Strong Predictor Of Poor Outcome Research Articles

Solitaire Flow Restoration Thrombectomy for Acute Ischemic Stroke

The promising results of the Solitaire Flow Restoration (FR) With the Intention for Thrombectomy (SWIFT) trial recently led to Food and Drug Administration (FDA) approval of the Solitaire FR stent retriever device for recanalization of cerebral vessels in patients with acute ischemic stroke. To report the early postmarket experience with this device since its FDA approval in the United States, which has not been previously described. We conducted a retrospective analysis of consecutive acute ischemic strokes cases treated between March 2012 and July 2012 at 10 United States centers where the Solitaire FR was used as a single device or in conjunction with other intraarterial endovascular approaches. A total of 101 patients were identified (mean age, 64.7 years; mean admission National Institutes of Health Stroke Scale [NIHSS] score, 17.6). Intravenous thrombolysis was administered in 39% of cases; other endovascular techniques were utilized in conjunction with the Solitaire FR in 52%. Successful recanalization (Thrombolysis in Myocardial Infarction 2/3) was achieved in 88%. The rate of symptomatic intracranial hemorrhage within the first 24 hours was 15%. In-hospital mortality was 26%. At 30 days, 38% of patients had favorable functional outcome (modified Rankin scale score ≤2). Severity of NIHSS score on admission was a strong predictor of poor outcome. Our study shows that a variety of other endovascular approaches are used in conjunction with Solitaire FR in actual practice in the United States. Early postmarket results suggest that Solitaire FR is an effective tool for endovascular treatment of acute ischemic stroke.

Successful Cerclage at Advanced Cervical Dilatation in the Second Trimester

ABSTRACTThe aim of our study is to verify whether some maternal features are related to pregnancy outcome of emergency cerclage when membranes are protruding through the dilated cervix. We present a retrospective review of 20 cases of emergency cervical cerclage performed over a 3 years period at Al Wasl hospital, a tertiary level centers in Dubai. Analysis shows presence of membrane prolapse with infection causing rupture of membranes, to be the strongest predictor of poor outcome. Analysis also reveals a significant association between initial white blood cell count and perinatal outcome. This information is helpful in decision making and counseling patients regarding the likely outcome.How to cite this articleDeb P, Aftab N, Rangwala T. Successful Cerclage at Advanced Cervical Dilatation in the Second Trimester. Int J Infertility Fetal Med 2013;4(2):56-58.

Increased LEF1 Expression and Decreased Notch2 Expression Are Strong Predictors of Poor Outcomes in Colorectal Cancer Patients

Background/Objective. We aimed to examine the expression of lymphoid enhancer factor 1 (LEF1) and Notch2 in colorectal cancer (CRC) and their association with clinicopathologic variables and CRC patients' prognosis. Methods. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot analysis were performed to assess the expression of LEF1 and Notch2 in 184 patients with CRC. Results. We observed a strong negative correlation between LEF1 expression and Notch2 expression (P < 0.001). Both LEF1 mRNA and protein expression increased while the Notch2 mRNA and protein expression decreased in tumor specimens compared with the matched paratumorous normal tissue (P < 0.001). An increase in LEF1 protein expression was significantly associated with lymph node metastases, distant metastasis, advanced TNM (tumor-node-metastasis) stage, and shorter overall survival. A decrease in Notch2 protein expression was associated with poorly differentiated tumors, lymph node metastases, distant metastasis, advanced TNM stage, and shorter overall survival of patients. In the multivariate Cox regression analysis, the LEF1 protein expression (P < 0.001), Notch2 protein expression (P < 0.001), TNM stage (P < 0.001), and the combination of increased LEF1 protein coexpression and decreased Notch2 protein coexpression (P < 0.001) were found to be independent prognostic indicators in CRC. Conclusion. Our results suggest that increased LEF1 coexpression and decreased Notch2 coexpression represent a risk factor for poor overall survival of CRC patients.

