Predictors Of Progression In Patients Research Articles

Intereye Asymmetry as a Predictor of Progression in Patients With Untreated Keratoconus: Findings From a Longitudinal Study.

The purpose of this study was to evaluate interocular predictors of progression in patients with untreated keratoconus. This is a multicenter longitudinal observational study with real-world data collected through the Save Sight Keratoconus Registry. Patients between the period of June 2000 and September 2022 were included in this study. Parameters such as patient age, sex, ocular history, visual acuity, K2, Max-K, and thinnest corneal thickness pachymetry (TCT) were analyzed. There were 4342 untreated eyes from 2171 patients with keratoconus. A total of 333 patients showed progression of either Max-K, TCT, or both, whereas 1838 patients showed stable parameters. Factors associated with a higher incidence of progression in Max-K were younger baseline age (HR 0.96 per year older; 95% CI 0.95-0.98, P < 0.0001) and a higher baseline intereye asymmetry in Max-K (HR 1.02 per higher diopter; 95% CI 1.00-1.04, P = 0.04). A younger baseline age was the only predictor of progression in TCT (HR 0.97 per year older; 95% CI 0.95-0.99, P = 0.001). Age is the most significant predictor of progression for both corneal thinning and progression of Max-K. Interocular asymmetry in Max-K at baseline could be used as part of an algorithm for determining the risk of keratoconus progression. It is recommended that patients with higher interocular asymmetry in Max-K have a closer follow-up of both eyes as they are at a higher risk of progression.

Factors associated with rapid progression in fibrotic interstitial lung disease

BackgroundEarly identification of fibrotic interstitial lung disease (F-ILD) patients with high risk of progression will help initiate early therapeutic intervention and potential improvement of outcomes. This study was designed to assess the predictors of progression in patients with F-ILD. MethodsPatients with F-ILD in Shanghai Pulmonary Hospital between January 1, 2019 and July 31, 2021 were retrospectively analyzed. The patients enrolled were divided into progressive group and non-progressive group according to the specified criteria. Baseline characteristics were collected and a multivariate regression was conducted to identify independent predictors of progression. ResultsOf the 177 F-ILD cases, 87 were enrolled in the progressive group and 90 were in the non-progressive group. The cohort included 11 types of F-ILD, primarily were connective tissue disease-associated interstitial lung disease (CTD-ILD) (43, 24.3 %), idiopathic pulmonary fibrosis (IPF) (39, 22.0 %), interstitial pneumonia with autoimmune features (IPAF) (32, 18.1 %), and unclassifiable (23, 13.0 %). The highest proportion of progression was seen in nonspecific interstitial pneumonia (NSIP) subgroup (66.7 %), followed by IPF (59.0 %) and HP (57.1 %). After adjusting for gender and age, a course of disease longer than 9.5 months (OR: 2.633; 95 % CI: 1.190–5.826, P = 0.017), lymphocyte in peripheral blood more than 2.24 (109/L) (OR: 2.670; 95 % CI: 1.095–6.510, P = 0.031), and emphysema in high-resolution computed tomography (HRCT) (OR: 2.387; 95 % CI: 1.017–5.640, P = 0.046) were independent predictors of progression in F-ILD patients. ConclusionsThis study suggested that in patients with F-ILD, long course of disease, elevated blood lymphocyte and emphysema on HRCT were independent predictors of progression, which may suggest utility in early therapeutic intervention.

Extent of Surgical Resection as a Predictor of Tumor Progression in Skull Base Chordomas: A Multicenter Volumetric Analysis

Skull-base chordomas are aggressive tumors with a propensity for recurrence/progression. Even with standard of care (SoC), 5-year recurrence rates are variable (19%-54%). This high recurrence/progression rate correlates with increased morbidity and mortality. We sought to analyze a multicenter cohort of skull base chordomas to identify predictors of progression in patients receiving SoC. The [Blinded]-Neurosurgery data registry was queried for skull base chordomas treated from 2008-2020. Patients with the histopathologic diagnosis of chordoma were included. The cohort was composed of patients with preoperative and postoperative magnetic resonance imaging. Tumor volume and radiologic characteristics were obtained from axial T2 sequences using a Digital Imaging and Communications in Medicine viewer. Survival analysis was performed using Kaplan-Meier method, and time-to-event multivariate regression was performed to identify independent predictors of progression. The cohort included 195 patients, of which 66 patients met inclusion criteria; median age was 44, and 28 (42%) were females. Fifty-four (82%) received SoC, 7 (11%) resection only, and 5 (8%) radiotherapy only. Median preoperative and postoperative tumor volumes were 11.55 cm3 (0.33-54.89) and 0.34 cm3 (0-42.52), respectively. Recurrence rate with SoC was 37%. Postoperative tumor volume (P= 0.010) correlated with progression. A postoperative volume of >4.9 cm3 (P= 0.044), ≤81.3% of tumor resection (P= 0.02), and lower-clivus location (P < 0.005) correlated with decreased time to progression. Skull base chordomas can be challenging to resect. Even though maximal resection and radiotherapy improve rate of tumor progression, many of these lesions eventually recur. We have identified a postoperative tumor volume of ≥4.9 cm3 and extent of resection of ≤81.3% in this cohort as predictors of progression in patients receiving SoC.

