Independent Predictive Marker Research Articles

Symptomatic plaque enhancement is associated with early-onset post-stroke depression

BackgroundThe association between imaging features closely associated with symptomatic intracranial atherosclerotic plaques and early-onset post-stroke depression (PSD) is currently unclear. Materials and methods76 ischemic stroke patients who underwent high-resolution vessel wall magnetic resonance imaging (HR-VWI) were divided into PSD and non-PSD groups according to their DSM-V diagnoses and HAMD-17 scores at 14 days after onset. Clinical data and the imaging features associated with symptomatic plaques (including the enhancement index (EI), remodeling index, and plaque surface irregularity) were compared between groups. Multifactorial logistic regression analysis was used to find independent predictors of early-onset PSD. Spearman rank correlation analysis explores the association between clinical data, symptomatic plaque imaging features, and HAMD-17 in patients. ResultsThe sample comprised 36 patients with early-onset PSD. The symptomatic plaque EI and infarct volume were significantly higher in depressed patients than in patients without depression (P < 0.05). Multivariate logistic regression showed that symptomatic plaque EI could be used as an independent predictor of early-onset PSD after correcting for the confounding factor of infarct volume (OR = 1.034, 95% CI:1.014–1.055, P = 0.001). In the total sample, symptomatic plaque EI, infarct volume, and HAMD-17 had a significant positive correlation with each other (P < 0.05). LimitationsThis study focused only on the patients' symptomatic plaques and did not monitor patients' systemic inflammation levels at the time of HR-VWI. ConclusionsThe degree of symptomatic plaque enhancement is an independent predictive imaging marker of early-onset PSD and can be used the early diagnosis of early-onset PSD.

High Neutrophil-Lymphocyte Ratio, Platelet-Lymphocyte Ratio and Low Lymphocyte Levels Are Correlated With Worse Pathological Complete Response Rates.

Objective: To investigate the effect of hemogram parameters on predicting pathological complete response (pCR) in locally advanced rectal cancer.Methodology: A total of 227 patients with rectal cancer treated with neoadjuvant concurrent chemoradiotherapy (CRT) were retrospectively analyzed. All patients were divided into two subgroups as high or low hemogram parameters according to the cut-off value obtained using the receiver operating characteristic (ROC) curve.Results: In patients with low neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) levels, pCR rate was statistically significantly higher than the group with high NLR and PLR levels (for NLR: 39.77% vs. 5.34%; p<0.001, for PLR: 32.38% vs 7.01%; p<0.001 respectively). In addition, the pCR rate was significantly better in patients with high lymphocyte levels compared to the group with low lymphocyte levels (33.33% vs. 7.5%; p<0.001, respectively). According to the multivariate logistic regression analysis result, NLR and PLR levels were considered as independent predictors to predict pathological complete response [p<0.001, HR: 0.128 (95% CI=0.051 - 0.322) for NLR; p=0.017, HR: 0.332 (95% CI=0.134 - 0.821) for PLR, respectively].Conclusion: Our study showed that high NLR, PLR, and low lymphocyte levels were correlated with worse pCR rates. In addition to that, NLR and PLR emerged as independent predictive markers.

Platelet to Lymphocyte Ratio Correlates With Carcinoma Progression in Pancreatic Intra Epithelial Neoplasia.

Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion to pancreatic adenocarcinoma (PDAC). Yet no criteria to quantify patients at risk for progression to PDAC with PanIN exist. Platelet to lymphocyte ratio is an inflammatory marker that has been associated with overall survival in patients with invasive malignancies including pancreatic cancer. Preoperative sarcopenia has been linked to more aggressive diseases in pancreatic neoplasms. We aimed to assess a relation between PLR and sarcopenia as predictors for tumor progression in patients undergoing pancreatic resection for IPMN. We retrospectively reviewed 102 patients (46 females, 56 males) who underwent pancreatic resection for PanIn. PLR was calculated and quantified using a cutoff of 110, sarcopenia was quantified using the skeletal muscle index (SMI) on preoperative abdominal imaging. Both were co-evaluated with additional demographic, clinical, pathological, and imaging data for possible correlation with PanIN associated PDAC. PLR was significantly elevated in patients with PanIN - associated PDAC (p=0.006). In the multivariate analysis, invasive carcinomas were significantly more prevalent in patients with PLR above 110 (OR=4.06, 95%CI=3.91-4.12, p=0.04). Patients with elevated PLR had a two-times higher risk to die in the postoperative period (HR=2.26, 95%CI=1.04-2.21, p=0.001). Patients with elevated PLR, preoperative jaundice and sarcopenia were the most likely to have PanIN-associated PDAC (OR=3.48, 95%CI=2.98-8.41, p=0.02). PLR is an independent predictive marker for the presence of PanIN associated invasive carcinoma.