Risk factors related to poor outcome after methanol poisoning and the relation between outcome and antidotes – a multicenter study

Introduction. Thorough prognostic and metabolic studies of methanol poisonings are scarce. Our aims were to evaluate the factors associated with sequelae and death from methanol poisoning, to develop a simple risk-assessment chart to evaluate factors associated with sequelae and death from methanol poisoning, and to compare the antidotes ethanol and fomepizole. Patients and methods. We present a retrospective observational case series of methanol-poisoned patients from Norway (1979 and 2002–2005), Estonia (2001) and Tunisia (2003/2004), and patients from two different centers in Iran (Teheran 2004–2009 and Mashhad 2009–2010) who were identified by a positive serum methanol and had a blood acid-base status drawn on admission. The patients were divided into different groups according to their outcome: Survived, survived with sequelae, and died. Results. A total of 320 patients were identified and 117 were excluded. Of the remaining 203 patients, 48 died, and 34 were discharged with neurological sequelae. A pH < 7.00 was found to be the strongest risk factor for poor outcome, along with coma (Glasgow Coma Scale (GCS) < 8) and a pCO2 ≥ 3.1 kPa in spite of a pH < 7.00. More patients died despite hyperventilation (low pCO2) in the ethanol group. Conclusions. Low pH (pH < 7.00), coma (GCS < 8), and inadequate hyperventilation (pCO2 ≥ 3.1 kPa in spite of a pH < 7.00) on admission were the strongest predictors of poor outcome after methanol poisoning. A simple flow-chart may help identify the patients associated with a poor outcome.

Increased expression of CD133 and reduced dystroglycan expression are strong predictors of poor outcome in colon cancer patients

BackgroundExpression levels of CD133, a cancer stem cell marker, and of the α-subunit of the dystroglycan (α-DG) complex, have been previously reported to be altered in colorectal cancers.MethodsExpression levels of CD133 and α-DG were assessed by immunohistochemistry in a series of colon cancers and their prognostic significance was evaluated.ResultsScattered cells positive for CD133 were rarely detected at the bases of the crypts in normal colonic mucosa while in cancer cells the median percentage of positive cells was 5% (range 0–80). A significant correlation was observed with pT parameter and tumor stage but not with tumor grade and N status. Recurrence and death from disease were significantly more frequent in CD133-high expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor groups for both disease-free (p = 0.002) and overall (p = 0.008) survival.Expression of α-DG was reduced in a significant fraction of tumors but low α-DG staining did not correlate with any of the classical clinical-pathological parameters. Recurrence and death from the disease were significantly more frequent in α-DG-low expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor tumors for both disease-free (p = 0.02) and overall (p = 0.02) survival. Increased expression of CD133, but not loss of α-DG, confirmed to be an independent prognostic parameters at a multivariate analysis associated with an increased risk of recurrence (RR = 2.4; p = 0.002) and death (RR = 2.3; p = 0.003).ConclusionsLoss of α-DG and increased CD133 expression are frequent events in human colon cancer and evaluation of CD133 expression could help to identify high-risk colon cancer patients.

Predictors of Failure of Endovascular Revascularization for Critical Limb Ischemia

To characterize predictors of failure when treating critical limb ischemia (CLI) patients with an endovascular intervention as the first-line strategy. This retrospective, registry-based study included 217 consecutive patients with 240 chronic critically ischemic limbs treated with infrainguinal percutaneous trans-luminal angioplasty (PTA) during 2006-2007 at Helsinki University Central Hospital, Finland. The primary outcome measures were death, major (above-ankle) amputation, and the need for surgical re-intervention within 6 months after the primary procedure. The secondary out-come measures were overall major amputation and survival rates as well as the overall need for surgical or any other (surgical or endovascular) type of re-intervention. Predictors of outcome endpoints were identified with a univariate screen, and a Cox regression model was used in the multivariate analysis. Compared to ulcer, gangrene was significantly more strongly associated with amputation within 6 months post-procedurally as well as during the whole follow-up period (p ≤ 0.028). The patient's inability to walk upon hospital arrival was a significant predictor of death, amputation and surgical re-intervention. Mediasclerotic ankle-brachial index (ABI) was an independent predictor of amputation as well as endovascular re-interventions. The strong predictors of poor outcome after endovascular revascularization for patients with CLI are cardiac morbidity, the inability to ambulate upon hospital arrival, and gangrene as a manifestation of CLI. The risk of amputation seems to be significantly higher for gangrene than for ulcer and this matter should be taken into account in the clinical classifications for CLI.