Clinical significance of CA125 in unresectable pancreatic cancer treated with first-line chemotherapy.

745 Background: Serum CA125 is a potential biomarker for diagnosis of peritoneal metastasis in gastric cancer. However, its significance of pancreatic cancer (PC) has not been investigated. Therefore, we aimed to clarify association between serum CA125 and ascites burden, and its kinetics during first-line chemotherapy for PC. Methods: This multicenter retrospective study comprised PC patients who received FOLFIRINOX or gemcitabine plus nab-paclitaxel in first-line setting between Jan 2014 and Dec 2021. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before chemotherapy. The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and clinical response during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 109 patients from 3 hospitals were assessable. The overall survival (OS) was significantly shorter in elevated group than that in non-elevated group (median, 10.7 vs. 21.3 months, p = 0.0002). The median value of CA125 before chemotherapy was elevated according to ascites burden (Non, 36U/ml; mild, 173U/ml; moderate/severe, 575U/ml; p &lt; 0.0001). CA125 elevation, CA19-9 elevation, poor performance status and poor glasgow prognostic score were independent prognostic factors in multivariate analysis. After chemotherapy, the median first-time measure of CA125 was performed in day 41. Among patients with peritoneal dissemination, the median change of CA125 was correlated with clinical response (CR/PR, -0.55%/day; SD, -0.24%/day; PD, 3.35%/day, p = 0.004). After chemotherapy, first-time measure of CA125 was performed in a median of day 41. According to the ROC curve analysis, the optimal cut-off value of increase in CA125 for progressive disease was 1.56 %/day (specificity 94.1%, sensitivity 80%). The median PFS and OS were 1.4 and 6.6 months in increased group and 3.3 months and 14.0 months in non-increased group, respectively (p = 0.016 and p = 0.028). Conclusions: CA125 is considered a clinically useful marker in unresectable PC treated with first-line chemotherapy because CA125 above the ULN is a poor prognostic factor for OS and an increased CA125 can be an early predictor of progression in patients with peritoneal dissemination.

Progression of Mitral Regurgitation in Rheumatic Valve Disease: Role of Left Atrial Remodeling.

IntroductionMitral regurgitation (MR) is the most common valve abnormality in rheumatic heart disease (RHD) often associated with stenosis. Although the mechanism by which MR develops in RHD is primary, longstanding volume overload with left atrial (LA) remodeling may trigger the development of secondary MR, which can impact on the overall progression of MR. This study is aimed to assess the incidence and predictors of MR progression in patients with RHD.MethodsConsecutive RHD patients with non-severe MR associated with any degree of mitral stenosis were selected. The primary endpoint was a progression of MR, which was defined as an increase of one grade in MR severity from baseline to the last follow-up echocardiogram. The risk of MR progression was estimated accounting for competing risks.ResultsThe study included 539 patients, age of 46.2 ± 12 years and 83% were women. At a mean follow-up time of 4.2 years (interquartile range [IQR]: 1.2–6.9 years), 54 patients (10%) displayed MR progression with an overall incidence of 2.4 per 100 patient-years. Predictors of MR progression by the Cox model were age (adjusted hazard ratio [HR] 1.541, 95% CI 1.222–1.944), and LA volume (HR 1.137, 95% CI 1.054–1.226). By considering competing risk analysis, the direction of the association was similar for the rate (Cox model) and incidence (Fine-Gray model) of MR progression. In the model with LA volume, atrial fibrillation (AF) was no longer a predictor of MR progression. In the subgroup of patients in sinus rhythm, 59 had an onset of AF during follow-up, which was associated with progression of MR (HR 2.682; 95% CI 1.133–6.350).ConclusionsIn RHD patients with a full spectrum of MR severity, progression of MR occurs over time is predicted by age and LA volume. LA enlargement may play a role in the link between primary MR and secondary MR in patients with RHD.

Urinary levels of pro-fibrotic transglutaminase 2 (TG2) may help predict progression of chronic kidney disease.

