and sclerostin levels.ConclusionThe reported miRNAs associated with estrogen status and bone metabolism could be potential biomarkers of bone pathophysiology and would facilitate studies on the prevention of postmenopausal osteoporosis. Our findings require validation in an extended cohort.

A signature of saliva-derived exosomal small RNAs as predicting biomarker for esophageal carcinoma: a multicenter prospective study

BackgroundThe tRNA-derived small RNAs (tsRNAs) are produced in a nuclease-dependent manner in responses to variety of stresses that are common in cancers. We focus on a cancer-enriched tsRNA signature to develop a salivary exosome-based non-invasive biomarker for human esophageal squamous cell carcinoma (ESCC).MethodsCancer-enriched small RNAs were identified by RNA sequencing of salivary exosomes obtained from ESCC patients (n = 3) and healthy controls (n = 3) in a pilot study and further validated in discovery cohort (n = 66). A multicenter prospective observational study was conducted in two ESCC high-incidence regions (n = 320 and 200, respectively) using the newly developed biomarker signature.ResultsThe tsRNA (tRNA-GlyGCC-5) and a previously undocumented small RNA were specifically enriched in salivary exosomes of ESCC patients, ESCC tissues and ESCC cells. The bi-signature composed of these small RNAs was able to discriminate ESCC patients from the controls with high sensitivity (90.50%) and specificity (94.20%). Based on the bi-signature Risk Score for Prognosis (RSP), patients with high-RSP have both shorter overall survival (OS) (HR 4.95, 95%CI 2.90–8.46) and progression-free survival (PFS) (HR 3.69, 95%CI 2.24–6.10) than those with low-RSP. In addition, adjuvant therapy improved OS (HR 0.47, 95%CI 0.29–0.77) and PFS (HR 0.36, 95%CI 0.21–0.62) only for patients with high but not low RSP. These findings are consistent in both training and validation cohort.ConclusionsThe tsRNA-based signature not only has the potential for diagnosis and prognosis but also may serve as a pre-operative biomarker to select patients who would benefit from adjuvant therapy.Trial registrationA prospective study of diagnosis biomarkers of esophageal squamous cell carcinoma, ChiCTR2000031507. Registered 3 April 2016 - Retrospectively registered.

BIOFACE: A prospective study of risk factors, cognition and biomarkers in a cohort of individuals with early‐onset mild cognitive impairment at Fundació ACE

AbstractBackgroundThe diagnosis of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) is based on either cerebrospinal fluid (CSF) or neuroimaging biomarkers (Albert et al, 2011). Currently, several non‐invasive and cheaper blood‐based biomarkers are being investigated, including neuronal‐derived plasma exosomes (NPEs) (Winston et al, 2016). The role of neuroinflammation, oxidative stress and early vascular changes, prior to the onset of amyloidosis, has been described in the pathogenesis of AD (Iturria‐Medina et al, 2016) and vascular‐related proteins can be traced in plasma and NPEs using proteomics. However, these changes have not been studied in early onset MCI (EOMCI), that is, when symptoms begin under the age of 65 (Rossor et al, 2010).ObjectiveTo describe the rationale, study design and baseline characteristics of the BIOFACE cohort, a two‐year prospective observational study on EOMCI conducted at Fundació ACE in Barcelona, Spain. The study goal is to characterize different clinical, neuropsychological and biomarker phenotypes and to investigate CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD.MethodParticipants underwent neurological and neuropsychological batteries and multimodal biomarkers including brain MRI, APOE genotyping, plasma and NPEs, saliva, CSF, non‐invasive arterial peripheral testing, anthropometrics and neuro‐ophthalmological examinations. In the final visit, participants will undergo brain MRI, lumbar puncture and blood extraction for NPEs.ResultNinety‐seven patients with EOMCI were recruited. Most participants were women (59.8%). Mean age at symptom onset was 57 years; mean MMSE score was 28 with a mean of 12.13 years of education. First degree and presenile family history of dementia was present in 60.8% and 15.5%, respectively. Depressive and anxiety disorders, along with vascular risk factors, were the most frequent comorbidities. Syndromic diagnoses were established: possible amnestic MCI (n=32), possible non‐amnestic MCI (n=33), probable amnestic MCI (n=16) and probable non amnestic MCI (n=16). CSF biomarkers (ATN classification): A+ (n=15), A‐T/N+ (n=13), A‐T‐N‐ (n=57).ConclusionBIOFACE is a two‐year observational study of cognition and biomarkers that will shed light on the physiopathology and the potential utility of plasma proteomics and NPEs as non‐invasive early diagnostic and prognostic biomarkers in individuals with early onset MCI.

