Marker Of Outcome In Patients Research Articles

Study of etiology, clinical profile, and outcome of altered sensorium patients admitted in a tertiary care hospital

Background: Altered sensorium is one of the most common presentations in patients coming to the emergency room. It includes decreased level of consciousness, attention disorder, arousal disorder, and cognitive disorder. The causes of altered sensorium can be varied, some of which are cerebrovascular diseases, alcoholism, cerebral trauma, hypoglycemia, epilepsy, drug intoxication, and neuroinfection. 4–10% of the patients presenting to the emergency department may have altered mental status. The outcome is dependent on early identification and effective treatment using investigations and imaging technologies, and it might range from full recovery to permanent damage to death. Aims and Objectives: (1) To study clinical profile and etiology in altered sensorium patients. (2) To assess outcomes in altered sensorium patients. Materials and Methods: In this prospective cross-sectional study, clinical examination and investigations are done and data are collected using pro forma for patients fulfilling the inclusion criteria. In this study, all altered sensorium patients were evaluated by detailed history, clinical examination, Glasgow Coma Scale (GCS), laboratory investigations, computed tomography brain, and other investigations. All patients were followed up till discharge or death of the patient in the hospital. Results: There were 270 patients who presented with encephalopathy, 184 (68%) were males. The majority of these patients 60 (22.2%) were in the age group of 51–60 years old. The most common cause is neurological in 109 (40.3%) patients, metabolic in 64 (24%) patients, and sepsis in 50 (19%) patients. Ischemic stroke 83 (76%) is the most common neurological cause. Hepatic encephalopathy was the most common cause of metabolic encephalopathy present in 21 (32%) patients. Pneumonia was the most common infection. There were 114 (42.2%) deaths. Septic encephalopathy is the most common cause of mortality. Early presentation to the hospital, higher GCS, and conscious level at presentation were good prognostic markers of outcome in patients, while septic encephalopathy was found to have the worst prognosis. Conclusion: The common etiologies of encephalopathy are neurological followed by metabolic and sepsis. Early presentation to the emergency room within 6 h of symptom onset, higher GCS, neurological and metabolic causes are associated with a good prognosis. The mortality rate was 42.2%. Septic encephalopathy is the most common cause of death with pneumonia being the most common source of infection.

Proteomic profile and predictive markers of outcome in patients with subarachnoid hemorrhage

BackgroundThe molecular mechanisms underlying development of posthemorrhagic hydrocephalus (PHH) following subarachnoid hemorrhage (SAH) remain incompletely understood. Consequently, treatment strategies tailored towards the individual patient remain limited. This study aimed to identify proteomic cerebrospinal fluid (CSF) biomarkers capable of predicting shunt dependency and functional outcome in patients with SAH in order to improve informed clinical decision making.MethodsVentricular CSF samples were collected twice from 23 patients with SAH who required external ventricular drain (EVD) insertion (12 patients with successful EVD weaning, 11 patients in need of permanent CSF shunting due to development of PHH). The paired CSF samples were collected acutely after ictus and later upon EVD removal. Cisternal CSF samples were collected from 10 healthy control subjects undergoing vascular clipping of an unruptured aneurysm. All CSF samples were subjected to mass spectrometry-based proteomics analysis. Proteomic biomarkers were quantified using area under the curve (AUC) estimates from a receiver operating curve (ROC).ResultsCSF from patients with SAH displayed a distinct proteomic profile in comparison to that of healthy control subjects. The CSF collected acutely after ictus from patients with SAH was moreover distinct from that collected weeks later but appeared similar in the weaned and shunted patient groups. Sixteen unique proteins were identified as potential predictors of shunt dependency, while three proteins were identified as potential predictors of functional outcome assessed six months after ictus with the modified Rankin Scale.ConclusionsWe here identified several potential proteomic biomarkers in CSF from patients with SAH capable of predicting (i) shunt dependency and thus development of PHH and (ii) the functional outcome assessed six months after ictus. These proteomic biomarkers may have the potential to aid clinical decision making by predicting shunt dependency and functional outcome following SAH.

Multimodal prediction of neoadjuvant treatment outcome by serial FDG PET and MRI in women with locally advanced breast cancer

PurposeTo investigate combined MRI and 18F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer.MethodsPatients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K1) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated.ResultsThirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31–66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18F-FDG PET (K1) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS.ConclusionMid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome.