Renal clinical chemistry only detects kidney dysfunction after considerable damage has occurred and is imperfect in predicting long term outcomes. Consequently, more sensitive markers of early damage and better predictors of progression are being urgently sought, to better support clinical decisions and support shorter clinical trials. Transglutaminase 2 (TG2) is strongly implicated in the fibrotic remodeling that drives chronic kidney disease (CKD). We hypothesized that urinary TG2 and its ε-(γ-glutamyl)-lysine crosslink product could be useful biomarkers of kidney fibrosis and progression. Animal models: a rat 4-month 5/6th subtotal nephrectomy model of CKD and a rat 8-month streptozotocin model of diabetic kidney disease had 24-hour collection of urine, made using a metabolic cage, at regular periods throughout disease development. Patients: Urine samples from patients with CKD (n = 290) and healthy volunteers (n = 33) were collected prospectively, and progression tracked for 3 years. An estimated glomerular filtration rate (eGFR) loss of 2–5 mL/min/year was considered progressive, with rapid progression defined as > 5 mL/min/year. Assays: TG2 was measured in human and rat urine samples by enzyme-linked immunosorbent assay (ELISA) and ε-(γ-glutamyl)-lysine by exhaustive proteolytic digestion and amino acid analysis. Urinary TG2 and ε-(γ-glutamyl)-lysine increased with the development of fibrosis in both animal model systems. Urinary TG2 was 41-fold higher in patients with CKD than HVs, with levels elevated 17-fold by CKD stage 2. The urinary TG2:creatinine ratio (UTCR) was 9 ng/mmol in HV compared with 114 ng/mmol in non-progressive CKD, 1244 ng/mmol in progressive CKD and 1898 ng/mmol in rapidly progressive CKD. Both urinary TG2 and ε-(γ-glutamyl)-lysine were significantly associated with speed of progression in univariate logistic regression models. In a multivariate model adjusted for urinary TG2, ε-(γ-glutamyl)-lysine, age, sex, urinary albumin:creatinine ratio (UACR), urinary protein:creatinine ratio (UPCR), and CKD stage, only TG2 remained statistically significant. Receiver operating characteristic (ROC) curve analysis determined an 86.4% accuracy of prediction of progression for UTCR compared with 73.5% for UACR. Urinary TG2 and ε-(γ-glutamyl)-lysine are increased in CKD. In this pilot investigation, UTCR was a better predictor of progression in patients with CKD than UACR. Larger studies are now warranted to fully evaluate UTCR value in predicting patient outcomes.

Baseline predictors of progression of Parkinson\u2019s disease in a sample of Egyptian patients: clinical and biochemical

BackgroundClinical progression of Parkinson’s disease (PD) is highly heterogeneous, and its predictors are generally lacking. Identifying predictors of early disease progression is important for patients’ management and follow-up. The current study aims to identify clinical, neuroimaging and biochemical baseline predictors of motor progression in patients with PD. Forty-five PD patients were assessed at baseline, 6 months and 1 year using MDS-UPDRS total and subscores, Hoehn and Yahr (H&Y), Schwab and England (S&E), International Physical Activity Questionnaire (IPAQ). Baseline New Freezing of Gait Questionnaire (NFOG-Q), Berg Balance Scale (BBS), Ten-Meter Walking Test (10-MWT), and Time Up and Go Test (TUG), Non-Motor Symptoms Scale (NMSS), Beck Depression Inventory (BDI), PD questionnaire 39 (PDQ-39), MRI brain, uric acid, lipid profile and glycated hemoglobin were performed.ResultsSignificant worsening of MDS-UPDRS total, part III scores, H&Y, S&E and IPAQ (p < 0.001) was detected. One-year progression of H&Y and S&E were significantly correlated to disease duration (p = 0.014, p = 0.025, respectively). Progression of H&Y was correlated to baseline TUG (p = 0.035). S&E progression was correlated to baseline MDS-UPDRS total score (rho = 0.478, p = 0.001) and part III (rho = 0.350, p = 0.020), H&Y (rho = 0.401, p = 0.007), PIGD (rho = 0.591, p < 0.001), NFOG-Q (rho = 0.498, p = 0.001), and TUG (rho = 0.565, p = 0.001). Using linear regression, there was no predictors of clinical progression among the used baseline variables.ConclusionDespite the significant motor and physical activity progression over 1 year that was correlated to baseline motor and gait severity, but without predictive value, further similar and longitudinal studies are warranted to detect predictors of early progression and confirm findings.

Оценка некоторых предикторов прогрессирования фиброза печени у больных гепатитом С после успешной элиминации вируса

Objective. To determine environmental and genetic factors associated with fibrosis progression after virus elimination as a result of direct-acting antiviral therapy by follow-up dispensary observation of patients with chronic hepatitis C with moderate and severe liver fibrosis (F2–F3 according to the METAVIR scoring system). Patients and methods. This study included 301 patients (166 men and 135 women) aged 20-64 years with chronic hepatitis C virus (HCV). A sustained virologic response was achieved in all patients after therapy with direct-acting antiviral agents. Patients were followed up for an average of 38 weeks (16–64). Patients were divided into two groups in order to perform comparative evaluation: group I included 257 patients with regression of liver fibrosis and group II – 44 patients with progression of liver fibrosis. Questionnaire and clinical and laboratory data were assessed. In addition, genetic studies of 24 singlenucleotide polymorphisms of genes involved in intracellular immune signaling pathway activation, interferon synthesis, metabolic regulation and cell proliferation were performed in both groups. Results. It was revealed that validated predictors of liver fibrosis progression in patients with chronic HCV after successful virus elimination as a result of therapy with direct-acting antiviral agents are the presence of concomitant type 2 diabetes mellitus, low ALT activity and serum osteopontin levels over 80 ng/mL at the beginning of therapy. Genetic predisposition to liver fibrosis progression is mediated by carriage of the AA genotype of HNF4α rs4812829 (OR = 3.55; 95% CI 1.21–10.41; p = 0.015). Additionally, the G-allele of NAT2 rs1495741, which marks fast xenobiotic acetylation, was found to have protective properties in the dominant genetic model. Carriers of GG- and GA-genotypes had an almost 2-fold lower risk of liver fibrosis progression after antiviral therapy than AA-genotype carriers (OR = 0.49; 95% CI 0.25–0.94; p = 0.029). Conclusion. The risk after successful hepatitis C virus elimination is significantly higher in patients with concomitant type 2 diabetes mellitus. ALT activity and serum osteopontin levels at the beginning of therapy can be estimated as predictors of liver fibrosis progression among laboratory parameters. Moreover, some genetic markers in the form of single-nucleotide polymorphisms of the HNF4α and NAT2 genes were established, which can be used to predict the development of liver fibrosis in patients with hepatitis C after therapy with direct-acting antiviral agents. Key words: hepatitis C, liver fibrosis, predictors, risk factors, diabetes mellitus, osteopontin, single-nucleotide polymorphisms, HNF4α gene, NAT2 gene