BIOFACE: A Prospective Study of Risk Factors, Cognition, and Biomarkers in a Cohort of Individuals with Early-Onset Mild Cognitive Impairment. Study Rationale and Research Protocols.

Background:Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI).Objective:To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD.Methods:Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations.Results:Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile.Conclusion:BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years.

A prospective study of inflammatory biomarkers and growth factors and risk of glioma in the UK Biobank

PurposeThe role of growth factors and inflammation in the onset of glioma is poorly understood, and conflicting reports of associations of circulating IGF-1 and inflammatory biomarkers with glioma risk exist in the literature. We examined associations between C-reactive protein (CRP), white blood cell count (WBC), neutrophil-to-lymphocyte ratio (NLR), and insulin-like growth factor-1 (IGF-1) and glioma risk in the UK Biobank cohort. MethodsHazard ratios (HR) and 95% confidence intervals (CI) for glioma according to circulating biomarkers concentrations were calculated using Cox proportional hazards regression, adjusted for age, sex, race, and education. Analyses were conducted separately for glioma overall and by glioma subtype. ResultsWe identified 417 incident glioma cases among 428,537 participants with 3,255,815 person-years of follow up. Weak, non-significant associations were observed with increasing levels of these biomarkers for risk of glioma overall or by glioma subtype. Among women only, IGF-1 in the highest quartile was positively associated with glioma risk compared to the lowest quartile (HR=1.64, 95%CI: 1.03–2.60, p-trend=0.08), as was NLR (HR=1.54, 95%CI: 1.00–2.39, p-trend=0.05). ConclusionIn this prospective cohort, we found no significant associations between the inflammatory biomarkers CRP and WBC and the development of glioma. NLR and IGF-1 were associated with risk in women, but not men. When considered with previous studies, further investigation of NLR and IGF-1 as markers of glioma risk appears warranted, particularly in women.

Association of IDO immune suppression with brain metastasis in non-small cell lung cancer.

e21215 Background: Indoleamine 2, 3-dioxygenase (IDO), a known immunoinhibitory enzyme, plays an important role on tumor metastasis through manipulation of host immune status. We have demonstrated that IDO level has prognostic value and low IDO level is associated with low risk of distant metastasis in patients with non-small cell lung cancer (NSCLC). However, the association between IDO immune status in patients with brain metastasis (BrM) is unknown. We hypothesized that the IDO1 activity are different in the NSCLC patients of various stages and in patients with or without BrM and the IDO mRNA expression in brain metastatic lesion differ from the primary tumor or metastasized regional lymph nodes. Methods: This was part of a prospective study of blood immune biomarkers for prognosis and prediction. Newly diagnosed or recurrent NSCLC patients were eligible. Blood samples were obtained before treatment start and plasma were used for the Kynurenine (Kyn) and tryptophan (Trp) measurement by the high-performance chromatography. Kyn and trp was detected with more than 95% re-productivity. IDO activity was defined as ratio of kyn/Trp. Student T-test and One-way anova were applied for group comparison. CI: confidence interval. P &lt; 0.05 was considered as statistical significance. The IDO cellular expression was analyzed by the http://ureca-singlecell.kr/ website tool using the GEO dataset GSE131907. Results: Between July 2019 and Dec 2020, a total of 121 patients with NSCLC were eligible. The mean concentration of Kyn was 1.69 uM in patients with stage IV (n = 60, CI: 1.38-2.00), compared with 1.57 in patients with stage I (n = 38, CI: 1.03-2.10), 1.63 in stage II (n = 13, CI: 1.03-2.23) and 2.01 in stage III (n = 10, CI: 0.72-3.30, mean = 2.01). The mean ratio of Kyn:Trp was 0.10 in stage IV (n = 60, CI: 0.07-0.12), compared with 0.13 in patients with stage I (n = 38, CI: 0.06-0.20), 0.15 in stage II (n = 13, CI: 0.03-0.29) and 0.15 in stage III (n = 10, CI: 0.12-0.29). In patients with stage IV, there was no significant difference in the kyn concentration in patients with BrM (n = 13) and those without BrM (n = 47) (mean: 1.74, CI: 0.47-2.41 v.s 2.03 mean: 1.12-3.08; p = 0.45). The IDO activity in the patients with BrM was not significantly different from that of patients without BrM (mean: 0.11, CI: 0.03-0.20 v.s mean: 0.13, CI: 0.08-0.17; p = 0.74). Interestingly, GEO dataset analysis of the IDO1 mRNA expressions in 44 patients showed enrichments in myeloid cells in primary lung cancer tumor, natural killer cells in metastasized lymph nodes, and B cells in brain metastatic lesion. Conclusions: This study demonstrated no significant differences in circulating IDO expressions in patients with brain metastasis but differential IDO patterns of cellular expression in brain metastasis from that of primary tumor in NSCLC patients. This finding suggests the need of new strategy of research for immune status in the brain metastatic process of non-small cell lung cancer.