Dynamic contrast-enhanced MRI in malignant pleural mesothelioma: prediction of outcome based on DCE-MRI measurements in patients undergoing cytotoxic chemotherapy

BackgroundThe malignant pleural mesothelioma (MPM) response rate to chemotherapy is low. The identification of imaging biomarkers that could help guide the most effective therapy approach for individual patients is highly desirable. Our aim was to investigate the dynamic contrast-enhanced (DCE) MR parameters as predictors for progression-free (PFS) and overall survival (OS) in patients with MPM treated with cisplatin-based chemotherapy.MethodsThirty-two consecutive patients with MPM were enrolled in this prospective study. Pretreatment and intratreatment DCE-MRI were scheduled in each patient. The DCE parameters were analyzed using the extended Tofts (ET) and the adiabatic approximation tissue homogeneity (AATH) model. Comparison analysis, logistic regression and ROC analysis were used to identify the predictors for the patient’s outcome.ResultsPatients with higher pretreatment ET and AATH-calculated Ktrans and ve values had longer OS (P≤.006). Patients with a more prominent reduction in ET-calculated Ktrans and kep values during the early phase of chemotherapy had longer PFS (P =.008). No parameter was identified to predict PFS. Pre-treatment ET-calculated Ktrans was found to be an independent predictive marker for longer OS (P=.02) demonstrating the most favourable discrimination performance compared to other DCE parameters with an estimated sensitivity of 89% and specificity of 78% (AUC 0.9, 95% CI 0.74-0.98, cut off > 0.08 min-1).ConclusionsIn the present study, higher pre-treatment ET-calculated Ktrans values were associated with longer OS. The results suggest that DCE-MRI might provide additional information for identifying MPM patients that may respond to chemotherapy.

Evaluating systemic immune-inflammation index in patients with implantable cardioverter defibrillator for heart failure with reduced ejection fraction.

Pro-inflammatory pathways play an important role in the follow-ups of patients with intracardiac defibrillators (ICDs) for heart failure (HF) reduced with ejection fraction (HFrEF). A newly defined index - the systemic immune-inflammation index (SII)-has recently been reported to have prognostic value in patients with cardiovascular disease. This study's aim is to evaluate the SII value regarding its association with long-term mortality and appropriate ICD therapy during a 10-year follow-up. This retrospective study included 1011 patients with ICD for HFrEF. The SII was calculated as the neutrophil-to-lymphocyte ratio × total platelet count in the peripheral blood. The study population was divided into two groups according to the SII's optimal cut-off value to predict long-term mortality. The long-term prognostic impact of SII on these patients was evaluated regarding mortality and appropriate ICD therapy. The patients with a higher SII (≥1119) had significantly higher long-term mortality and appropriate ICD therapy rates. After adjustment for all confounding factors, the long-term mortality rate was 5.1 for a higher SII. (95% CI: 2.9-8.1). The long-term appropriate ICD therapy rate was 2.0 for a higher SII (95% CI: 1.4-3.0). SII may be an independent predictive marker for both long-term mortality and appropriate ICD therapy in patients with HFrEF.

Arterial Stiffness as a Cardiovascular Risk Factor for the Development of Preeclampsia and Pharmacopreventive Options

Arterial Stiffness (AS) describes the rigidity of the arterial walls. Epidemiological studies have shown that increased AS is an independent predictive marker of Cardiovascular (CV) morbidity and mortality in both pregnant and non-pregnant women. Preeclampsia (PE), a form of pregnancy-induced hypertension, affects approximately 5% of pregnancies worldwide. Preeclamptic women have a higher risk of CV Disease (CVD), mainly because PE damages the heart's ability to relax between contractions. Different pharmacological approaches for the prevention of PE have been tested in clinical trials (e.g., aspirin, enoxaparin, metformin, pravastatin, and sildenafil citrate). In current clinical practice, only low-dose aspirin is used for PE pharmacoprevention. However, low-dose aspirin does not prevent term PE, which is the most common form of PE. Compromised vascular integrity precedes the onset of PE and therefore, AS assessment may constitute a promising predictive marker of PE. Several non-invasive techniques have been developed to assess AS. Compared with normotensive pregnancies, both Carotid-Femoral Pulse Wave Velocity (cfPWV) and Augmentation Index (AIx) are increased in PE. In view of simplicity, reliability, and reproducibility, there is an interest in oscillometric AS measurements in pregnancies complicated by PE.