Spinal Radiographic Progression and Predictors of Progression in Patients With Radiographic Axial Spondyloarthritis Receiving Ixekizumab Over 2 Years.

To evaluate the long-term effect of ixekizumab (IXE) on radiographic changes in the spine in patients with radiographic axial spondyloarthritis (r-axSpA) by measuring change from baseline through 2 years in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS), and to identify potential predictors of progression. This study evaluates patients from COAST-V (ClinicalTrials.gov: NCT02696785, biologic disease-modifying antirheumatic drug-naïve) and COAST-W (NCT02696798, tumor necrosis factor inhibitor-experienced) who had mSASSS data at baseline in the originating studies and 108 weeks after baseline in the extension study COAST-Y (NCT03129100). We examined the proportion of patients who did not have spinal radiographic progression through 2 years (108 weeks) of treatment with IXE (80 mg every 2 or 4 weeks) and the change from baseline to year 2 in mSASSS. Potential predictors of spinal radiographic progression were also evaluated. Among patients with evaluable radiographs who were originally assigned to IXE (n = 230), mean (SD) change in mSASSS from baseline at year 2 was 0.3 (1.8). The proportion of nonprogressors over 2 years was 89.6% if defined as mSASSS change from baseline < 2 and 75.7% if defined as mSASSS change from baseline ≤ 0. Predictors of structural progression at year 2 (mSASSS change > 0) were age ≥ 40, baseline syndesmophytes, HLA-B27 positivity, and male sex. Week 52 inflammation in Spondyloarthritis Research Consortium of Canada spine was also a predictor of radiographic progression at year 2 in patients with magnetic resonance imaging data in COAST-V (n = 109). The majority of patients with r-axSpA receiving IXE had no radiographic progression in the spine through 2 years of treatment. Predictors were generally consistent with previous studies.

Prognostic signs of an unfavorable course of coronary heart disease in patients with type 2 diabetes mellitus

Background. Despite the successful development of medical technologies in the diagnosis of coronary heart disease, mortality due to cardiovascular diseases in the population of patients with diabetes mellitus (DM) is not reduced. The development of an algorithm for the early diagnosis of coronary heart di­sease and ways to correct it is a topical problem of cardiology and endocrinology. The purpose is to determine prognostic signs for an unfavorable course of coronary heart disease and develop a table of test probabilities in order to enhance the effectiveness of risk stratification in patients with type 2 DM. Materials and methods. During 2017–2019, there were observed 40 patients (16 men and 24 women) with type 2 DM in combination with coronary heart disease. We took into account the presence of acute myocardial infarction, acute cerebrovascular accidents (stroke), repeated surgical interventions (percutaneous coronary intervention, coronary artery bypass grafting) for the last 3 years. The average age of patients was 65.5 years. Results. In total, 119 signs recorded in the first three days from the moment of patient’s admission were analyzed as possible predictors of an unfavorable prognosis. As markers of coronary heart disease, parameters were adopted that showed the highest occurrence in the group of patients with adverse course of DM and coronary heart disease. The most patho­gnomonic predictors of coronary heart disease progression in patients with type 2 DM were left ventricular systolic dysfunction (ejection fraction &lt; 40 %), systolic blood pressure &gt; 160 mmHg or diastolic blood pressure above 100 mmHg, electrocardiographic signs of myocardial ischemia, persisting upon discharge from the hospital. Conclusions. Criteria that negatively affect the long-term outcome of coronary heart disease in patients with type 2 diabetes are decompensation of DM, in particular, a high level of fasting glycemia (&gt; 13 mmol/l), as well as an increase in total cholesterol and low-density lipoprotein cholesterol.

Gain of TPPP as a predictor of progression in patients with bladder cancer.