One-Year Prospective Study of Plasma Biomarkers From CNS in Patients With Mild Traumatic Brain Injury.

Objective: To investigate the longitudinal evolution of three blood biomarkers: neurofilament light (NFL), glial fibrillary acidic protein (GFAP) and tau, in out-patients and hospitalized patients with mild traumatic brain injury (mTBI) compared to controls, along with their associations—in patients—with clinical injury characteristics and demographic variables, and ability to discriminate patients with mTBI from controls.Methods: A longitudinal observation study including 207 patients with mTBI, 84 age and sex-matched community controls (CCs) and 52 trauma controls (TCs). Blood samples were collected at 5 timepoints: acute (<24 h), 72 h (24–72 h post-injury), 2 weeks, 3 and 12 months. Injury-related, clinical and demographic variables were obtained at inclusion and brain MRI within 72 h.Results: Plasma GFAP and tau were most elevated acutely and NFL at 2 weeks and 3 months. The group of patients with mTBI and concurrent other somatic injuries (mTBI+) had the highest elevation in all biomarkers across time points, and were more likely to be victims of traffic accidents and violence. All biomarkers were positively associated with traumatic intracranial findings on MRI obtained within 72 h. Glial fibrillary acidic protein and NFL levels were associated with Glasgow Coma Scale (GCS) score and presence of other somatic injuries. Acute GFAP concentrations showed the highest discriminability between patients and controls with an Area Under the Curve (AUC) of 0.92. Acute tau and 2-week NFL concentrations showed moderate discriminability (AUC = 0.70 and AUC = 0.75, respectively). Tau showed high discriminability between mTBI+ and TCs (AUC = 0.80).Conclusions: The association of plasma NFL with traumatic intracranial MRI findings, together with its later peak, could reflect ongoing secondary injury or repair mechanisms, allowing for a protracted diagnostic time window. Patients experiencing both mTBI and other injuries appear to be a subgroup with greater neural injury, differing from both the mTBI without other injuries and from both control groups. Acute GFAP concentrations showed the highest discriminability between patients and controls, were highly associated with intracranial traumatic injury, and showed the largest elevations compared to controls at the acute timepoint, suggesting it to be the most clinically useful plasma biomarker of primary CNS injury in mTBI.

Coagulopathy and Venous Thromboembolic Events Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