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with recurrent oral squamous cell carcinoma treated with nivolumab

The immune checkpoint inhibitor (ICI), nivolumab, has revolutionised the treatment of recurrent and metastatic oral cancer. However, the response rate to ICIs remains low, and identifying predictors of nivolumab response is critical. Although the neutrophil-to-lymphocyte ratio (NLR) has been suggested as a predictive marker of nivolumab response in patients with various types of cancer, its utility in oral squamous cell carcinoma (OSCC) has not been elucidated. In this retrospective multicentre cohort study, we evaluated the association between NLR and outcome of nivolumab treatment in 64 patients with OSCC treated between 2017 and 2020. The objective response and disease control rates were 25.1% and 32.9%, respectively. The rates for complete and partial responses were 15.7% (10/64) and 9.4% (6/64), respectively; stable and progressive disease rates were 7.8% (5/64) and 67.1% (43/64), respectively. Complete and partial responses were classified as responders, and stable and progressive diseases were classified as non-responders. The median (range) pre-treatment NLR among responders was 4.3 (2.8–8.0), which decreased to 4.0 (2.6–6.3) after nivolumab treatment, and the median (range) pre-treatment NLR among non-responders was 5.1 (2.7–7.9), which increased to 6.4 (4.0–14.0) with tumour growth. Moreover, overall survival was significantly worse in the group with a higher post-treatment NLR (≥5) than in the group with a lower NLR (<5). Patients with a post-treatment NLR of ≥6 had worse outcomes for salvage chemotherapy following nivolumab treatment. Thus, post-treatment NLR could be a useful marker for predicting the response to nivolumab treatment or salvage chemotherapy in patients with OSCC.

Analysis of the PARP1, ADP-Ribosylation, and TRIP12 Triad With Markers of Patient Outcome in Human Breast Cancer

PARP inhibitors (PARPi) are increasingly used in breast cancer therapy, including high-grade triple-negative breast cancer (TNBC) treatment. Varying treatment responses and PARPi resistance with relapse currently pose limitations to the efficacy of PARPi therapy. The pathobiological reasons why individual patients respond differently to PARPi are poorly understood. In this study, we analyzed expression of PARP1, the main target of PARPi, in normal breast tissue, breast cancer, and its precursor lesions using human breast cancer tissue microarrays covering a total of 824 patients, including more than 100 TNBC cases. In parallel, we analyzed nuclear adenosine diphosphate (ADP)-ribosylation as a marker of PARP1 activity and TRIP12, an antagonist of PARPi-induced PARP1 trapping. Although we found PARP1 expression to be generally increased in invasive breast cancer, PARP1 protein levels and nuclear ADP-ribosylation were lower in higher tumor grade and TNBC samples than non-TNBCs. Cancers with low levels of PARP1 and low levels of nuclear ADP-ribosylation were associated with significantly reduced overall survival. This effect was even more pronounced in cases with high levels of TRIP12. These results indicate that PARP1-dependent DNA repair capacity may be compromised in aggressive breast cancers, potentially fueling enhanced accumulation of mutations. Moreover, the results revealed a subset of breast cancers with low PARP1, low nuclear ADP-ribosylation, and high TRIP12 levels, which may compromise their response to PARPi, suggesting a combination of markers for PARP1 abundance, enzymatic activity, and trapping capabilities might aid patient stratification for PARPi therapy.

Prognostic Impact of Right Ventricular Strain in Isolated Severe Tricuspid Regurgitation

Right ventricular (RV) systolic function is an established marker of outcomes in patients with severe tricuspid regurgitation (TR). Timely detection of RV dysfunction using conventional two-dimensional echocardiography is challenging. RV strain has emerged as an accurate and sensitive tool for the evaluation of RV function, with the capability to detect subclinical RV dysfunction. The aim of this study was to evaluate the prognostic value of RV strain parameters in early stages of severe TR. Consecutive patients with at least severe TR (severe, massive, or torrential) and the absence of a formal indication for tricuspid valve intervention in secondary TR evaluated in the Heart Valve Clinic were prospectively included. RV systolic function was measured using conventional echocardiographic indices (RV fractional area change, tricuspid annular plane systolic excursion, and Doppler tissue imaging S wave [S']) and speckle-tracking echocardiography-derived automatic peak global longitudinal strain and free wall longitudinal strain (FWLS) using an automated two-dimensional strain analytic software. A combined end point of hospital admission due to heart failure or all-cause mortality was defined. A total of 266 patients were enrolled in the study, and 151 were ultimately included. Strain parameters detected a higher percentage of abnormal RV values compared with conventional indices. During a median follow-up period of 26months (interquartile range, 13-42months), 35% of the patients reached the combined end point. Cumulative event-free survival was significantly worse in patients with impaired RV global longitudinal strain and RV FWLS. Conventional indices of RV systolic function were not associated with outcomes (P>.05 for all). On multivariate analysis, RV FWLS was independently associated with mortality and heart failure (adjusted hazard ratio for abnormal RV FWLS, 5.90; 95% CI, 3.17-10.99; P<.001). In early stages of severe TR, RV FWLS is more frequently impaired compared with conventional indices of RV function. Among all parameters, RV FWLS is the strongest predictor of mortality and heart failure, independent of additional prognostic markers.

Effect of renal function on the prognostic importance of chloride in patients with heart failure.