The present study investigated the role of tubulin polymerization promoting protein (TPPP) in the regulation of bladder cancer (BC) cell proliferation and migration, in addition to the association between TPPP gene copy number amplification and clinicopathological characteristics of BC. TPPP gene amplification was measured in human BC epithelial cells and samples obtained from 52 patients with BC via fluorescence in situ hybridization. TPPP gain was defined as mean TPPP copy number >2.2 per nucleus (cutoff). The neutrophil-to-lymphocyte ratio (NLR) was also obtained from the preoperative data of the patients. For in vitro assays, BC cell lines were transfected with either TPPP small interfering RNAs or scrambled control, following which cell proliferation and migration were determined using Cell Counting Kit-8 and Transwell migration assays, respectively. The percentage of cells with TPPP copy number amplification in the four BC epithelial cell lines (MGH-U1, -U1R, -U3, -U4) examined (86.0-100.0%) was found to be higher compared with that in the normal human uroepithelial cell lines (3.0 and 9.0%). Patients were divided into one- (1.9%), two- (55.8%), three- (7.7%), four- (26.9%) and five-copy (7.7%) types. Results calculated using Fisher's exact test indicated that the gain of TPPP in patients with BC associated significantly with age (P<0.05), advanced histological grade (P<0.001), tumor stage (P<0.05), histological type (P<0.001) and NLR (P<0.05). In MGH-U1R and MGH-U4 cells, cell proliferation and migration were revealed to be significantly lower following TPPP knockdown compared with those in cells transfected with the scrambled control. In conclusion, findings from the present study suggest that TPPP is important for cell proliferation, cell migration and BC progression, such that TPPP copy number assessment would be advised for preoperative urine cytology for urothelial neoplasia diagnosis.

Interim and end-treatment 18F-Fluorocholine PET/CT and bone scan in prostate cancer patients treated with Radium 223 dichloride

To assess the predictive and prognostic aim of interim and end-treatment 18F-fluorocholine PET/CT (FCH-PET/CT) and 99mTc-methilen diphosphonate bone scintigraphy (BS) in patients with castration-resistant prostate cancer and bone metastases (CRPC-BM) treated with Radium 223 dichloride (223Ra). Prospective and multicentre ChoPET-Rad study including 82 patients with CRPC-BM. Baseline, after 3 (interim) and 6 doses (end-treatment) BS and FCH PET/CT were performed in patients who meet the study criteria. Clinical variables, imaging and clinical progression were obtained and their association with progression free survival (PFS), and overall survival (OS) was studied. Agreement between BS and FCH PET/CT response was assessed using Kappa (K) analysis. Median of PFS and OS was 3 and 16 months, respectively. Agreement between interim BS and FCH PET/CT was weak (K: 0.28; p = 0.004). No agreement was observed between end-treatment diagnostic studies. Interim and end-treatment FCH PET/CT were related to PFS (p = 0.011 and p < 0.001, respectively). Therapeutic failure and interim BS and FCH PET/CT showed association with OS (p < 0.001, p = 0.037 and p = 0.008, respectively). Interim and end-treatment FCH PET/CT were good predictors of biochemical progression in patients treated with 223Ra. Therapeutic failure and progression in interim BS or FCH PET/CT were adverse factors for OS.

Polyclonal free light chains in IgA-nephropathy: correlation with clinical and morphological parameters and prognostic significance

BACKGROUND. Mechanisms of the initiation of renal interstitial inflammation and fibrosis caused by immunoglobulin monoclonal free light chains (mFLC) in monoclonal gammopathy are well established. As far as these damage pathways are considered to be universal we hypothesize that polyclonal free light chains (pFLC) could have a similar effect on tubular and interstitial tissue and lead to chronic kidney disease (CKD) progression in primary glomerulopathies. THE AIM of this retrospective study was to analyze the association of pFLC kappa (pFLC-κ) and lambda (pFLC-λ) assessed in serum by Freelite® with clinical and morphological parameters and CKD progression in IgA-nephropathy (IgAN) cohort.PATIENTS AND METHODS. In this retrospective study, we enrolled 24 patients with IgAN proven by kidney biopsy (KBx). pFLC-κ and pFLC-λ levels were assessed in all cases at the time of KBx by Freelite® method (N pFLC-κ=3.3-19.4 mg/l, N pFLC-λ=5.7-26.3 mg/l). The normal κ/λ ratio was the inclusion criterion. In all cases, we determined serum creatinine, estimated glomerular filtration rate by CKD-EPI method (eGFRCKD-EPI), and daily proteinuria. Morphological findings were defined semiquantitatively by light and immunofluorescence microscopy. Oxford MEST-C score was evaluated as well as % of glomerulosclerosis. Correlation between parameters was assessed by Spearman’s coefficient. Cox proportional hazards regression was used to analyze the association of parameters with the progression of CKD estimated as an elevation of serum creatinine ≥25 % from the initial level or the initiation of renal replacement therapy at the end of the follow-up period (median was 28 (7; 37) months).RESULTS. Median of pFLC-κ 30.2 (6.1; 67.5) mg/l, median of pFLC-λ 27.6 (11.1; 92.1) mg/l. Levels of pFLC-κ and pFLC-λ were increased in 66.7 % and 50 % of patients, respectively. eGFR CKD-EPI median was 41 (26; 65) ml/min/1.73m2. Serum creatinine correlates with pFLC-κ (R=0.62, p&lt;0.01) and pFLC-λ (R=0.45, p=0.03). Among morphological parameters pFLC-κ correlates with interstitial inflammation (R=0.47, p=0.02), tubular atrophy (R=0.54, p&lt;0.01), interstitial fibrosis (R=0.44, p=0.03), peritubular capillaritis (R=0.42, p=0.04), T-score (R=0.66, p&lt;0.01) and combined MEST-C score (R=0.45, p=0.03). For pFLC-λ the correlations with tubular atrophy (R=0.45, р=0.03) and Т-score (R=0.56, p&lt;0.01) were shown. In Univariate Cox regression analysis pFLC-κ and pFLC-λ were associated with CKD progression (Exp(ß)=1.053; 95,0 %CI 1.003-1.105; p=0.038 and Exp(ß)= 1.041; 95,0 %CI 1.002-1.082; p=0.038, respectively) CONCLUSION. Polyclonal FLC, mostly pFLC-κ, were associated with tubulointerstitial inflammation and fibrosis in patients with IgAN. Increased levels of either pFLC-κ or λ could be proposed as a predictor of CKD progression in patients with IgAN.