Positron Lymphography: Multimodal, High-Resolution, Dynamic Mapping and Resection of Lymph Nodes After Intradermal Injection of 18F-FDG

The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of (99m)Tc-sulfur colloid ((99m)Tc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media ((99m)Tc-SC and isosulfan blue), unwieldy γ-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of (18)F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from (18)F-FDG was evaluated to optically guide surgical resection of LNs. Imaging of (18)F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of (18)F-FDG and was compared with that of (99m)Tc-SC. Verification of uptake and the ability to use (18)F-FDG CR to guide nodal removal were confirmed histologically. Intradermal injection of (18)F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. (18)F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection. Intradermal (18)F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).

Increased expression of CD133 is a strong predictor of poor outcome in stage I colorectal cancer patients

Objective. Stage I colorectal carcinomas display a highly variable behavior which is not accurately predicted by the available prognostic markers. CD133 is considered a useful marker to identify the so-called cancer stem cells in colorectal cancers (CRCs) and its expression has been shown to have prognostic significance in CRC patients. This study aimed to verify whether immunohistochemical evaluation of CD133 might correlate with the progression risk of stage I CRC patients. Material and methods. Expression levels of the CD133 molecule were analyzed and compared in two series of stage I surgically resected CRC patients showing disease progression and death for the disease and patients with no evidence of disease progression after at least 6 years after surgery. Results. A positive staining for CD133 was detected in 52% of the cases with poor prognosis and only in 9% of the group with good prognosis, and this difference was highly significant (p < 0.001). A significant correlation was detected between CD133 expression and histological parameters, such as tumor budding, vascular invasion, and presence of lymph node micrometastases but not tumor grading, gender, and age. Disease-free survival and cancer-specific survival of CD133 negative tumors were significantly longer compared to positive cases. In multivariate analyses, CD133 staining confirmed to be a predictor of shorter survival independent from vascular invasion but not from lymph nodes micrometastases. Conclusions. These findings demonstrate that CD133 immunostaining is a useful predictor of high risk progression in stage I CRC patients and might help to identify patients eligible for adjuvant chemotherapy.

P-003 Baseline DWI volume predicts successful recanalization in multimodal endovascular therapy for acute ischemic stroke

BackgroundEffective reperfusion is associated with better outcome from acute cerebral ischemia. The pre-intervention clinical and imaging predictors of procedural success in patients treated with multimodal mechanical device strategies (Merci ±...

Neurodevelopmental outcome of preterm very low birth weight infants born from 2005 to 2007

ObjectiveTo evaluate short-term neurodevelopmental outcome (at 24 months of corrected age) and correlations with obstetric and neonatal factors in a sample of preterm very low birth weight infants born and admitted to an Italian tertiary centre between 2005 and 2007. Methods156 infants with a birth weight ≤ 1500 g (gestational age, range: 27–31 weeks) were followed at regular intervals through neurodevelopmental (neurological and psychomotor) assessment up to 24 months of corrected age. A statistical analysis was conducted in order to look for correlations between pre- and perinatal variables and neuropsychomotor outcome at 24 months. Results131 children were classified as normal and the other 25 presented sequelae classified as “minor” in 17 cases and as “major” in eight. The most significant risk factors for a poor outcome were preterm premature rupture of the membranes, bronchodysplasia, late-onset sepsis, postnatal steroid therapy and male gender. The presence of severe abnormalities on brain ultrasound scan and of an abnormal neurological assessment at 40 weeks at term equivalent age were strong predictors of poor outcome. ConclusionsOur study is one of the few investigating the short-term outcome of preterm VLBW Italian children born in the second half of the 2000s. Neurodevelopmental assessment at 24 months revealed a marked reduction in major sequelae. Several risk factors for a poor neurodevelopmental outcome identified in children born in earlier periods were confirmed in these children born in recent years.