A Hypoxia-Associated Prognostic Gene Signature Risk Model and Prognosis Predictors in Gliomas.

Most solid tumours are hypoxic. Tumour cell proliferation and metabolism accelerate oxygen consumption. The low oxygen supply due to vascular abnormalisation and the high oxygen demand of tumour cells give rise to an imbalance, resulting in tumour hypoxia. Hypoxia alters cellular behaviour and is associated with extracellular matrix remodelling, enhanced tumour migration, and metastatic behaviour. In light of the foregoing, more research on the progressive and prognostic impacts of hypoxia on gliomas are crucial. In this study, we analysed the expression levels of 75 hypoxia-related genes in gliomas and found that a total of 26 genes were differentially expressed in The Cancer Genome Atlas (TCGA) database samples. We also constructed protein–protein interaction networks using the STRING database and Cytoscape. We obtained a total of 10 Hub genes using the MCC algorithm screening in the cytoHubba plugin. A prognostic risk model with seven gene signatures (PSMB6, PSMD9, UBB, PSMD12, PSMB10, PSMA5, and PSMD14) was constructed based on the 10 Hub genes using LASSO–Cox regression analysis. The model was verified to be highly accurate using subject work characteristic curves. The seven-gene signatures were then analysed by univariate and multivariate Cox. Notably, PSMB10, PSMD12, UBB, PSMA5, and PSMB6 were found to be independent prognostic predictive markers for glioma. In addition, PSMB6, PSMA5, UBB, and PSMD12 were lowly expressed, while PSMB10 was highly expressed, in the TCGA and GTEx integrated glioma samples and normal samples, which were verified through protein expression levels in the Human Protein Atlas database. This study found the prognostic predictive values of the hypoxia-related genes PSMB10, PSMD12, UBB, PSMA5, and PSMB6 for glioma and provided ideas and entry points for the progress of hypoxia-related glioma.

Prognostic value of immune factors in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma

BackgroundBoth activated tumor-infiltrating lymphocytes (TILs) and immune-suppressive cells, such as regulatory T cells (Tregs), in the tumor microenvironment (TME) play an important role in the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC).MethodsThe densities of TILs, programmed death receptor 1 (PD-1) + T cells, and forkhead box P3 (Foxp3) + T cells were analyzed by immunohistochemical staining. The associations of the immunological status of the PDAC microenvironment with overall survival (OS) time and disease-free survival (DFS) time were evaluated.ResultsPDAC patients with a high density of TILs in the TME or PD-1-positive T cells in tertiary lymphoid aggregates (TLAs) demonstrated a significantly better prognosis than those with a low density of TILs or PD-1-negativity, respectively. Moreover, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than those with low levels of Foxp3-expressing T cells. Importantly, even with a high density of the TILs in TME or PD-1-positive T cells in TLAs, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than patients with low levels of Foxp3-expressing T cells. A PDAC TME with a high density of TILs/high PD-1 positivity/low Foxp3 expression was an independent predictive marker associated with superior prognosis.ConclusionCombined assessment of TILs, PD-1+ cells, and Foxp3+ T cells in the TME may predict the prognosis of PDAC patients following surgical resection.

Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer.