BackgroundCoagulopathy after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is recognized but few details have been studied.ObjectivesThe aim of this study was to investigate changes in coagulation biomarkers and their predictive ability for venous thromboembolism (VTE).MethodsPatients undergoing CRS and HIPEC at Uppsala University Hospital, Sweden, from 2004 to 2014 were included in a prospective study of coagulation biomarkers. Prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), fibrinogen, antithrombin, D-dimer, and platelets were sampled on postoperative days 1, 2, 5, and 10. Logistic regression analysis was used to evaluate predictive capacity for coagulation-related complications.ResultsOverall, 380 patients were included (214 females, mean age 56 years); 38 patients had a history of thromboembolism and 57 were active smokers. Mean perioperative blood loss was 1228 mL and 231 (61%) received perioperative blood transfusions. PT-INR and APTT were elevated directly after surgery but returned to normal levels on postoperative day 5. Conversely, fibrinogen, platelet count, D-dimer, and antithrombin increased by postoperative day 5 and continued to increase up to day 10. There were 23 radiologically verified cases of VTE within 6 months. The multivariate analysis identified a completeness of cytoreduction score of 2–3 (p = 0.047) and day 2 D-dimer (p = 0.0082) as independent risk factors for postoperative VTE.ConclusionSignificant postoperative changes in coagulation biomarkers occur with dynamic changes over 10 days postoperatively. The incidence of symptomatic VTE was low. Residual tumor at completion of surgery and elevated D-dimer on day 2 were independent risk factors for postoperative VTE.

Unique diagnostic signatures of concussion in the saliva of male athletes: the Study of Concussion in Rugby Union through MicroRNAs (SCRUM)

ObjectiveTo investigate the role of salivary small non-coding RNAs (sncRNAs) in the diagnosis of sport-related concussion.MethodsSaliva was obtained from male professional players in the top two tiers of England’s elite...

Reverse Cardiac Remodeling and ARNI Therapy

To review reverse cardiac remodeling and guideline-directed medical and device therapy (GDMT) within the context of recent data on combined angiotensin receptor/neprilysin inhibitor (ARNI) therapy. Preliminary data suggested that ARNI therapy led to significant reversal of deleterious cardiac remodeling. More definitive data regarding impact of ARNI therapy on remodeling parameters are now available from two prospective trials, PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure) and EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction). Both studies demonstrated marked improvements in biomarker and echocardiographic parameters of reverse cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF). Much of the observed clinical benefit of sacubitril/valsartan therapy in patients with HFrEF is likely related to significant reverse cardiac remodeling. Ongoing trials will assess the role for ARNI therapy in patients with heart failure with preserved ejection fraction (HFpEF) and in the post-myocardial infarction setting. Future studies should comprehensively assess predictors of response to ARNI therapy.

A Prospective Cohort Study of Biomarkers in Squamous Cell Carcinoma of the Anal Canal (SCCAC) and their Influence on Treatment Outcomes.

Background: Although Chemoradiation (CRT) is the curative treatment for SCCAC, many patients present primary resistance. Since it is a rare tumor, response predictors remain unknown.Methods: We performed a prospective cohort study to evaluate biomarkers associated with CRT response, progression-free survival (PFS), and overall survival (OS). The primary endpoint was response at 6 months (m). Tumor DNA and HPV were analyzed by next-generation sequencing, while KI-67 and PD-L1 by immunohistochemistry in tumor tissue.Results: Seventy-eight patients were recruited between October/2011 and December/2015, and 75 were response evaluable. The median age was 57 years, 65% (n=49) were stage III and 12% (n=9) were HIV positive (HIV+). At 6m, 62.7% (n=47) presented CR. On multivariate analyses, stage II patients were 4.7 more likely to achieve response than stage III (OR, 4.70; 95%CI, 1.36-16.30; p=0.015). HIV+ was associated with a worse response (OR, 5.72; 95%CI, 2.5-13.0; p<0.001). 5-year PFS and OS rates were 63.3% and 76.4%, respectively, with a median follow up of 66m. On multivariate analyses, older age (HR 1.06, p=0.022, 95%IC 1.01-1.11) and absence of CR at 6m (HR 3.36, p=0.007, 95%IC 1.39-8.09) were associated with inferior OS. The 5-year OS rate was 62.5% in HIV+ group compared to 78% among HIV- pts, although this difference was not statistically significant (p=0.4). PIK3CA, MET and TP53 mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS.Conclusions: Clinical stage III and HIV+ were associated with worse response to CRT at 6m. The absence of CR was the main factor associated with poor 5-year OS.

Prospective validation study of prognostic biomarkers to predict adverse outcomes in patients with COVID-19: a study protocol

IntroductionAccurate triage is an important first step to effectively manage the clinical treatment of severe cases in a pandemic outbreak. In the current COVID-19 global pandemic, there is a lack...