Hypochloremia has recently gained interest as a potential marker of outcomes in patients with heart failure (HF). The exact pathophysiologic mechanism linking hypochloremia to HF is unclear but is thought to be mediated by chloride-sensitive proteins and channels located in kidneys. This analysis aimed to understand whether renal dysfunction (RD) affects the association of hypochloremia with mortality in patients with HF. Using data from a nationwide registry, 438 cases with complete data on serum chloride concentration and 1-year survival were included in the analysis. Patients with an estimated glomerular filtration rate of <60 mL/min/m2 at baseline were accepted as having RD. Hypochloremia was defined as a chloride concentration <96 mEq/L at baseline. For HF patients without RD at baseline, patients with hypochloremia had a significantly higher 1-year all-cause mortality than those without hypochloremia (41.6% vs 13.0%, log-rank p < 0.001) and the association remained significant after multivariate adjustment (odds ratio (OR): 2.55, 95% confidence interval (CI): 1.25-5.21). The evidence supporting the association was very strong in this subgroup (Bayesian Factor (BF)10: 48.25, log OR: 1.56, 95% CI: 0.69-2.43). For patients with RD at baseline, there was no statistically significant difference for 1-year mortality for patients with or without hypochloremia (36.3% vs 29.7, log-rank p = 0.35) and there was no evidence to support an association between hypochloremia and mortality (BF10: 1.18, log OR :0.66, 95% CI: -0.02 to 1.35). In patients with HF, the association between low chloride concentration and mortality is limited to those without RD at baseline.

Multiparametric MRI as a Predictor of PSA Response in Patients Undergoing Stereotactic Body Radiation (SBRT) Therapy for Prostate Cancer

<h3>Purpose/Objective(s)</h3> In order to maximize the therapeutic ratio, it is important to identify adverse prognostic features in men with prostate cancer, especially amongst those with intermediate risk disease, which represents a heterogeneous group. These men may benefit from treatment intensification. Prior studies have shown pretreatment mpMRI may predict biochemical failure in patients with intermediate and/or high-risk prostate cancer undergoing conventionally fractionated external beam radiotherapy and/or brachytherapy. This is the first study to evaluate pretreatment mpMRI findings as a marker for outcome in patients undergoing SBRT. <h3>Materials/Methods</h3> We identified all patients treated at our institution with linear accelerator-based SBRT to 3625 cGy in 5 fractions, with or without androgen deprivation therapy (ADT) from November 2015 to March 2021. All patients underwent SpaceOAR placement followed by pre-treatment MRI. Post-treatment PSA measurements were obtained 4 months after SBRT, followed by every 3-6 months thereafter. A two-sample t-test was used to compare preoperative mpMRI features with clinical outcomes. <h3>Results</h3> 123 men were included in the study. The table below summarizes the pretreatment patient characteristics. Patients with higher pretreatment diameter of the largest intraprostatic lesion, number of prostate lesions, and maximal PI-RADS score were associated with higher PSA nadir and longer time to PSA nadir (p<0.0001). When separated by ADT treatment, this association remained for patients who were not treated with ADT (p<0.001). In patients who received ADT, the pretreatment MRI variables were each significantly associated with time to PSA nadir (p<0.01) but not with PSA nadir (p>0.30). <h3>Conclusion</h3> Our experience shows a significant association between mpMRI features and PSA outcome in patients treated with SBRT with or without ADT. Since PSA nadir has been shown to correlate with biochemical failure, this information may help radiation oncologists better counsel their patients regarding outcome after SBRT and can help inform future studies regarding who may benefit from treatment intensification with, for example, ADT and / or boost to dominant intraprostatic lesion.

A Systematic Review and Meta-Analysis of Cerebrospinal Fluid Amyloid and Tau Levels Identifies Mild Cognitive Impairment Patients Progressing to Alzheimer's Disease.

Reported levels of amyloid-beta and tau in human cerebrospinal fluid (CSF) were evaluated to discover if these biochemical markers can predict the transition from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD). A systematic review of the literature in PubMed and Web of Science (April 2021) was performed by a single researcher to identify studies reporting immunologically-based (xMAP or ELISA) measures of CSF analytes Aβ(1-42) and/or P-tau and/or T-tau in clinical studies with at least two timepoints and a statement of diagnostic criteria. Of 1137 screened publications, 22 met the inclusion criteria for CSF Aβ(1-42) measures, 20 studies included T-tau, and 17 included P-tau. Six meta-analyses were conducted to compare the analytes for healthy controls (HC) versus progressive MCI (MCI_AD) and for non-progressive MCI (Stable_MCI) versus MCI_AD; effect sizes were determined using random effects models. The heterogeneity of effect sizes across studies was confirmed with very high significance (p < 0.0001) for all meta-analyses except HC versus MCI_AD T-tau (p < 0.05) and P-tau (non-significant). Standard mean difference (SMD) was highly significant (p < 0.0001) for all comparisons (Stable_MCI versus MCI_AD: SMD [95%-CI] Aβ(1-42) = 1.19 [0.96,1.42]; T-tau = −1.03 [−1.24,−0.82]; P-tau = −1.03 [−1.47,−0.59]; HC versus MCI_AD: SMD Aβ(1-42) = 1.73 [1.39,2.07]; T-tau = −1.13 [−1.33,−0.93]; P-tau = −1.10 [−1.23,−0.96]). The follow-up interval in longitudinal evaluations was a critical factor in clinical study design, and the Aβ(1–42)/P-tau ratio most robustly differentiated progressive from non-progressive MCI. The value of amyloid-beta and tau as markers of patient outcome are supported by these findings.