Simple SummaryRectal cancer is the 8th most common cancer globally. Most patients with locally advanced rectal cancer receive neoadjuvant therapy based on 5-fluorouracil and radiotherapy showing variable responses. About 70–90% of patients present partial response, while 20% show treatment resistance. Repositioning drugs approved by regulatory agencies or drugs currently in clinical trials is a strategy to accelerate the development of drug-based cancer therapies. We compared rectal cancer gene expression signatures with reverse drug-induced gene-expression profiles of cancer cell lines to identify potential drugs for repositioning. Our analyses revealed that approved topoisomerase II inhibitors are candidate drugs for rectal cancer treatment. We also verified TOP2A copy number gains and increased expression in rectal tumors. These TOP2A alterations were independent predictive markers of topoisomerase inhibitor efficacy in colorectal cancer cells that closely represent rectal cancer signatures. Topoisomerase inhibitors are potentially helpful to treat rectal cancer patients with TOP2A imbalances.Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predicted repurposable drugs, topoisomerase II inhibitors (doxorubicin, teniposide, idarubicin, mitoxantrone, and epirubicin) presented a high potential to reverse rectal cancer gene expression signatures. We showed that these drugs effectively reduced the growth of colorectal cancer cell lines closely representing rectal cancer signatures. We also found a clear correlation between topoisomerase 2A (TOP2A) gene copy number or expression levels with the sensitivity to topoisomerase II inhibitors. Furthermore, CRISPR-Cas9 and shRNA screenings confirmed that loss-of-function of the TOP2A has the highest efficacy in reducing cellular proliferation. Finally, we observed significant TOP2A copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate TOP2A status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients.

A signature based on 11 autophagy genes for prognosis prediction of colorectal cancer.

AimTo develop an autophagy-gene-based signature that could help to anticipate the therapeutic effects of Colorectal Cancer (CRC).MethodsWe downloaded the gene expression profiles of CRC samples from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Genes with significant prognostic value in CRC were screened through univariate Cox regression analysis, while the LASSO Cox regression method was applied to screen optimal genes to construct the autophagy‐related prognostic signature.Results11 autophagy genes were identified and selected for the establishment of prognosis prediction model for CRC patients. The CRC patients were classified into the low- and high-risk groups according to the optimal cutoff value. The time-dependent ROC curves indicated the good performance of this model in prognosis prediction, with AUC values of 0.66, 0.66, and 0.67 at 1, 3 and 5 years for TCGA samples, as well as AUC values of 0.63, 0.65 and 0.64 for GEO samples, respectively. The multivariate Cox regression analysis results confirmed risk score as the independent marker for prognosis prediction in CRC. Besides, the constructed nomogram also had high predictive value. The results analysis on the tumor infiltrating immune cells (TIICs) relative ratios and mRNA levels of key immune checkpoint receptors indicated the signature was closely related to immune microenvironment of CRC in the context of TIICs and immune checkpoint receptors’ mRNA level. The proportion of MSI-L + MSI-H in the high-risk group was higher than that in the low-risk group. Moreover, the tumor purity was evaluated by estimate function package suggested that lower tumor purity in CRC might lead to a poorer prognosis.ConclusionThe autophagy-related features obtained in this study were able to divide the CRC patients into low- and high-risk groups, which should be contribute to the decision-making of CRC treatment.

Oxidative Modification of Lipoproteins: A Potential Role of Oxidized Small dense LDL in Enhanced Atherogenicity

Atherosclerosis (AS) is a multifaceted inflammatory syndrome of the arterial wall to which number of mediators have been implicated in lesion progression. Triglyceride (TG)-rich lipoproteins consist of the large diversity of lipoprotein particles that fluctuate in density, size, and apolipoprotein composition. Two foremost phenotypes, on basis of size, chemical configuration, and density, of low-density-lipoprotein (LDL) have been recognized i.e., pattern A, having LDL diameter greater than 25.5nm (large buoyant LDL or lb-LDL) and pattern B, having LDL diameter less than or equal to 25.5nm (small-dense LDL or sd-LDL). Small-dense low-density-lipoprotein (sd-LDL) particles are produced by potential intravascular hydrolysis of TG-rich VLDL particles via lipoprotein lipases (LPLs), hepatic lipases (HLs) and cholesterol ester transfer protein (CETP). sd-LDL is more atherogenic due to its smaller size, increased penetration into the arterial wall, extended plasma half-life, lesser binding affinity for LDL receptors (LDL-R) as well as lower resistance to oxidative stress when equated with lb-LDL. The higher atherogenic potential of sd-LDL is due to its enhanced susceptibility to oxidation, owing to high polyunsaturated fatty acids (PUFA), low cholesterol and Apoprotein B (ApoB) content. An enhanced understanding of sd-LDL metabolism at the molecular level, transport and clearance may result in the development of sd-LDL as an independent predictive marker for AS events and may be used to maintain cholesterol homeostasis and prevent the succession of AS.