Role of endoplasmic reticulum stress in renal damage after myocardial infarction.

Myocardial infarction (MI) is associated with renal alterations resulting in poor outcomes in patients with MI. Renal fibrosis is a potent predictor of progression in patients and is often accompanied by inflammation and oxidative stress; however, the mechanisms involved in these alterations are not well established. Endoplasmic reticulum (ER) plays a central role in protein processing and folding. An accumulation of unfolded proteins leads to ER dysfunction, termed ER stress. Since the kidney is the organ with highest protein synthesis fractional rate, we herein investigated the effects of MI on ER stress at renal level, as well as the possible role of ER stress on renal alterations after MI. Patients and MI male Wistar rats showed an increase in the kidney injury marker neutrophil gelatinase-associated lipocalin (NGAL) at circulating level or renal level respectively. Four weeks post-MI rats presented renal fibrosis, oxidative stress and inflammation accompanied by ER stress activation characterized by enhanced immunoglobin binding protein (BiP), protein disulfide-isomerase A6 (PDIA6) and activating transcription factor 6-alpha (ATF6α) protein levels. In renal fibroblasts, palmitic acid (PA; 50-200 µM) and angiotensin II (Ang II; 10-8 to 10-6M) promoted extracellular matrix, superoxide anion production and inflammatory markers up-regulation. The presence of the ER stress inhibitor, 4-phenylbutyric acid (4-PBA; 4 µM), was able to prevent all of these modifications in renal cells. Therefore, the data show that ER stress mediates the deleterious effects of PA and Ang II in renal cells and support the potential role of ER stress on renal alterations associated with MI.

Early PSA decline as a predictor of progression in patients with metastatic castration-naïve prostate cancer (mCNPC) treated with abiraterone acetate and prednisone (AA/P).

e17542 Background: Treatment intensification with androgen deprivation therapy (ADT) plus AA/P is a standard of care in patients with metastatic castration naïve prostate cancer (mCNPC). Despite initial responses, nearly all men will eventually progress to castration resistant disease (CRPC). Early changes in PSA while on ADT plus AA/P has significant clinical and therapeutic implications for mCNPC patients, yet limited data is available. We aimed to assess PSA patterns while on therapy with ADT plus AA/P and time to CRPC. Methods: mCNPC patients treated with ADT plus AA/P between June 2017 and February 2019 at the Cleveland Clinic, were included. The primary objective was to describe patterns of PSA change evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. Other endpoints of interest included PSA progression by PCWG3 and CRPC-free survival at 12 and 18 months. Results: A total of 130 patients, 82% Caucasian, median age 69 years, with 50% with de-novo mCNPC, 47% high-volume (60.8% Gleason score ≥8, 16.2% visceral disease, and 53.8%had ≥3 bony lesions) were included. Half of the patients achieved undetectable PSA ( &lt; 0.03) while on therapy. The median time to PSA &lt; 0.03 was 13.1 months (95%CI, 7.6-NE). The greatest PSA reduction occurred at the first 3 months (80%, p &lt; 0.0001), changes after 3 months were small, (4% from 3 to 6 months, p &lt; 0.0001; 3% from 6 to 9 months, p &lt; 0.0001) and not significant from 9 to 12 months. The 12 and 18-months mCRPC-free survival after initiation of ADT plus AA/P was 88.1% and 81.3%, respectively. A PSA &gt; 0.2 at 3 months was associated with a shorter time to mCRPC (p = 0.002). Similarly, a PSA reduction &lt; 98% at 3 months was associated with worse outcomes (12 mo CRPC survival 68.0% vs. 94.9%, respectively; p &lt; 0.001). Conclusions: In this data set, timing and depth of serologic response predicted the early development of CRPC in patients receiving ADT plus AA/P. Further validation is ongoing using data from large randomized clinical trials.

Update on Risk Stratification Model of Smoldering Multiple Myeloma: A Systematic Review

