Markers For Prediction Of Outcome Research Articles

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.

Added Value of Frequency of Imaging Markers for Prediction of Outcome After Intracerebral Hemorrhage: A Secondary Analysis of Existing Data.

Frequency of imaging markers (FIM) has been identified as an independent predictor of hematoma expansion in patients with intracerebral hemorrhage (ICH), but its impact on clinical outcome of ICH is yet to be determined. The aim of the present study was to investigate this association. This study was a secondary analysis of our prior research. The data for this study were derived from six retrospective cohorts of ICH from January 2018 to August 2022. All consecutive study participants were examined within 6 h of stroke onset on neuroimaging. FIM was defined as the ratio of the number of imaging markers on noncontrast head tomography (i.e., hypodensities, blend sign, and island sign) to onset-to-neuroimaging time. The primary poor outcome was defined as a modified Rankin Scale score of 3-6 at 3 months. A total of 1253 patients with ICH were included for final analysis. Among those with available follow-up results, 713 (56.90%) exhibited a poor neurologic outcome at 3 months. In a univariate analysis, FIM was associated with poor prognosis (odds ratio 4.36; 95% confidence interval 3.31-5.74; p < 0.001). After adjustment for age, Glasgow Coma Scale score, systolic blood pressure, hematoma volume, and intraventricular hemorrhage, FIM was still an independent predictor of worse prognosis (odds ratio 3.26; 95% confidence interval 2.37-4.48; p < 0.001). Based on receiver operating characteristic curve analysis, a cutoff value of 0.28 for FIM was associated with 0.69 sensitivity, 0.66 specificity, 0.73 positive predictive value, 0.62 negative predictive value, and 0.71 area under the curve for the diagnosis of poor outcome. The metric of FIM is associated with 3-month poor outcome after ICH. The novel indicator that helps identify patients who are likely within the 6-h time window at risk for worse outcome would be a valuable addition to the clinical management of ICH.

Net water uptake as a predictive neuroimaging marker for acute ischemic stroke outcomes: a meta-analysis.

To assess the role of net water uptake (NWU) in predicting outcomes in acute ischemic stroke (AIS) patients. A systematic review and meta-analysis were performed, adhering to established guidelines. The search covered PubMed, Scopus, Web of Science, and Embase databases until July 1, 2023. Eligible studies reporting quantitative ischemic lesion NWU in admission CT scans of AIS patients, stratified based on outcomes, were included. Data analysis was performed using R software version 4.2.1. Incorporating 17 original studies with 2217 AIS patients, NWU was significantly higher in patients with poor outcomes compared to those with good outcomes (difference of medians: 5.06, 95% CI: 3.00-7.13, p < 0.001). Despite excluding one outlier study, considerable heterogeneity persisted among the included studies (I2 = 90.8%). The meta-regression and subgroup meta-analyses demonstrated significantly higher NWU in patients with poor functional outcome, as assessed by modified Rankin Scale (difference of medians: 3.83, 95% CI: 1.98-5.68, p < 0.001, I2 = 72.9%), malignant edema/infarct (difference of medians: 8.30, 95% CI: 4.01-12.58, p < 0.001, I2 = 95.6%), and intracranial hemorrhage (difference of medians: 5.43, 95% CI: 0.44-10.43, p = 0.03, I2 = 91.1%). NWU on admission CT scans shows promise as a predictive marker for outcomes in AIS patients. Prospective, multicenter trials with standardized, automated NWU measurement are crucial for robustly predicting diverse clinical outcomes. The potential of net water uptake as a biomarker for predicting outcomes in acute ischemic stroke patients holds significant promise. Further validation through additional research could lead to its integration into clinical practice, potentially improving the accuracy of clinical decision-making and allowing for the development of more precise patient care strategies. • Net water uptake, a CT-based biomarker, quantifies early brain edema after acute ischemic stroke. • Net water uptake is significantly higher in poor outcome acute ischemic stroke patients. • Net water uptake on CT scans holds promise in predicting diverse acute ischemic stroke outcomes.