Abstract 163: Regulation of periostin by DDR2 in cancer-associated fibroblasts controls tumor invasion and metastasis in ovarian cancer

Abstract Ovarian cancer has the highest mortality of all gynecological malignancies. As such, there is a need to decipher molecular mechanisms that underlie tumor metastasis in ovarian cancer. Increased expression of receptor tyrosine kinase, DDR2, has been associated with worse patient survival. Identifying downstream targets of DDR2may allow specific modulation of ovarian cancer metastatic pathways with few off-target effects. Additionally, stromal cells play a critical role in metastasis. The crosstalk between tumor and stromal cells cans hift the balance between tumor progression or inhibition. We identified periostin to be highly expressed by fibroblasts expressing DDR2compared to fibroblasts without DDR2(Fold change=2.0, P=0.03).We show that DDR2regulates periostin in ovarian cancer associated fibroblast (CAFs). DDR2and periostin expression in the CAFs leads to512% increase in mesothelial cell clearance ratio(P=0.0004) and matrigel invasion(612vs 193invading cells/hpf, P&amp;lt;0.0001). Mice injected withCAFs expressing periostin as well as ovarian cancer tumor cells have 72% increased tumor burden compared to mice with CAFs that do not express periostin (P=0.006). High periostin expression in CAFs leads to decreased T-cell proliferation and cytotoxicity. We validate periostin as a marker for patient outcome in ovarian cancer patients. Patients with high periostin expression have worse overall survival thant hose with low periostin expression. Mapping regulatory networks involved in tumor initiation and progression is important for identification of novel therapeutic targets. Citation Format: Favour A. Akinjiyan, Ritu M. Dave, Katherine C. Fuh. Regulation of periostin by DDR2 in cancer-associated fibroblasts controls tumor invasion and metastasis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 163.

Identifying Circulating Tumor DNA Mutations Associated with Neoadjuvant Chemotherapy Efficacy in Local Advanced Breast Cancer.

Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer. Neoadjuvant chemotherapy (NACT) has become standard therapy for local advanced breast cancer (LABC). The aim of our study was to investigate plasma ctDNA as a prognostic marker for outcome in patients with LABC treated with NACT. A total of 56 patients with LABC were involved in this study. ctDNA mutations were investigated by using a 100 gene panel-target capture next-generation sequencing. The patients then received standard NACT therapy: adriamycin and cyclophosphamide and paclitaxel (AC-T) or AC-TH (AC-T+ Trastuzumab) regimen. The efficacy of NACT was evaluated by Miller-Payne grading system. A predictive and weight model was used to screen ctDNA point mutation biomarkers for NACT. The ctDNA mutational profile of LABC patients was identified. For nonsynonymous mutations, the top 5 mutated genes were MTHFR (51/56, 91.1%), XPC (50/56, 89.3%), ABCB1 (48/51, 94.1%), BRCA2 (38/56, 67.9%), and XRCC1 (38/56, 67.9%). In addition, the mutation frequencies of PIK3CA and TP53 were 32.1% (18/56) and 26.8% (15/56), respectively. The predictive model indicated that XRCC1 44055726 (TG>-) mutation (25/56, 44.6%) was significantly associated with Miller-Payne 4-5 and Miller-Payne 3-5 responses. While mTOR 11249132(G>C) mutation (23/56, 41.1%) was associated with Miller-Payne 1-4 or Miller-Payne 1-3 responses. Furthermore, XRCC1 44055726 (TG>-) accompanied by mTOR wild type predicted a good NACT efficacy in all response classification systems. The ROC curves to discriminate good neoadjuvant chemotherapy efficiency (Miller-Payne 4-5) and poor efficiency (Miller-Payne 1-3) were created, and AUC value was 0.77. Our results suggested that ctDNA mutation of XRCC1 44055726 (TG>-) might be a positive biomarker for NACT therapy in LABC, while mTOR 11249132(G>C) mutation was potentially associated with NACT resistance.