Elderly trauma patients have high circulating noradrenaline levels but attenuated release of adrenaline, platelets, and leukocytes in response to increasing injury severity

High patient age is a strong predictor of poor outcome in trauma patients. The present study investigated the effect of age on mortality and biomarkers of sympathoadrenal activation, tissue, endothelial, and glycocalyx damage, coagulation activation/inhibition, fibrinolysis, and inflammation in trauma patients at admission. Prospective observational study. Single level I trauma center. Eighty adult trauma patients (≥18 yrs) who met criteria for full trauma team activation and had an arterial cannula. Blood sampling a median of 68 min (interquartile range 48-88) post injury. Data on demography, biochemistry, Injury Severity Score, and 30-day mortality were recorded and plasma/serum was analyzed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, annexin V, thrombomodulin, syndecan-1), platelet activation (soluble CD40 ligand), coagulation activation/inhibition (prothrombin fragment 1.2, thrombin/antithrombin complex, antithrombin, protein C, activated protein C, protein S, soluble endothelial protein C receptor, tissue factor pathway inhibitor, von Willebrand factor, fibrinogen, factor XIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1), and inflammation (interleukin-6, terminal complement complex). Patients were stratified according to the median age (46 yrs) of the full cohort. Older trauma patients had markedly higher noradrenaline (p < .001) but an attenuated increase in adrenaline with increasing Injury Severity Score and lower platelets and leukocytes (both p < .05) compared to the younger patients. Older patients displayed a biomarker profile suggestive of enhanced release, activation, and consumption of the natural anticoagulants (low antithrombin, high activated protein C, protein S, and tissue factor pathway inhibitor) and hyperfibrinolysis (high tissue-type plasminogen activator) (all p < .05 vs. younger patients). Age was an independent predictor of mortality (hazard ratio 1.04 [95% confidence interval 1.01-1.07], p = .005) after adjusting for Injury Severity Score, prehospital Glasgow Coma Scale, and plasma catecholamines. In trauma patients, the association between age and mortality was confirmed. Older patients had high plasma noradrenaline but attenuated adrenaline release with higher Injury Severity Score, impaired platelet and leukocyte mobilization, enhanced consumption of anticoagulants, and hyperfibrinolysis, which may all contribute to the poor outcome in these patients.

Low molecular weight cyclin E is associated with p27-resistant, high-grade, high-stage and invasive bladder cancer

Expression of low molecular weight (LMW) isoforms of cyclin E is a strong predictor of poor outcome in patients with breast cancer. The purpose of this study was to examine the expression of full-length and LMW cyclin E in bladder cancer cell lines and patient tumors. We used western blotting, immunoprecipitation and kinase assays to examine the expression and activity of key cell cycle-regulatory proteins in various human bladder cell lines, both tumorigenic and non-tumorigenic. We also analyzed cyclin E expression, kinase activity and immune complex binding partners in 43 tissue samples from grade 2 and 3 transitional cell carcinomas. Cyclin E was overexpressed and LMW isoforms were present only in bladder cancer cells. Overexpression of LMW isoforms of cyclin E and increased cyclin E kinase activity were both significantly associated with tumorigenicity of the bladder cell lines (p = 0.005 and 0.022, respectively). Binding of the cyclin-dependent kinase inhibitors p21 and p27 to LMW cyclin E did not inhibit the kinase activity of cyclin E and cyclin-dependent kinase 2 in primary tumor samples overexpressing LMW cyclin E. Full-length and LMW cyclin E were significantly overexpressed in grade 3 tumors compared with grade 2 tumors (p = 0.004). Finally, LMW cyclin E levels were significantly associated with a non-papillary growth pattern (p = 0.031) and invasiveness (p = 0.021) of the bladder tumors and poor overall survival (p = 0.06). These results suggest that LMW cyclin E can be used as a new prognostic marker for bladder cancer.