C-reactive protein (CRP) as a predictive marker for outcomes with avelumab + axitinib (A + Ax) in patients with poor-risk advanced renal cell carcinoma (aRCC): Exploratory analysis from JAVELIN Renal 101.

670 Background: Analyses from the phase 3 JAVELIN Renal 101 trial (NCT02684006) suggested that CRP levels at baseline (BL) and early after treatment may predict outcomes with A + Ax in patients with aRCC. In addition, many patients with International Metastatic RCC Database Consortium (IMDC) poor risk who had prolonged progression-free survival (PFS) and overall survival (OS) were observed at the third interim analysis of OS. We analyzed the association between CRP levels and prolonged PFS/OS with A + Ax in patients with IMDC poor risk. Methods: CRP levels were assessed at screening and on day 1 of each 6-week cycle. Patients in the A + Ax arm with 3 or 4-6 IMDC risk factors were categorized into subgroups with CRP normal (BL CRP &lt;10 mg/L), normalized (BL CRP ≥10 mg/L and ≥1 CRP value decreased to &lt;10 mg/L during 6-week treatment), or non-normalized (CRP ≥10 mg/L at BL and during 6-week treatment). CRP levels were compared in patients with prolonged PFS/OS (PFS ≥24 months [mo] and OS ≥30 mo) or PFS &lt;24 mo (any OS duration). Results: In the A + Ax arm (N=442), 44 and 29 patients had 3 or 4-6 IMDC risk factors, of whom 7 and 5 had prolonged PFS/OS, and 26 and 20 had PFS &lt;24 mo, respectively (Table). Most patients with 3 or 4-6 risk factors with prolonged PFS/OS were in the normal or non-normalized CRP group, respectively. In patients with 3 risk factors with prolonged PFS/OS, CRP levels were generally low at BL and remained low for 24 mo. In patients with 4-6 risk factors with prolonged PFS/OS, CRP levels were high at BL and decreased markedly within 6 weeks, then maintained for 24 mo. Conclusions: In patients with poor-risk aRCC treated with A + Ax, a low CRP level at BL and during treatment or a rapid decrease in high CRP levels might predict favorable long-term outcomes, although CRP levels are unspecific and may increase/decrease with other diseases/comorbidities. Clinical trial information: NCT02684006 . [Table: see text]

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.

A CLINICAL STUDY TO FIND OUT THE RED CELL DISTRIBUTION WIDTH (RDW) CORRELATION WITH NEONATAL SEPSIS MORTALITY

Introduction: In developing countries like India neonatal sepsis is a major cause of mortality . Red cell distribution width (RDW) reflect the degree of inflammation and oxidative stress .As RDW is a readily available pramater and recent studies found that it can taken as a marker of mortality in critical patients 1,2,.However, its role in neonates remains unexplored. Hence, the objective of the present study was to evaluate the association of RDW with neonatal sepsis and its role as a predictive marker for outcome in neonatal sepsis.3, 5 Aims And Objectives: To find out the predictive value of RDW in relation to neonatal sepsis. Materials And Method: Prospective observational study was carried out in a NICU of Saraswathi Institute Of Medical Sciences for a period of 1 year. RDW values of septic neonates are compared with controls .A total of 50 septic neonates and 50 controls were enrolled of same gestational age and weight.RDW values are arranged as above 50th percentile and below 50th percentile. The outcomes of two groups are assessed in relation with RDW. Result And Conclusion: RDW levels were higher among septic neonates as compared to controls with p value of &lt;.001.High RDW is associated with neonatal sepsis and it can take as a marker for mortality associated with neonatal sepsis.