Clinical Utility of Liquid Biopsy (Cell-free DNA) Based EGFR Mutation Detection Post treatment Initiation as a Disease Monitoring Tool in Patients With Advanced EGFR-mutant NSCLC

IntroductionPlasma cfDNA-based mutation analysis has shown disease-monitoring potential in various cancers. We assessed the potential of cfDNA-based EGFR mutation testing as a monitoring tool in patients with NSCLC. Patients and MethodsPatients with NSCLC harboring EGFR mutations receiving first-line treatment as per institutional protocol were enrolled. EGFR mutation status was determined using plasma samples at baseline and post treatment initiation. Patients in whom EGFR mutation was detected or persisted after treatment initiation were considered circulating tumor DNA (ctDNA)-positive. Progression-free survival (PFS) and overall survival (OS) for ctDNA-positive and negative patients post treatment initiation were the primary endpoints; concordance for baseline EGFR status between tissue and plasma and proportion of patients who were ctDNA-positive post treatment initiation were the secondary endpoints. ResultsWe enrolled 158 patients; 76 received gefitinib, and 82 received gefitinib plus chemotherapy. Median follow-up duration was 42 months. About 25% of patients were ctDNA-positive post treatment initiation. Median PFS for ctDNA-negative patients post treatment initiation was 14 (95% confidence interval [CI], 12.0-17.0) months, while that for ctDNA-positive patients was 8 (95% CI, 6.0-10.0) months. Median OS for ctDNA-negative patients post treatment initiation was 27 (95% CI, 24.0-32.0) months, while that for ctDNA-positive patients was 15 (95% CI, 11.0-19.0) months. Concordance at baseline between tissue and plasma samples was 75.4%. ConclusionPlasma-based EGFR mutation detection post treatment initiation can be used as a predictive marker for outcome in patients with EGFR-mutant NSCLC receiving first-line treatment.

Abstract PD3-05: The paradoxical role of RalA and RalB in triple negative breast cancer

Abstract Background: Breast Cancer (BC) is the most common cancer and leading cause of cancer associated mortality in women worldwide. TNBC patients have the highest mortality mainly due to lack of receptors for targeted therapies. RalA and RalB are small GTPases that are known to regulate growth and metastasis in several cancers. However, roles for these GTPases in BC is poorly understood. The goal of this study was to investigate the contributions of RalA and RalB in TNBC. Methods: Control, RalA or RalB CRISPR knockout (KO) MDA-MB-231 cells were injected into the mammary gland of nod-skid-gamma (NSG) mice. Tumor growth was monitored and groups were taken as they met early removal criteria. Tumors and lungs were formalin-fixed and paraffin embedded. Tumors underwent immunohistochemical staining for Ki-67 and Cleaved caspase-3 and lungs were stained for hematoxylin and eosin and imaged on a Leica Aperio ScanScope XT to calculate lung metastasis. RalA or RalB were also depleted in MDA-MB-231 and MVT1 cells by shRNA. In addition, RalA depleted MDA-MB-231 cells were labeled with luciferase and injected into the tail vein of NSG mice and imaged on an IVIS spectrum to test seeding and lung colonization. Immunohistochemistry of patient TMAs was preformed on a Bond RX autostainer using RalA (Abcam, ab126627, 1:2000). Immunohistochemical stains were imaged on a PerkinElmer’s Vectra® Automatic Imaging System and quantified using inForm® Advanced Image Analysis software. Statistical significance of Kaplan-Meier survival curves were determined by log rank. Results: RalA knockout and depletion slowed primary orthotopic tumor growth in MDA-MB-231 and MVT1 cells. RalB KO had the opposite effect and increased growth rate compared to controls and RalA KO cells. Ki67 and cleaved caspase 3 IHC staining of tumors indicate KO of RalA decreased proliferation, whereas KO RalB increased proliferation with no change in apoptosis. RalA KO decreased the number and area of lung metastasis in both spontaneous and experimental metastasis assays. RalB KO or depletion caused an increase in the area and number of metastasis. Utilizing data from the METABRIC and TCGA BC datasets, elevated RALA, but not RALB, was prognostic of worse outcome in the overall BC populations and the TNBC populations specifically. RALA was shown to be more highly expressed in BC, particularly TNBC, relative to normal mammary tissue whereas RalB was decreased in BC and TNBC. IHC staining of a TMA comprised of all BC subtypes and a TMA of only TNBC samples confirmed RalA as a prognostic marker of patient outcome. Conclusions: RalA and RalB have important but paradoxical roles in TNBC. Citation Format: Jonathan M. Spehar, Katie A. Thies, Matthew W. Cole, Rachel E. Schafer, Dillon S. Richardson, Sarah A. Steck, Manjusri Das, Arthur W. Lian, Alo Ray, Sue E. Knoblaugh, Cynthia D. Trimmers, Gina M. Sizemore, Steven T. Sizemore. The paradoxical role of RalA and RalB in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-05.