Very Low Vitamin D Levels are a Strong Independent Predictor of Mortality in Hospitalized Patients with Severe COVID-19

BackgroundThere is controversy regarding the association between hypovitaminosis D and COVID-19 outcomes.Aim of the studyWe assessed the association between 25-hydroxyvitamin D levels and COVID-19 outcomes in hospitalized subjects with severe SARS-CoV-2 infection.MethodsRetrospective cohort study. Serum 25-hydroxyvitamin D levels of subjects with severe COVID-19 pneumonia were measured at hospital admission, between March 17th, 2020, and March 1st, 2021.ResultsOut of 2,908 patients, 571 (19.6%) had vitamin D deficiency (defined as a serum 25-hydroxyvitamin D level <12.5 ng/mL [<31.25 nmol/L]), and 1069 (36.7%) had levels between 12.5 ng/mL (31.25 nmol/L) and 20 ng/mL 850 nmol/L). Compared to subjects without vitamin D deficiency, those with 25-hydroxyvitamin D level <12.5 ng/mL had higher rates of in-hospital mortality at 30 d (28.0 vs. 17.3%; p <0.001), global mortality (31.9 vs. 20.8%; p <0.001), mechanical ventilation requirement (23.8 vs. 17.2%; p <0.001), and significantly longer hospital stay (median [interquartile range] of 9 [6–17 d] vs. 7 [5–12 d], p <0.001). In the unadjusted analysis, the risk of in-hospital death was greater for patients with vitamin D deficiency (HR 1.43; 95% CI, 1.20–1.70; p <0.001). After adjusting for confounders, the risk of in-hospital death within 30 d remained significantly greater in patients with vitamin D deficiency (HR 1.46; 95% CI, 1.21–1.76; p <0.001). The risk was reduced but remained significant with 25-hydroxyvitamin D levels between 12.5 ng/mL and 20 ng/mL (HR 1.31; 95% CI 1.10–1.55, p = 0.02). In comparison with other clinical biomarkers, vitamin D deficiency was an independent predictive marker of in-hospital mortality after adjusting for confounders.ConclusionVery low 25-hydroxyvitamin D levels measured at hospital admission were significantly associated with in-hospital mortality and are a useful prognostic biomarker in severe COVID-19 patients.

Role of Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio in Predicting the Response to First Line Chemotherapy in Colorectal Cancer Patients with Synchronous Liver Metastases: A Retrospective Study

Background: There is some evidence that high levels of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are associated with poor survival in several malignancies including colorectal cancer (CRC); however data on the significance of these markers to predict response to systemic therapy is limited. Objectives: The aim of this study was to assess the role of pretreatment NLR and PLR in predicting response to first line chemotherapy in CRC patients with synchronous metastases. Methods: Clinical records of 81 CRC patients with synchronous liver metastases, who underwent upfront chemotherapy, were included in this retrospective study. The optimal cut of value for NLR and PLR was determined according to receiver operating characteristic (ROC) curve analysis. Correlation between response to chemotherapy and NLR or PLR was evaluated. Results: The optimal cut off for NLR and PLR was 2.666 and 182.589, respectively. Patients with low NLR had significantly higher objective response (complete response + partial response) compared to patients with high NLR (54.3% versus 13%, respectively, P: &lt; 0.001). In patients with low PLR, 41.2% had objective response compared to 13.3% of patients with high PLR (P = 0.012). The univariate analysis determined that, both NLR and PLR are significantly associated with better objective response, but in multivariate analysis, only NLR was identified as an independent predictive marker of response [odds ratio = 4.55; P = 0.013]. Conclusions: Results of this study indicate that, measuring NLR might provide us an inexpensive method to predict response to first-line chemotherapy in CRC patients with synchronous liver metastases.

Clinical value of blood markers to assess the severity of coronavirus disease 2019

BackgroundSevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is threatening the world with the symptoms of seasonal influenza. This study was conducted to investigate the patient characteristics and clinical value of blood markers to assess the severity of coronavirus disease 2019 (COVID-19).Methods187 patients, diagnosed with COVID-19 (non-severe and severe cases) and admitted to hospital between January 27th and March 8th of 2020, were enrolled in the present study.ResultsA higher proportion of clinical symptoms, including cough, expectoration, myalgia, and fatigue were observed in the non-severe group. The level of white blood cell count, neutrophils, CRP, IL-6 and IL-8 were significantly increased, while the platelet count was remarkedly decreased in the severe group. The risk model based on lymphocyte, IL-6, IL-8, CRP and platelet counts had the highest area under the receiver operator characteristic curve (AUROC). The baseline of IL-6, IL-8 and CRP was positively correlated with other parameters except in the cases of lymphocyte, hemoglobin and platelet counts. The baseline of the platelet count was negatively correlated with other parameters except in the lymphocyte and hemoglobin counts. Additionally, there was no connection between the severity of COVID-19 and cultures of blood, sputum or catheter secretion.ConclusionsThe present study suggested that high leucocyte and low platelets counts were independent predictive markers of the severity of COVID-19.