Clearing of circulating tumour DNA predicts clinical response to first line tyrosine kinase inhibitors in advanced epidermal growth factor receptor mutated non-small cell lung cancer

ObjectivesEpidermal growth factor receptor (EGFR) mutations confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, a subset of patients has limited or no response. We investigated the initial dynamics of EGFR mutations detected in circulating tumour DNA (ctDNA) during treatment as a predictive marker of outcome. MethodsA total of 225 patients with advanced EGFR mutated NSCLC were included for consecutive blood sampling in this prospective multicentre study. Out of these, 146 patients received first line TKI and had a baseline blood sample available for EGFR mutation testing with the Cobas® EGFR mutation test V2. For examinations on clearing and clinical outcome, 98 patients who had detectable ctDNA at baseline and at least one follow-up blood sample were included. ResultsFor patients with EGFR mutations present in plasma at baseline, clearing of mutations from the blood during first line TKI served as a positive predictor for objective response rate (p = 0.0008), progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p < 0.0001). This was seen both for patients who cleared the ctDNA within the first 7 weeks of treatment and patients who cleared the ctDNA at a slower pace. Baseline mutation presence was a negative predictor for PFS (p = 0.0069) and OS (p = 0.0340). ConclusionThe current study is the first to confirm, in a sizeable Caucasian cohort, that clearing of EGFR mutations predict outcome to first line TKI in patients with EGFR mutated NSCLC.

536P - A prospective study of diffusion-weighted magnetic resonance imaging for predicting outcome following chemoradiotherapy, in squamous cell carcinomas of the anus

BackgroundAnal Squamous Cell Carcinoma (ASCC) is radically treated by chemoradiotherapy (CRT). The use of DW-MRI as a predictive marker of outcome would enable early individualisation of treatment. We aimed to quantify the changes in mean apparent-diffusion-coefficient (ADCMean) between a DW-MRI at diagnosis and on fraction 8-10 of CRT as a biomarker for cellularity, and correlate these with outcome. MethodsThis prospective study recruited patients with ASCC between October 2014 and November 2017. DW-MRI was performed at diagnosis and after fraction 8-10 of radical CRT. A region of interest (ROI) was delineated for all primary tumours and any lymph nodes >2cm on high-resolution T2 –weighted images and propagated to the ADC map. A pre-defined cut-off for percentage change in ADCMean (ΔADC) was set at<20%. Complete response (CR) was assessed 3 months following completion of CRT. Routine clinical follow up data from patients were collected from NHS electronic systems. ResultsTwenty-three of 29 recruited patients underwent paired DW-MRI scans. The median (range) tumour volume was 13.6 cm3 (2.8 cm3 to 84.9 cm3). The median ΔADCMean between scans was 20.7% (95% CI: 12.7%, 34.1%). Nine of 23 (43%) patients had a change of ADCMean <20%. Two patients failed to achieve a CR, with ΔADCMean of 14.6% and 20.3%, respectively. On routine follow up, 2 further patients had relapsed, with ΔADCMean of -1.2% and 6.8%. ConclusionsIn a subset of patients, <20% ΔADCMean on DW-MRI between diagnosis and day 8-10 of CRT was observed. Four patients in the study demonstrated persistent or recurrent disease, all of whom demonstrated an ADC on or below the pre-specified cut-off. Further investigation of the predictive merit of DW-MRI change, and the optimum cut-off is needed in larger cohorts. Clinical trial identificationNCT02145416. Legal entity responsible for the studyUniversity of Oxford. FundingCRUK EPSRC Cancer Imaging Centre in Oxford, the CRUK Oxford Centre and the NIHR.M Hawkins is supported by Medical Research Council grant MC_UU_00001/2. DisclosureR. Muirhead: Honoraria (self), Fee for lecture: Boehringer Ingelheim. V. Goh: Research grant / Funding (self): Siemens. All other authors have declared no conflicts of interest.