Short time to positivity of blood culture predicts mortality and septic shock in bacteremic patients: a systematic review and meta-analysis

BackgroundThe value of time to positivity (TTP) on diagnosis for catheter-related bloodstream infection and distinguishment on bacteria group and infection source has been investigated. However, the relationship between TTP and patient outcome requires verification, and we performed a systematic review and meta-analysis.MethodsWe searched PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science for publications associated with the topic. We included studies that researched the TTP on predicting patient mortality and septic shock. Quality assessment is performed with Critical Appraisal Skills Programme (CASP). The analysis is performed using Review Manager Version 5.0.24. on articles available for data extraction on the exact population of each outcome group. The existence of publication bias was assessed by funnel plots. Statistical heterogeneity was evaluated using the Cochran Q and {I}^{2} statistics. The outcome is reported as an odds ratio. PROSPERO registration: CRD42021272286.ResultsTwenty-four eligible studies were included in our study. Twenty-four in the mortality group and six in the septic shock group. Mortality is significantly associated with the short time to positivity group with an odds ratio of 2.98 (95% CI: 2.25–3.96, p-value < 0.001). The odds ratio for developing septic shock in the short TTP group is 4.06 (95% CI: 2.41–6.84, p-value < 0.001). Subgroup analysis revealed short TTP as a significant predictor of mortality and septic shock in Gram's positive and Gram's negative related bloodstream infections. TTP is not associated with mortality among patients with candidaemia.ConclusionsShort time to positivity is a reliable marker for patient outcome in certain bacterial species. Studies concerning confounding factors such as the delay in bottle loading and other confounding factors are needed to enhance external validity.

Hyperuricemia as a prognostic marker for long-term outcomes in patients with myocardial infarction with nonobstructive coronary arteries

BackgroundHyperuricemia (HUA) has been proved as a predictor of worse outcomes in patients with coronary artery disease. Here, we investigated the prognostic value of HUA in a distinct population with myocardial infarction with nonobstructive coronary arteries (MINOCA).MethodsA total of 1179 MINOCA patients were enrolled and divided into HUA and non-HUA groups. HUA was defined as a serum uric acid level ≥ 420 μmol/L in men or ≥ 357 μmol/L in women. The primary study endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan–Meier, Cox regression, and receiver-operating characteristic analyses were performed.ResultsPatients with HUA (prevalence of 23.5%) had a significantly higher incidence of MACE (18.7% vs. 12.8%; p = 0.015) than patients without during the median follow-up of 41.7 months. HUA was closely associated with an increased risk of MACE even after multivariable adjustment (hazard ratio 1.498, 95% confidence interval: 1.080 to 2.077; p = 0.016). HUA remained a robust risk factor of MACE after propensity score matching analysis. Moreover, HUA showed an area under the curve (AUC) of 0.59 for predicting MACE. Incorporation of HUA to the thrombolysis in myocardial infarction (TIMI) score yielded a significant improvement in discrimination for MACE.ConclusionsHUA was independently associated with poor prognosis after MINOCA. Routine assessment of HUA may facilitate risk stratification in this specific population.

Lymphocyte Ratios Progressively Worsen in Non-Survivors of COVID-19

Background:Brazil became the South American epicenter for coronavirus disease (COVID-19) soon after the first case was diagnosed in February 2020 with the highest infection rate occurring in the state of Sao Paulo. COVID-19 is characterized by marked thrombo-inflammation mechanisms, and neutrophil-lymphocyte ratio (NLR) among many clinical and laboratory data, is becoming an inflammatory marker of severity and mortality of COVID-19. We evaluated the serial weekly lymphocyte ratios, which are easily derivable from the routine blood counts, in the survivors and non-survivors of COVID-19 at the Clinical Hospital of University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil, from time of diagnosis to the 3 rd week of care. This hospital is one of the referral centers for COVID-19 patients in this state.Methods: In this retrospective study, we reviewed the medical notes of 320 adults hospitalized patients with PCR-confirmed COVID-19 at the Clinical Hospital of UNICAMP, from March 2020 to March 2021. The serial weekly hematological parameters (analyzed using automated counter - XN 9000™, Sysmex, Japan) from the time of diagnosis were analyzed and lymphocytes ratios (neutrophil-lymphocyte, NLR, platelet-lymphocyte PLR, and monocyte-lymphocyte MLR) were calculated. The survivors (n=257) were those who recovered from the disease and were discharged from the hospital, while the non-survivors (n=63) were those who died in the course of treatment. Statistical analyses were performed using SPSS (version 22). Unpaired data of Survivors and Non-survivors with COVID-19 were compared using Mann-Whitney tests. Repeated measures were compared within and between groups using univariate and multivariate tests in general linear models. All results were considered significant if p<0.05.Results: Of the 320 patients, 257 (80.3%) were survivors and had lower mean age than the non-survivors (57.73 vs 64.65 years, p<0.001). At diagnosis, the non-survivors had a lower lymphocyte count (p=0.002), basophil count (p=0.049), and hematocrit (p=0.021) than the survivors, Table 1.We used general linear models for repeated measures and corrected for the patients who did not stay long enough to have a complete series of blood counts, Figure 1 A-G. Multivariate tests between the survivor and non-survivor groups showed significant variations with serial weekly lymphocyte count (p<0.001), neutrophil count (P=0.005), NLR (p=0.009), MLR (p=0.010), and PLR (p=0.035) but not with the weekly monocyte count (p=0.352) and platelet count (p=0.505). The NLR was higher and PLR was lower in the non-survivors at diagnosis (p<0.001 and p=0.047 respectively), both were higher in the 2 nd week post-diagnosis (p<0.001 and 0.043 respectively), and in the 3 rd week (p<0.001 and p=0.043 respectively) (Figure 1D and E). The MLR was not significantly different at diagnosis but became elevated in the following two weeks post-diagnosis (p=0.09, p=0.022, and p<0.001 respectively) (Figure 1F).Conclusions: The non-survivors were older and their NLR and MLR tend to increase from the time of diagnosis while their PLR tend to decrease after the 2 nd week post-COVID-19 diagnosis and treatment. On the other hand, all three ratios significantly decrease in the survivors. While neutrophilia and lymphopenia improved in the survivor, they worsen in non-survivors. These cells may have contributed towards the recovery by ameliorating the inflammatory response in survivors, and death by worsening the response in non-survivors of COVID-19. This study shows that serial lymphocyte count, neutrophil count, NLR, PLR, and MLR could serve as good and easily accessible markers of outcomes in patients with COVID-19 and could be used for monitoring of response to treatment. [Display omitted] DisclosuresCosta: Novartis: Consultancy.