External validation of the T.O.HO. score and derivation of the modified T.O.HO. score for predicting stone-free status after flexible ureteroscopy in ureteral and renal stones.

The T.O.HO. scoring system was developed to predict stone-free status after flexible ureterenoscopy (fURS) lithotripsy applied for ureter and renal stones. This study aimed to perform the external validation of the T.O.HO. score in the Turkish population and propose a modification for this system. Patients who underwent fURS for kidney and ureteral stones between January 2017 and January 2020 were retrospectively analysed. The patient and stone characteristics and perioperative findings were noted. The T.O.HO. score was externally validated and compared with the STONE score. Stone-free parameters were evaluated with the multivariate analysis. Based on the results of this analysis, the T.O.HO. score was modified and internally validated. A total of 621 patients were included in the study. The stone-free rate was determined as 79.8% (496/621) after fURS. The regression analysis showed that stone area had better predictive power than stone diameter (P=.025). Lower pole (reference), middle pole [odds ratio (OR)=0.492 P=.016] and middle ureteral (OR=0.227, P=.024) localisations, stone density (OR=1.001, P<.001), and stone volume (OR=1.008, P<.001) were determined as independent predictive markers for stone-free status. Based on the effect size of the stone surface area in the nomogram, stone volume was divided into five categories, at 1-point intervals. The AUC values of the T.O.HO., STONE, and modified T.O.HO. score in predicting stone-free status were calculated as 0.758, 0.634, and 0.821, respectively. The modified T.O.HO. created by adding stone volume was statistically significantly superior to the original version (ROC curve comparison, P<.001). The T.O.HO. score effectively predicted stone-free status after fURS. However, modified T.O.HO. SS showed the best predictive performance compared with original T.O.HO. SS.

Cumulative C-reactive Protein in the Perioperative Period as a Novel Marker for Oncological Outcome in Patients with Colorectal Cancer Undergoing Curative Resection.

Objectives: Systemic inflammatory response is strongly associated with poor oncological outcome in colorectal cancer (CRC). Perioperative inflammation caused by surgical stress can lead to the development of postoperative infectious complications (PIC) as well as cancer-related inflammation. We aimed to evaluate the prognostic potential of perioperative systemic inflammation by calculating the time-dependent cumulative C-reactive protein (CRP) levels during the perioperative period. Methods: We analyzed clinicopathological data from 540 patients with CRC who underwent potentially curative surgery at our institution. The time-dependent aggregated CRP level was denoted “cumulative CRP,” which represents the area under the line of time (days) and the CRP levels preoperatively and on postoperative days 1, 3, and 7. Results: Cumulative CRP was significantly higher in patients with CRC undergoing open surgery than in patients undergoing laparoscopic surgery. In multivariate analysis, high cumulative CRP was an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in both the laparoscopic and open surgery groups. Patients with CRC and high cumulative CRP had significantly poorer DFS and OS than those with low cumulative CRP, including those patients without PIC. Conclusions: Cumulative CRP is an independent predictive marker of OS and DFS in patients with CRC who undergo curative surgery.

Renal Tubular Damage Marker, Urinary N-acetyl-β-D-Glucosaminidase, as a Predictive Marker of Hepatic Fibrosis in Type 2 Diabetes Mellitus.