Reverse Cardiac Remodeling Following Initiation of Sacubitril/Valsartan in Patients With Heart Failure With and Without Diabetes

ObjectiveThis study sought to determine whether patients with heart failure and reduced ejection fraction (HFrEF) with type 2 diabetes mellitus (T2DM) have similar reverse cardiac remodeling with sacubitril/valsartan as patients without T2DM. BackgroundSacubitril/valsartan promotes reverse cardiac remodeling and improves outcomes in patients with HFrEF. Patients with HFrEF with T2DM have worse prognosis than those without T2DM. MethodsIn this post hoc analysis of PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure), we examined changes in N-terminal pro–b-type natriuretic peptide (NT-proBNP), measures of cardiac remodeling, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores from baseline to 12 months following initiation of sacubitril/valsartan between patients with HFrEF with and without T2DM. Using latent growth curve modeling, we evaluated the longitudinal association between changes in NT-proBNP, left ventricular ejection fraction, and KCCQ-OS. ResultsAmong 794 patients enrolled, 361 (45.5%) had T2DM. NT-proBNP concentrations were modestly higher at baseline among patients with T2DM but were reduced after initiation of sacubitril/valsartan. Cross-sectional improvement was observed in left ventricular ejection fraction (T2DM: 28.3% at baseline and 37% at 12 months vs. non-T2DM: 28.1% at baseline and 38.3% at 12 months) and KCCQ-OS (T2DM: 71 at baseline and 83 at 12 months vs. non-T2DM: 76 at baseline and 88 at 12 months). Similar changes were also observed for other echocardiographic measures. In longitudinal analyses, the average NT-proBNP change was similar in patients with T2DM (–5.6% vs. –7.1% per 90-day interval; p = 0.64), whereas improvements in KCCQ-OS scores were slightly smaller (2.1 vs. 3.46 per 90-day interval; p = 0.07). ConclusionsSacubitril/valsartan favorably affects natriuretic peptide levels, reverse cardiac remodeling, and health status in patients with HFrEF with and without T2DM. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183)

Quantification of neurological blood‐based biomarkers in critically ill patients with COVID‐19

BackgroundMultiple neurological manifestations of COVID‐19 have been reported such as headache, anosmia, ischemic stroke, and cerebral hemorrhages. Objective characterization of the acute neurological damage in critically ill patients with COVID‐19 has not yet been reported.MethodWe performed a prospective observational study of plasma brain biomarkers in critically ill patients with respiratory failure that were diagnosed with (COVID‐19) or without (ICU control) COVID‐19. Demographics, co‐morbidities, daily clinical physiologic and laboratory data were collected. Plasma samples were drawn for measurement of neurofilament‐light chain (NF‐L), total tau (t‐tau), ubiquitin carboxy‐terminal hydrolase L1 (UCH‐L1), and glial fibrillary acidic protein (GFAP). The primary neurological outcome was delirium as defined by the intensive care delirium screening checklist (ICDSC, scale 1 ‐ 8). Associations between brain biomarkers and markers of respiratory failure of COVID‐19 were analyzed.Result27 patients with COVID‐19 and 19 ICU controls were enrolled. The concentration of plasma GFAP, UCH‐L1 and NF‐L levels was higher in both groups compared to healthy controls. Compared to ICU controls, patients with COVID‐19 had significantly higher GFAP (272 [150‐555] pg/ml vs 118 [78.5‐168] pg/ml, p=0.0009). In patients with COVID‐19, GFAP (rho=0.5115, p=0.0064), UCH‐L1 (rho=0.4056, p=0.0358) and NF‐L (rho=0.6223, p=0.0005) were positively correlated with the ICDSC score and were higher in patients diagnosed with delirium (ICDSC ≥4) in the COVID‐19 group but not ICU controls. There were no associations between PaO2/FiO2 or diagnosis of ARDS and plasma concentration of GFAP, t‐tau, UCH‐L1, or NF‐L in patients with COVID‐19.ConclusionPlasma GFAP is 2‐fold higher in critically ill patients with COVID‐19 compared to ICU controls, and higher concentrations of GFAP, UCH‐L1 and NF‐L are associated with delirium specifically in patients with COVID‐19.