The incidence, time distribution and prognostic value of monomorphic ventricular tachycardia in ST-elevation myocardial infarction: the prespecified analysis of VALIDATE SWEADHEART trial

Abstract Background The assessment of prognostic impact of ventricular arrhythmias in ST-elevation myocardial infarction (STEMI) is currently based mainly on their timing with regard to the symptom onset and does not distinguish between monomorphic ventricular tachycardia (VT) and polymorphic VT/ventricular fibrillation (VF). However, recent data indicate long-term hazard of monomorphic VT occurring early in the course of STEMI. Purpose To evaluate the incidence, time distribution and prognostic value of early monomorphic VT compared to polymorphic VT/VF in STEMI patients treated by primary percutaneous coronary interventions (PCI). Methods A prespecified analysis of the multicentre prospective registry-based randomised VALIDATE-SWEDEHEART trial included STEMI patients enrolled at 16 sites in Sweden between June 2014 and September 2016. Source data verification regarding the type and timing of arrhythmia from all patients with VT/VF during STEMI was performed. Survival status was obtained from the Swedish national population registry. Endpoint was total mortality at 180 days. Results In total, 2886 patients were identified. Among them, 97 (3.4%) had VF or polymorphic VT, 16 (0.5%) monomorphic VT, 6 (0.2%) had other undefined shockable rhythm. Total mortality (10.9% vs 2.8%, p≤0.001) was higher among patients with VT/VF. VT/VF was associated with total mortality (HR 3.18 95% CI 1.74–5.8; p≤0.001) after adjustment on age, gender and myocardial infarction localisation. In patients discharged from hospital, VT/VF did not influence the long-term prognosis. Patients with monomorphic VT had similar clinical characteristics as compared to those with polymorphic VT/VF. The time distribution of VT/VF differed with regard to the type of arrhythmia: 63% of monomorphic VT/VF episodes occurred after PCI (n=10) compared to 24% (n=23) of all documented polymorphic VT/VF, p=0.003. Total mortality (12.5% vs 10.3%, p=0.678) did not differ between patients with monomorphic VT and polymorphic VT/VF. In Cox model, total mortality was not associated with the type of arrhythmia (Figure). Conclusion Early VT/VF is a marker of poor short-term outcome in patients with STEMI, which does not affect long-term prognosis in those who are successfully resuscitated and discharged from hospital. The incidence of monomorphic VT in STEMI treated by primary PCI is low, and it occurs mainly after PCI. Though no significant difference in mortality was found between patients with monomorphic VT and polymorphic VT/VF, the observed low incidence hampers drawing conclusions with regard to the prognostic hazard impact of monomorphic VT. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Swedish Heart Lung Foundation