Background: Smoldering multiple myeloma (SMM) was stratified into risk classes based on several models including Mayo clinic and Spanish myeloma working group models. After the revision of diagnostic criteria for multiple myeloma (MM) in 2014, the ultra-high risk SMM patients (&gt;80% clonal plasma cells at two years) were re-classified as active MM patients. Thus, predictors of progression in patients currently diagnosed as SMM are unknown and reassessment of existing models is required. We aim to identify the risk factors associated with progression in SMM patients classified according to updated guidelines. Methods We performed a literature search following PRISMA guidelines and used following bibliographic databases: MEDLINE (Ovid and PubMed), EMBASE, The Cochrane Library and Cochrane Central Register of Controlled Trials (CENTRAL), as well as annual meetings abstracts from inception till 1st,August 2019. We used MeSH and Emtree terms as well as performed open search for "smoldering multiple myeloma", "smoldering myeloma", and "asymptomatic multiple myeloma". Two independent reviewers screened the literature. We used snowballing technique to screen abstracts and reference within articles to include titles. Cochrane collaboration tool was used to asses risk of bias among included studies Results Our search retrieved 419 titles. After going through the titles and abstracts 38 articles were selected for full text review. Final review led to inclusion of 11 articles. Levels of serum M proteins, percentage of bone marrow plasma cells (BMPCs), serum free light chain ratio (FLCr) and PET/CT scan findings of whole body were most consistently and reliably indicated the progression of SMM to MM (Table 1). New studies are suggesting that B-cell maturation levels (BCMA), evolving M-proteins (eMP) and evolving hemoglobin levels (eHb) are also an accurate measure of SMM progression and should be incorporated in the risk stratification models. A study by Gonsalves WI et al. also suggested that levels of circulating clonal plasma cells with a cutoff of 150 was an important prognostic marker in their study. Immunoparesis status and role of Bence Jones proteins in reliably predicting the progression of SMM was debatable because they were significant in univariate analysis but were not significant in multivariate analysis (Table 1). Conclusion Serum M protein levels (2 g/dL), percentage of BMPCs (20%), serum FLCr (20) and PET/CT scan were reliable in predicting the prognosis of smoldering MM. New techniques like B-cell maturation levels(74.4 ng/mL), evolving M-proteins and evolving hemoglobin levels can play a significant role in proposing future risk predictive models of SMM. Role of immunoparesis and Bence Jones proteins is debatable. Table 1 Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau.

Prospective Study of Chromogranin A as a Predictor of Progression in Patients with Pancreatic, Small-Intestinal, and Unknown Primary Neuroendocrine Tumors

Background: Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease. Methods: We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1–24 months. In a post hoc analysis, CgA measured 3–6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels. Results: In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman’s rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to –20%), –12% (23 to –38%), and –73% (–55 to –83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%. Conclusions: In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression.

P915Clinical characteristics, natural history and predictors of disease progression in patients with degenerative mitral stenosis

Abstract Background Mitral annular calcification (MAC) is a common echocardiographic finding and an increasingly recognized cause of degenerative mitral stenosis (DMS). However, little is known about the natural history and predictors of disease progression of DMS, especially compared with rheumatic mitral stenosis (RMS). Purpose To compare the clinical characteristics and disease progression among patients with DMS and those with RMS, and to investigate the determinants of disease progression in DMS patients. Methods We retrospectively reviewed consecutive MS patients with a trans-mitral mean gradient ≥2 mmHg who underwent echocardiography at our institution between January 2014 and December 2017. We selected patients who had an initial and follow-up echocardiography with a ≥3-month interval and without prior and interim mitral valve intervention. DMS was defined as MS with MAC with normal or minimally reduced leaflet motion without tips restriction. RMS was defined as MS with tip restriction, thickening and restriction of leaflet mainly. We defined MAC severity as mild (focal), moderate (marked density &gt;1/3 but &lt;1/2 of the mitral annulus) and severe (marked density involving &gt;1/2 of the mitral annulus) based on previous reports. We calculated disease progression from the annual increase rate of trans-mitral mean gradient. First, we compared the backgrounds and disease progression between DMS group and RMS group. Second, we investigated the predictors of disease progression in DMS group. Results We enrolled 111 patients (64 in DMS group and 47 in RMS group) with a mean follow-up period of 2.1 years. Patients in DMS group were significantly older (79±9 vs. 70±10 years; P&lt;0.01), had higher prevalence of hypertension (P&lt;0.01) and coronary artery disease (P=0.02), and had higher plasma BNP level (P&lt;0.01) than those in RMS group. Baseline trans-mitral mean gradient was slightly lower in DMS group than in RMS group (3.9±1.9 vs. 4.7±1.8 mmHg; P=0.02). There were wide variations among individuals in progression rate (range: 0 to 3.5 mmHg/year in DMS group and 0 to 5.8 mmHg/year in RMS group, respectively), and the progression rate was comparable between DMS group and RMS group (0.49±0.79 vs. 0.61±1.37 mmHg/year; P=0.59). In DMS group, higher prevalence of dyslipidemia (P=0.01) and lower baseline trans-mitral mean gradient (P&lt;0.01) were significantly associated with disease progression even after adjustment for age and sex. Unexpectedly, there was no significant difference in the disease progression regardless of the MAC severity among DMS group (Picture). MAC severity and disease progression Conclusions Progression in DMS group is highly variable, but generally slow as that in RMS group. Initial mean gradient was inversely associated with disease progression in DMS group. Furthermore, baseline MAC severity did not correlate with the progression, suggesting the importance of follow-up echocardiography in spite of the MAC severity and initial mean gradient.