Capecitabine for the treatment of pancreatic cancer

ABSTRACTIntroduction: Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) which is converted to 5FU by a series of reactions catalyzed by different enzymes, the last of the enzymes being thymidine phosphorylase (TP). TP is found to be elevated in tumor cells in comparison to normal cells, which consequently tumor-localizes the production of 5-FU, thereby limiting its systemic toxicity. Today, capecitabine is extensively used for the treatment of many solid malignancies, with a particular focus in breast and gastrointestinal tumors, but also in pancreatic cancer.Areas covered: This review summarizes the pharmacology and the clinical evidence relevant to the use of capecitabine in the treatment of pancreas cancer. The authors provide, furthermore, provide their expert perspectives on its use.Expert opinion: Capecitabine has the advantage over other therapeutics in so much that it has both convenient oral administration and a favorable toxicity profile. Current data has promised the use of capecitabine in all stages of pancreatic cancer. However, predictive markers for outcome and toxicity remain to be validated.

Cystatin C as a predictor of mortality in elderly patients with chronic kidney disease

Background: The prevalence of chronic kidney disease (CKD) in the elderly is high. Serum cystatin C is an accurate marker of kidney function and it also has prognostic utility in CKD patients. The aim of our study was to determine the prediction of serum cystatin C and other markers of kidney function on long-term survival in elderly CKD patients.Methods: Fifty eight adult Caucasian patients, older than 65 years, without known malignancy, thyroid disease and/or not on steroid therapy were enrolled in the study. In each patient, 51CrEDTA clearance, serum creatinine, serum cystatin C, and estimated glomerular filtration rate using different equations were determined on the same day and patients were then followed for 11 years or until their death.Results: The means are as follows: 51CrEDTA clearance 53.3 ± 17.4 ml/min/1.73 m2, serum creatinine 1.62 ± 0.5 mg/dl, serum cystatin C 1.79 ± 0.5 mg/l, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation 40.1 ± 14 ml/min/1.73 m2, Berlin Initiative Study 2 (BIS2) equation 38.9 ± 10.7 ml/min/1.73 m2, full age spectrum (FAS) creatinine equation 43.8 ± 13.8 ml/min/1.73 m2, FAS cystatin C equation 40.1 ± 11.7 ml/min/1.73 m2. In the follow up period, 47 (81%) patients died. Cox regression analysis showed different hazard ratios (HRs) for death: for 51CrEDTA clearance HR 1.022 (95% CI 1.004–1.042; p = .015), serum creatinine HR 1.013 (95% CI 1.006–1.019; p = .001), serum cystatin C HR 2.028 (95% CI 1.267–3.241; p = .003), CKD-EPI creatinine equation HR 1.048 (95% CI 1.019–1.076; p = .001), BIS2 equation HR 1.055 (95% CI 1.021–1.088; p = .001), FAS creatinine equation HR 1.046 (95% CI 1.017–1.074; p = .001), FAS cystatin C equation HR 1.039 (95% CI 1.010–1.071; p = .009).Conclusions: Our results showed the highest HR for serum cystatin C among kidney function markers for prediction of outcome in elderly CKD patients.

Plasma KRAS as a biomarker for pancreatic ductal adenocarcinoma (PDAC).

316 Background: PDAC needs validated diagnostic biomarkers for early detection and predictive markers for outcome. As 95% of PDACs harbor KRAS mutations (mKRAS), circulating tumor DNA (ctDNA) has potential utility in PDAC. We assessed the ability to detect and correlate mKRAS in a metastatic PDAC cohort from Memorial Sloan Kettering Cancer Center. Methods: 10 mL of whole blood was collected. cfDNA was extracted with QIAmp or QIAsymphony DNA extraction kits (Qiagen, Valencia, CA). Directed (KRAS G12D, G12R, G12V, Q61H) or multiplex (G12A, G12C, G12D, G12R, G12S, G12V, G13D) digital droplet PCR (ddPCR) was performed with Raindrop Plus (Raindance Technologies, Billerica, MA) or QX200 (BioRad, Hercules, CA) ddPCR systems. Number and size of liver, lung and lymph node metastases, peritoneal disease (mild, moderate, severe), ascites (trace, small, large) and bone mets (Y/N) were assessed by CT scan. Results: See table. 21 (55%) had detectable ctDNA (ctDNA(+)) with mean mutant allele fraction of 4.5% (0.015-36.8). ctDNA (+) vs (-) PFS and OS from collection were 6.9 and 8.4 months vs. 9.9 and 10.5 (p=0.89 for both). CA19-9, PFS and OS did not correlate with ctDNA tertile (p=0.15, 0.54 &amp; 0.50). On treatment and disease activity were not associated with ctDNA status (p= 0.20 &amp; 0.60). Number and size of liver mets were associated with ctDNA (+) (p=0.006 &amp; 0.007). Conclusions: ctDNA KRAS detection was measurable in metastatic disease with rates consistent with other PDAC reports. Median PFS, OS were lower in ctDNA (+) group but not statistically significant in this diverse cohort. Number and size of liver metastases were significantly higher in ctDNA (+). Future study should focus on practice changing applications with standardized collection, intra-patient comparisons and role of liver disease burden. We have initiated studies to evaluate plasma KRAS prior to and during treatment to address its value as a predictive assay and explore factors affecting ctDNA detection. [Table: see text]