ROX INDEX A PROMISING NONINVASIVE INDEX

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Respiratory Rate-Oxygenation Index (ROX index), defined as the ratio of oxygen saturation, fractional percentage of inspired oxygen (SpO2/FiO2) to respiratory rate (RR), has been found to be a predictor of patients who will improve with High-Flow Nasal Oxygen (HFNO) therapy. Limited information exists on ROX index in COVID-19 patients with acute respiratory failure. One study in such patients reported ROX-Index of ≥ 5.37 at four hours after admission was significantly associated with a lower risk for intubation after hour four. AIMS AND OBJECTIVE: 1. The objective of this study was to evaluate the ROX index at admission as an early marker of outcome in patients with COVID-19 pneumonia with acute respiratory failure. 2. To study if this index can be effectively used as an rescue alarm system so as to effectively triage patients requiring immediate attention. METHODS: 100 patients admitted to our hospital with COVID-19 and ARDS were retrospectively studied. Age, gender, admission ROX index, need for invasive mechanical ventilation (MV), hospital length of stay (LOS), and mortality were studied. Pearson’s Correlation analysis was performed to determine the impact of ROX Index on need for MV, hospital LOS and mortality. RESULTS: 1. Of the hundred (100) patients, fifty-two patients were male (52%) 2. Mean age was 47.7 + 16.7 years. 3. Twenty-three percent (23%) of patients required MV;4. The mean LOS was 8.6 + 6 days, twenty-two (22%) patients expired. 5. Mean Admission ROX index in subjects was 15 + 6.5 with ROX index 11.7 + 6 in non-survivors compared to 16 + 6 in survivors (p =0.018, independent t-test) [Figure 1]. 6. Pearson’s correlation analysis indicated a significant correlation between admission ROX index and survival (r = 0.28;p= 0.01), but not with hospital LOS (r=-0.02, p=0.8). 7.A dmission ROX index in patients requiring MV was 11 + 7 and 15 + 6 in those not requiring MV (p =0.06, independent t-test). CONCLUSIONS: Higher ROX index at admission is associated with higher mortality and need for MV. Further studies are required to delineate if there is a specific value that can predict need for MV and mortality. Future studies are also needed to determine whether ROX index progression from admission in the first 48 hours can predict outcome in these patients. CLINICAL IMPLICATIONS: ROX index is thus a promising non-invasive index and can be efficiently use especially when the healthcare system is oversaturated in the times of covid. To use this in rescue alarm system requires further investigation. DISCLOSURES: No relevant relationships by Sarang Patil, source=Web Response

Serum alanine aminotransferase as an early marker of outcomes in patients receiving anti-PD-1 or anti-CTLA-4 antibody

Immune-oncology (IO) drug therapy is effective against various types of cancer. Although several, potential, clinical predictive markers have been identified, none so far have proven reliable. Herein we evaluated changes in serum alanine aminotransferase (ALT), which is upregulated by the accumulation of activated CD8+T cells in the liver, as a potentially reliable predictive marker. We retrospectively analyzed 265 patients with advanced malignancies at three institutions between 2016 and 2019. The patients received IO drug therapy. We defined the ALT ratio (ALR) as the serum ALT value at baseline / the highest serum ALT during IO drug therapy, then determined whether the ALR correlated with the objective response rate or progression-free survival. The median follow-up was 3.1 months. We observed objective responses in 65 patients. The ALR ranged from 0.19 to 32.2 (median 1.5), and a significant ALR increase was observed in responders (p < 0.001). In receiver operating characteristic analysis, ALR = 1.55 had the highest sensitivity and specificity. The patients with ALR < 1.55 had a significantly poorer PFS than those with ALR ≥ 1.55. A high ALR was associated with a tumor response and good PFS in patients with advanced malignancies. The ALR based on activated cytotoxic T lymphocyte dynamics is therefore a reliable predictive marker.

Exercise-induced changes in miRNA expression in coronary artery disease.

Micro ribonucleic acids (miRNAs) are small non-coding RNA molecules that control gene expression by translational inhibition. Exercise has been shown to affect several miRNAs' expression in healthy subjects, but this has not yet been studied in patients with coronary artery disease (CAD). Since exercise training confers beneficial long-term effects and may also trigger acute coronary events, it is of utmost interest to be able to identify those who are risk for untoward effects. Therefore, we set out toassess miRNA expression in response to maximal ergospirometry in patients with CAD. Total RNA was extracted from blood drawn immediately before and 5min after maximal cycle-ergospirometry (10 male and 10 female CAD patients). A qRT-PCR was performed for 187 target miRNAs associated with endothelial function/dysfunction, cardiovascular disease, myocardial infarction, and sudden cardiac death. In response to a maximal ergospirometry, 33 miRNAs significantly changed their expression levels. Of these miRNAs 16 were significantly differently expressed between gender. Using multi-variance analysis, nine miRNAs (let-7e-5p; miR-1; miR-19b-1-5p; miR-103a-3p; miR-148b-3p; miR-181b-5p; miR-188-5p; miR-423-5p; miR-874-3p) showed significantly different responses to maximal ergospirometry between genders. We report for the first time that in patients with CAD, miRNA expression is amenable to maximal ergospirometry and that the extent of changes differs between genders. Affected by exercise and gender were miRNAs that are associated, among others, with pathways for glucose metabolism, oxidative stress, and angiogenesis. Future studies should assess whether disease-specific miRNA expression in response to maximal exercise might serve as a marker for patient outcome.