BackgroundNon-alcoholic steatohepatitis is closely associated with the progression of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). We investigated whether urinary N-acetyl-β-D-glucosaminidase (u-NAG), an early renal tubular damage biomarker in DKD, could be related to the degree of hepatic fibrosis in patients with T2DM.MethodsA total of 300 patients with T2DM were enrolled in this study. Hepatic steatosis and fibrosis were determined using transient elastography. The levels of urinary biomarkers, including u-NAG, albumin, protein, and creatinine, and glucometabolic parameters were measured.ResultsBased on the median value of the u-NAG to creatinine ratio (u-NCR), subjects were divided into low and high u-NCR groups. The high u-NCR group showed a significantly longer duration of diabetes, worsened hyperglycemia, and a more enhanced hepatic fibrosis index. A higher u-NCR was associated with a greater odds ratio for the risk of higher hepatic fibrosis stage (F2: odds ratio, 1.99; 95% confidence interval [CI], 1.04 to 3.82). Also, u-NCR was an independent predictive marker for more advanced hepatic fibrosis, even after adjusting for several confounding factors (β=1.58, P<0.01).ConclusionThe elevation of u-NAG was independently associated with a higher degree of hepatic fibrosis in patients with T2DM. Considering the common metabolic milieu of renal and hepatic fibrosis in T2DM, the potential use of u-NAG as an effective urinary biomarker reflecting hepatic fibrosis in T2DM needs to be validated in the future.

Genomic Complexity in Chronic Lymphocytic Leukemia Defined By Array-Based Analysis: Definitions, Associations with Other Biomarkers and Clinical Impact

Background: The advent of efficacious but also very expensive novel treatment regimens for high-risk chronic lymphocytic leukemia (CLL), has highlighted the need for accurate risk-stratification. Published evidence indicates that classic chromosome banding analysis (CBA) offers valuable complementary information to the routinely performed FISH analysis in CLL, potentially improving risk assessment. Indeed, recent studies identified complex karyotype (CK; defined as ≥3 abberations) as an independent predictive marker for refractoriness to ibrutinib and venetoclax, although for CLL, a precise evidence-based definition of genomic complexity (GC) is yet to be made. Array-based (CGH/SNP) analysis is capable of globally assessing the CLL genome, does not require in vitro mitogens, offers increased detection depth, and allows for easier standardization.Aims: 1. Determine a prognostic relevant definition of GC in CLL by array-based analysis. 2. Head-to-head comparison of the sensitivity of CBA versus array-based analysis.Methods: 1911 CLL and monoclonal B-cell lymphocytosis (MBL) patients (CLL=1895, 99% and MBL=16, 1%, respectively) were analyzed with CGH or SNP arrays mostly performed within the first year from diagnosis and before treatment administration (66% and 84%, respectively). For a subgroup (N=206) both CBA and array results were available (<1 year in between analyses). Main features of the studied cohort: median age: 60.7 years, males: 1252 (68%), Binet: A/B/C:623/324/141 (57%/30%/13%), IGHV-mutated CLL (M-CLL): 536/1082 (50%), del(13q): 1020/1910 (53%), del(11q): 353/1911 (19%), TP53 aberrations (TP53 abs, deletions and/or mutations of the TP53 gene): 205/1911 (11%). Recurrent chromosomal aberrations i.e. del(13)(q14), del(11)(q22.3) and del(17)(p13.1) defined by array were included in all analyses irrespective of size, while the cut-off for other aberrations are indicated.Results: First, analysis was performed using a size cut-off ≥5Mb according to Schoumans et al (Genes Chrom Cancer 2016). Applying the criteria ≥3 structural and/or numerical aberrations to define GC, 451/1911 cases (24%) displayed GC analyzed with CGH/SNP arrays. GC was significantly related (p<0.001) with advanced clinical stage (Binet B/C), IGHV-unmutated CLL (U-CLL), del(11q), del(13q) and TP53 abs. On univariate analysis, GC was associated with inferior OS (median: 10.0 vs 12.2 (p<0.001) years). GC cases were stratified into those with 3 (‘low-GC’, N=174, 39%), 4 (‘intermediate-GC’, N=103, 23%) and ≥5 (‘high-GC’, N=174, 39%) aberrations. High-GC cases differed significantly (p<0.05) from the other two subgroups, being enriched for U-CLL and TP53 abs (84% and 45%, respectively). The median OS was 5.8 years for the high-GC vs 10 years for the low- and 8.1 years for the intermediate-GC group (p<0.01). Only ‘high-GC’ remained significant (p<0.01) on multivariate analysis along with TP53 abs and IGHV status (see table).Lowering the array cut-off to 1Mb (N=353) resulted in detection of a higher number of aberrations (3.04 vs 2.34) compared to 5Mb cut-off (95% CI paired differences 0.475-0.924). Although a lower array cut-off resulted in upstaging of high risk GC (22 vs 12%), the median OS in the ‘high risk’ group was increased as compared to the cut-off of 5Mb (8.4 vs 5.5 years).Array-analysis (5Mb cut-off) showed a higher number of total detected aberrations as compared to CBA (2.35 vs 1.84, 95% CI paired differences 0.221-0.798). With array more patients were defined as GC with higher discriminatory power regarding survival (concordance index: 58 vs 55%) than with CBA. Prognostic impact of array vs CBA and of specific aberrations is currently being analyzed.Conclusion: According to this largest performed array-based analyses, current definitions for CK defined by the presence of ≥3 structural or numerical aberrations based on classical cytogenetic approaches may be suboptimal when applied for cases analyzed by array techniques. Instead, ≥5 aberrations detected by arrays were linked to high-risk disease, independent of clinical stage, IGHV and TP53 status. Since a lower array cut-off resulted in the detection of additional aberrations, without however been accompanied by the same dismal outcome as the 5Mb cut-off, further studies are warranted in order to define the actual prognostic relevance of smaller aberrations. [Display omitted] DisclosuresEldering:Roche: Research Funding; Gilead: Research Funding; Celgene: Research Funding. Ghia:Pharmacyclics LLC, an AbbVie Company: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Adaptive: Consultancy; AbbVie: Consultancy; Roche: Consultancy; Novartis: Research Funding. Stamatopoulos:Janssen Pharmaceuticals: Honoraria, Research Funding; Novartis SA: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Strefford:Roche: Research Funding. Kater:Celgene: Consultancy, Research Funding; Johnson & Johnson: Research Funding; Abbvie: Research Funding.