Current Predictors of Atrial Fibrillation Progression

Aim. To identify predictors of progression of atrial fibrillation (AF) in patients with hypertension (HT), coronary heart disease (CHD) and chronic heart failure (CHF) with recurrent AF. Material and methods . The study included 31 2 patients with recurrent AF. The patients were divided into 3 groups according to a leading underlying condition: essential HT (n=1 36), CHD (n=11 2), and CHF with III-IV functional class by NYHA (n=64). The average follow-up duration was 60±3 months. Progression of AF was defined as development of long-standing persistent or permanent AF. Results. All three groups of patients with recurrent AF revealed progression of the arrhythmia from paroxysmal or persistent to a sustained permanent form during the 5-year prospective follow-up. The rate of AF progression in the patients with CHF was significantly higher and accounted for 59% as compared to 46% in the patients with hypertension (p=0.002) and 51% in the patients with CHD (p=0.008). AF progression in patients with HT correlated significantly with left ventricular (LV) hypertrophy (odds ratio [OR] 1.25; 95% confidence interval [95%CI] 1.03-1.52) and increased arterial wall stiffness (OR 2.3; 95%CI 1.95-2.65). The independent predictors of arrhythmia progression in patients with CHD were a history of myocardial infarction (OR 1.23; 95%CI 0.9-1.5), irreversible LV wall motion abnormalities (OR 1.41; 95%CI 1.1-1.7), and increased plasma level of N-terminal pro-A-type natriuretic peptide (Nt-proANP; OR 1.16; 95%CI 0.8-1.4). Reduction in LV ejection fraction below 40% (OR 0.84; 95%CI 0.7-0.89) and increased plasma N-terminal pro-B-type natriuretic peptide (Nt-proBNP; OR 2.3; 95%CI 1.93-2.67) were independent predictors of AF progression from persistent to permanent form in the patients with systolic heart failure. Conclusion. Progression of AF is related to the underlying cardiovascular disease. The early vascular aging syndrome and LV hypertrophy are the main factors of AF progression in patients with HT. Previous myocardial infarction with irreversible hypokinesia is associated with AF progression in patients with CHD. Reduced LV ejection fraction and increased plasma BNP predict AF progression in patients with CHF.

Abstract P4-08-08: Genomic progression, detected by circulating tumor DNA (ctDNA) sequencing, as an early predictor of disease progression in metastatic breast cancer (MBC)

Abstract Background: The availability of multiple therapies has transformed the landscape of MBC, but also brought the challenge of selecting the right therapy for an individual patient. Furthermore, in patients with Hormone Receptor positive (HR+) breast cancer who have bone metastases only it may be difficult to assess effectiveness of therapy via imaging. Peripheral ctDNA detection and analysis by next-generation sequencing (NGS) has gained popularity in cancer diagnosis and therapeutics due to its relative noninvasiveness, ease of use, and high sensitivity. Here, we explore the utility of ctDNA change as a predictor for disease progression in MBC. We hypothesized that genomic progression is a harbinger of subsequent radiologic progression in patients with MBC. Methods: We analyzed change from pre-treatment (baseline) to on-treatment ctDNA mutant allele fraction (MAF) among patients with MBC. Patients receiving standard-of-care therapies or investigational agents on clinical trials at our institution were included. All patients were followed from the date of baseline test until death or data cutoff (6/20/2018). All peripheral blood specimens were collected and analyzed between 1/7/2016 and 3/1/2018 via NGS (Guardant360®). Peripheral blood specimens were sequenced prior to initiation of a new therapeutic regimen (baseline) and subsequently at least once while on-treatment, on average 4-12 weeks later. All patients had a follow-up CT scan of chest, abdomen and pelvis 2-4 weeks after the on-treatment NGS. A priori, we defined genomic progression as increase in ctDNA total MAF of at least 20% from baseline. We utilized Cox regression analysis to identify whether genomic progression was a predictor of radiologic progression, adjusting for common prognostic variables. Results: All patients (N= 77) were female, predominantly White (83.1%), and median age was 57 (range 32 to 77). Fifty one out of 77 patients (66.2%) were ER+, 5 HER2+, and 9 had triple negative breast cancer. The median MAF at baseline was 2.2% (range 0% - 61.7%). Common genomic alterations in ctDNA included PIK3CA, TP53, ESR1, AKT1, NF1. 27 out of 77 (35%) patients showed disease progression on the first subsequent CT scan, while 59 out of 77 (76.6%) progressed during the follow up time. We found that an increase in ctDNA MAF of at least 20% was a strong predictor of disease progression (HR =2.46, CI [1.14-5.32], p=0.02), compared to those who had a MAF increase of less than 20% or a decrease in total MAF. In multi-variable analysis, adjusting for age, number of prior therapies, type of therapy, and visceral metastases, increase in ctDNA remained a significant predictor for subsequent disease progression (HR =3.84, CI [1.63-9.07], p=0.002). Subset results in patients with bone metastases only, and relative comparison of ctDNA with standard tumor markers will be presented at the meeting. Conclusions: Genomic progression, identified by an increase in ctDNA MAF, is potentially an early predictor of subsequent disease progression in patients with MBC. Further research is needed to prospectively evaluate the clinical utility of ctDNA change as a surrogate marker in guiding treatment decision-making for patients with MBC. Citation Format: Velimirovic M, Juric D, Niemierko A, Spring LM, Vidula N, Malvarosa G, Yuen M, Moy B, Isakoff SJ, Ellisen LW, Bardia A. Genomic progression, detected by circulating tumor DNA (ctDNA) sequencing, as an early predictor of disease progression in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-08.