The prognostic value of neutrophil-to-lymphocyte ratio on mortality in critically ill trauma patients.

Recent studies suggest that the neutrophil-lymphocyte ratio (NLR) as a marker of inflammation is associated with mortality in surgical patients. The aim of this study was to determine the prognostic impact of NLR in critically ill trauma patients. This is a retrospective cohort study involving all trauma patients 16 years or older admitted to the surgical intensive care unit of a Level 1 trauma center (January 2013 to January 2014). The predictive capacity of NLR on mortality was assessed using a receiver operating characteristic curve analysis. To identify the effect of the NLR on survival, a separate log-rank test was used. Multivariable Cox proportional hazard modeling was used to identify independent predictors of mortality. During the study period, 1,356 patients met inclusion criteria. Of these, 74% were male, 86% sustained blunt trauma, and the median age was 49 years (interquartile range [IQR], 35). The median Glasgow Coma Scale (GCS) score and Injury Severity Score (ISS) were 15 (IQR, 3) and 13 (IQR, 14), respectively. With the use of the receiver operating characteristic curve analyses at intensive care unit Days 2 and 5, optimal NLR cutoff values of 8.19 and 7.92 were calculated by maximizing the Youden index. Kaplan-Meier curves revealed an NLR greater than or equal to these cutoff values as a marker for increased in-hospital mortality (p < 0.001, log-rank test). The Cox regression model demonstrated that an NLR greater than 8.19 and 7.92 are independently associated with in-hospital mortality at Days 2 and 5, respectively (hazard ratio, 1.602 [p = 0.019] and 3.758 [p < 0.001]). NLR is associated with mortality in critically ill trauma patients. Prospective validation of its role as a predictive marker for outcomes is warranted. Prognostic study, level III.

(300) - Exercise Hemodynamics in PAH: Lessons Utilizing an Indwelling Hemodynamic Monitor