Dynamic Changes in Absolute Lymphocyte Counts During Eribulin Therapy Are Associated With Survival Benefit.

We investigated the usefulness of dynamic changes in absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) during eribulin therapy as predictive markers for survival benefit including post-progression survival (PPS). We retrospectively investigated 94 advanced breast cancer (ABC) patients who underwent eribulin therapy between July 2011 and June 2020. The multivariate analysis showed that high baseline ALC and low NLR were independent predictive markers for overall survival (OS) (p=0.007 and p=0.011, respectively) and PPS (p=0.005 and p=0.007, respectively). Dynamic changes in ALC were also associated with OS and PPS (p=0.015, and p=0.026, respectively) and were an independent predictive marker for PPS (p=0.021). Baseline ALC and NLR and dynamic changes in ALC during eribulin therapy were significantly associated with survival benefit including PPS for patients with ABC.

413-P: Renal Tubular Damage Marker, Urinary N-acetyl-b-d-glucosaminidase, as a Predictive Marker of Hepatic Fibrosis in Type 2 Diabetes

Background: Nonalcoholic steatohepatitis is closely associated with the progression of diabetic kidney disease (DKD) in type 2 diabetes (T2D). We investigated whether urinary N-acetyl-β-D- glucosaminidase(u-NAG), an early renal tubular damage biomarker in DKD, could be related to the degree of hepatic fibrosis in patients with T2D. Methods: A total of 300 patients with T2D were enrolled in the study. Hepatic steatosis and fibrosis were determined using transient elastography. The levels of urinary biomarkers, including u-NAG, albumin, protein, and creatinine, and glucometabolic parameters were measured. Results: Based on the median value of u-NAG to creatinine (u-NCR), subjects were divided into normal and high u-NCR groups. The high u-NCR group showed a significantly longer duration of diabetes, worsened hyperglycemia, and a more enhanced hepatic fibrosis index. A higher u-NCR was associated with a greater odds ratio for the risk of higher hepatic fibrosis stage (F2 OR 1.99; 95% CI [1.04-3.82]; F3 and F4 OR 2.40, 95% CI [1.52-3.80]). In addition, u-NCR was an independent predictive marker for more advanced hepatic fibrosis even after adjusting for several confounding factors (β = 1.58, P &amp;lt;0.01). Conclusions: The elevation of u-NAG was independently associated with a higher degree of hepatic fibrosis in patients with T2D. Considering the common metabolic milieu of renal and hepatic fibrosis in T2D, the potential use of u-NAG as an effective urinary biomarker reflecting hepatic fibrosis in T2D needs to be validated in the future. Disclosure H. Kim: None. Y. Kim: None. M. Lee: None. Y. Lee: None. E. Kang: None. B. Cha: None. B. Lee: None.