Pulmonary arterial hypertension (PAH) remains a morbid disease requiring better markers for outcome prediction. Although invasive hemodynamics (Hemos) provides valuable prognostic information, their routine use is impractical. The CardioMEMS™ HF System (CMHFS) is indicated for wireless monitoring of PA pressure in heart failure patients (pts). It allows daily Hemo measurements reflecting the total Hemo burden of disease over time. Importantly, assessment of exercise Hemos may allow a novel modality for assessment of therapeutic interventions in PAH. We tested the feasibility of assessing exercise Hemos in PAH pts implanted with the CMHFS during the 6-minute walk distance (6MWD). 11 PAH pts had the CMHFs implanted. Device mPAP, sPAP, dPAP, HR, and CO (sensor pressure based algorithm) and CMHFS derived total pulmonary resistance (TPR), right ventricular (RV) stroke volume and index (SV, SVI), RV work (W), RV power (P) and compliance (SV/PP) were collected pre and post 6MWD and compared using paired-t tests at 1 & 4 mos. Changes in values b/t 1 and 4 mos were also analyzed. Pts consisted of newly (45%) and previously (55%) diagnosed pts with NYHA Class III or IV sxs. All Implanted pts were female, aged 57 ± 9 with IPAH (45%), scleroderma-related (45%) and anorexigen-related (5%) PAH with a mPAP 45 ± 14 mmHg and pulmonary vascular resistance of 600 ± 384 dyn.s.cm-5. There were no peri-procedural complications and no device related SAE’s within the first month post implant. PAH meds were optimized per the treating MD over time. As compared to pre 6MWD Hemos, there was a significant increase (p <0.05) in post 6MWD HR, TPR, sPAP, dPAP, mPAP, RVW and RVP and a significant decrease (p<0.05) in SV, SVI and C. These changes persisted at 4 mos. When comparing changes in isolated pre and post 6MWD values between 1 and 4 mos, there were no differences in pre 6MWD values. However, significant positive changes (p<0.05) in post 6MWD SV, SVI, RVW occurred with a consequent significant decrease in TPR. Use of the CMHFS in a select group of PAH pts with advanced symptoms appears safe and demonstrated with exercise a significant increase in pulmonary pressure and resistance with a coincident decline in RV performance, coupling and efficiency that persisted over time and only marginally improved with optimization of therapy. The clinical impact on these changes will need to be further explored.

Chronic Myeloid Leukemia (CML): BCR-ABL Transcript Levels Halving Time and Relative Reduction Ratio at Months 3 As New Predictors of Outcome. an Argentine Pilot Study

▪BCR-ABL transcript levels (IS%BCR-ABL) in CML patients (pts) allow to define molecular response (MR) to TKIs. MR at 3 months (M3>10%) is the strongest predictor of bad outcome and a point of divergence for changing therapy. Emerging biomarkers are being proposed in order to optimize prognosis in addition to initial MR and other clinical markers. The rate of BCR-ABL decline measured as halving time (HT) for transcript level reduction (RT0.5) at month 3 in 1GTKI (imatinib) treated pts, and the fractional clearance as a relative BCR-ABL ratio (RR3) during the first 3 months in 2GTKI (dasatinib) treated pts were recently proposed as predictive markers of outcome. Optimal responses (OR) were defined upon %ISBCR-ABL values at 3, 6 and 12 months: M3 ≤10%, M6 ≤1% y M12 ≤0,1%. Early time point prognostication could allow better outcome predictions and rapid therapeutic interventions.Aim: to determine whether the rate of BCR-ABL decline as HT and the BCR-ABL transcripts reduction as relative ratio at M3 from baseline, have predictive value in CML pts treated with 2GTKIs.Method: BCR-ABL transcript level was measured by Q-PCR according international recommendations and results were reported as BCR-ABL/ABL on the international scale (IS BCR-ABL %). Molecular monitoring was performed prior treatment (M0) and at months 3 (M3), 6 (M6), 12 (M12) and every 6 months thereafter. RT0.5 from baseline to M3 was calculated as the time to halve by considering an exponential model of reduction during the period. The median RT0.5 and quartiles, were calculated to define rapid declines as those HT in the lowest quartile. RR3 was determined as a relative ratio of transcript clearance at M3 from baseline. The median RR3and quartiles, were considered to define high BCR-ABL clearance as those in the highest quartile. Fisher statistical test was used to determine whether the proportions of good responses were statistically different depending on the decline rate.Results: A total of 77 CML pts were included, first line treatment: Dasatinib (D) 28%, Nilotinib (N) 32% and Imatinib (I) 40%. Sokal risk score was available in 70% pts: low (L) 67%, intermediate (In) 22% and high (H) 11%. Molecular assessment: prior therapy M0 (90%), M3 (60%), M6 (79%), M12 (78%) and M0+M3+M12(39%). Deep responses (MR4.0) were considered as IS%BCR-ABL<0,01 or no detectable transcripts in ≥10000 ABL copies. OR according to first line TKI (I vs D+N), were: M3≤10%: 75% vs 90% and M12 ≤0,1%: 50% vs 65%. RT0.5 median values for I vs D+N groups were 32d vs 16d and RR3 median values were 79% vs 98%. RT0.5 ≤13d and RR3 ≥99% were cut off values for fast responses and high clearance in pts treated with 2GTKI(83%). Milestone molecular result M3≤10% showed 20% pts with M12>0,1% and without MR4.0. All of these pts showed RT0.5 >13d and RR3 <99%. From total pts with OR, 80% pts achieved MR4.0 and all showed RR3≥99% meanwhile the remaining 20% pts who never achieved MR4.0 had RR3<99%. Higher frequencies of OR were observed in low Sokal risk pts, in RT0.5 ≤13d pts and in pts with RR3 ≥99%. High Sokal risk pts had poorer results at milestones molecular responses but those with rapid initial decline (RT0.5 ≤13d) and high BCR-ABL clearance (RR3 ≥99%) achieved molecular responses similar to those observed in the low risk sokal group.Conclusions: Faster BCR-ABL decline and high clearance were related to OR and MR4.0 achievement in 2GTKIs patients. No direct relation between Sokal Index and M12≤ 0,1% was observed. Patients with RT0.5 ≤13d showed higher frequencies of good responses. Statistical differences were not found probably due to low sample numbers. Our data suggests that RT0.5 in 2GTKIs (N+D) patients could have a similar predictive value as reported by Branford in 2014, even though it is known that BCR-ABL measurements tend to be less satisfactory when control gene is ABL, owing to possible non-linear ratios. Whilst there were no statistical correlations probably due to the low sample number, pts with OR but no MR4.0 had low reduction rate RR3<99%. RR3>99% could provide a stronger predictive value for milestone optimal responses achievement in high risk pts. It will be necessary to extend this study including a higher number of patients treated with 2G TKIs. [Display omitted] DisclosuresVarela:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pavlovsky:Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Pavlovsky:Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment.

Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome. We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r(2) = 0.8)-based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma. We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001). We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome.

Trends in the treatment of early-stage Hodgkin lymphoma.

Trends in the treatment of early-stage Hodgkin lymphoma.

37PD - Snps in Angiogenic Factors As Predictive Markers for Outcome in Patients (P) with Advanced Non-Squamous Nsclc (NS-NSCLC) Treated with Carboplatin, Paclitaxel (CP) and Bevacizumab (BEV). Final Results of Angiomet Spanish Lung Cancer Group Trial

37PD - Snps in Angiogenic Factors As Predictive Markers for Outcome in Patients (P) with Advanced Non-Squamous Nsclc (NS-NSCLC) Treated with Carboplatin, Paclitaxel (CP) and Bevacizumab (BEV). Final Results of Angiomet Spanish Lung Cancer Group Trial

Antiangiogenic therapy in recurrent breast cancer with lymphangitic spread to the chest wall: A randomized phase II trial of bevacizumab with sequential or concurrent oral vinorelbine and capecitabine

ObjectivesTo assess efficacy of bevacizumab in combination with oral chemotherapy in patients with breast cancer with lymphangitic spread to the chest wall (LBC). To identify surrogate biomarkers of response to bevacizumab. Patients and methodsWe randomly assigned patients to receive bevacizumab plus either sequential or concurrent oral vinorelbine and capecitabine every 3 weeks. The primary endpoint was time to ultimate progression (TTP); the response rate and overall survival (OS) were secondary endpoints. We performed gene expression profiling on baseline tissue samples collected from triple negative LBC. We assessed circulating endothelial cells (CEC), circulating endothelial progenitors (CEP) and circulating pericyte progenitors (CPP). ResultsA total of 66 patients were enrolled. There was no difference in TTP (median TTP 5.3 vs. 4.8 months, p = 0.21) and in OS (median OS 15.8 vs 11.9 months; p = 0.25) when comparing concurrent vs sequential treatment, respectively. Response rate was 25% vs 28% in the concurrent vs sequential arm (p = 1.00), respectively. A set of 16 genes predictive of response to bevacizumab was identified. The counts of CEPs and viable CECs below the median value were associated with an improved overall survival: 26.6 vs 9.5 months for CEPs and 22.6 vs 11.0 months for viable CECs, respectively (p = 0.02). ConclusionsOral chemotherapy and bevacizumab (BEVIX) is an active regimen in patients with LBC. We support the importance of using LBC as a biological model for investigating angiogenesis inhibitors. CECs and CEPs biomarkers have been identified as predictive markers of outcome and warrant further investigation.

Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

Factors Affecting Clinical Outcomes after CLAG/CLAG-M Chemotherapy in Relapsed/Refractory Acute Myeloid Leukemia

Backgroud:Substantial number of acute myeloid leukemia(AML) patients does not respond to induction chemotherapy (refractory) or relapse after achieving complete remission (CR) with standard induction chemotherapy. In relapsed/refractory AML, therapeutic options are still undefined and unsatisfactory. By the way, new regimen integrating cladribine yields promising outcomes in recent studies. We intended to reveal the efficacy of CLAG/CLAGM and to find out predictive markers for outcome in relapsed/refractory AML patients.Methods:Relapsed/refractory AML patients who were treated with CLAG or CLAGM between 2004.5 - 2014.7 in two institutions (Seoul National University Hospital/Seoul National University Bundang Hospital) were retrospectively reviewed. The regime CLAG consists of cladribine 5mg/m2 on days 1-5, cytarabine 2gm/m2 on days 1-5 and filgrastim 5 mcg/kg on days 0-5. The regimen CLAGM includes addition of mitoxantrone 10mg/m2 to CLAG regimen on days 1-3. We analyzed factors affecting complete remission(CR), relapse free survival(RFS) and overall survival(OS).Results:The total of 56 patients (Male:Female = 36:20, median age 51 years) were analyzed. Overall CR rate was 50%, CR rate was 44% for CLAG, 55% for CLAGM respectively, and was not significantly different between the two regimens (p=0.511). Poor predictive markers for CR rates after CLAG/CLAGM included secondary AML (p=0.006), and poor cytogenetic risk group based on MRC criteria (p<0.001). CR rate was higher whether patients achieved CR before CLAG/CLAGM (p = 0.015). In patients who achieved CR after CLAG/CLAGM, the median RFS was 3.4 months (95% CI 2.0 – 4.9 months); 2.0 months (95% CI 0.0 – 4.7 months) for CLAG and 3.4 months (95% CI 1.0 – 5.9 months) for CLAGM.The median OS who received CLAG/CLAGM was 13.5 months (95% CI; 10.2 – 16.7 months); 13.2 months (95% CI ; 8.9 – 17.5 months) for CLAG and 13.5 months (95% CI ; 10.4 – 16.6 months) for CLAGM, no statistical difference (p=0.899). Poor prognostic factor for OS included secondary AML (p<0.001), poor cytogenetic risk group (p<0.001), presence of FLT3-ITD mutation(p=0.019), whether patients failed to achieve CR before CLAG/CLAGM (p<0.001). Moreover, favorable factor for OS was whether CR period was more than 6 months in 1stinduction chemotherapy (p<0.001) in replased AML patients. The survival period after CLAG/CLAGM chemotherapy was improved when allogeneic stem cell transplantation(ASCT) was given after CLAG/CLAGM as consolidation therapy (p=0.044).Conclusion:CLAG/CLAGM is an efficacious regimen for refractory/relapsed AML as previously reported. Especially whether the patients achieved CR before CLAG/CLAGM is favorable prognostic factor. However, only limited benefit is shown in secondary AML patients and poor cytogenetic risk group patients. Allogeneic ASCT as consolidation therapy is definitely necessary to improve outcome. DisclosuresNo relevant conflicts of interest to declare.