Early risk factors for neonatal mortality in CAKUT: analysis of 524 affected newborns

Congenital abnormalities of the kidney and urinary tract (CAKUT) are significant causes of morbidity. The aim of the study was to determine predictive factors of mortality in newborns with CAKUT. All 29,653 consecutive newborns hospitalized in a tertiary neonatal unit between 1996 and 2006 were evaluated. The main outcome was neonatal mortality. The variables analyzed as risk factors were maternal age, first pregnancy, low birth weight (LBW), prematurity, oligohydramnios, and CAKUT associated with other malformations (Associated CAKUT). CAKUT was detected in 524 newborns, with an overall prevalence of 17.7 per 1,000 live births. A total of 325 (62%) cases were classified as urinary tract dilatation, 79 (15.1%) as renal cystic disease, and 120 (22.9%) as other subgroups. In the urinary tract dilatation subgroup, independent risk factors for early mortality were Associated CAKUT [odds ratio (OR) 20.7], prematurity (OR 4.5) LBW (OR 3.8), oligohydramnios (OR 3.0), and renal involvement (OR 3.0). In the renal cystic disease subgroup, two variables remained associated with neonatal mortality: LBW (OR 12.3) and Associated CAKUT (OR 21.4). The presence of extrarenal anomalies was a strong predictor of poor outcome in a larger series of infants with CAKUT.

Abstract 4036: Collateral Status And Stroke Severity Is Important In Thrombolytic Therapy Of Internal Carotid Artery Occlusion

Background: Despite the poor prognosis in patient with internal carotid artery occlusion (ICAO), optimal management is uncertain. However, mechanical thrombectomy showed promising results in recanalization of ICAO, the prognosis of patients with ICAO after thrombolytic therapy is still unsatisfactory. The futile recanalization of ICAO might be related from the initial poor collateral flow and severe stroke. We performed a retrospective analysis of clinical and imaging data of patients who received endovascular treatments due to acute symptomatic ICAO to reveal the factors associated with good outcome at 3 months. Methods: From the stroke database, patients with ICAO were recruited. Inclusion criteria were 1) acute symptomatic ICAO within 6 hours of symptom onset, 2) attempted endovascular revascularization, and 3) enabled 3 months follow-up. Factor associated good outcome (modified Rankin scale score 0-2) at 3 months were evaluated including collateral grading, which was assessed with the ASITN/SIR Collateral Flow Grading System on pre-treatment angiography. A score of grade 0-1 was designated as poor, grade 2-3 as good collateral flow (no patients with ICAO showed grade 4 collateral). Results: During 8 year study period, total 80 patients were enrolled , good collateral flow was shown in 35 patients (44%) and poor collateral in 45 (56%). The patients with good collateral had lower National Institute of Health Stroke Scale (NIHSS) score comparing with poor collateral (15 ± 5 vs. 18 ± 4, p = 0.008) and less frequently suffered symptomatic intracranial hemorrhage (14% vs. 40%, p = 0.02). Multivariate analysis revealed that good collateral flow before treatments [OR 6.77, 95% CI, 1.12-41.05] and complete recanalization after treatments [OR 9.18, 95% CI, 1.13-74.04] were independent predictors of good outcome at 3 months. Whereas, higher NIHSS score were strong predictor of poor outcome [OR 0.74, 95% CI, 0.577-0.95] after adjusting age, sex, onset-to-treatment time, parenchymal hematoma, initial glucose and systolic blood pressure. Conclusions: In acute symptomatic carotid artery occlusion, the patient with initial good collateral flow with less severe neurological deficit and subsequent complete recanalization had higher chance of good outcome. To avoid futile recanalization in ICAO, collateral assessment and achieving complete recanalization might be important.

Abstract 3198: Procedural Outcomes in Mechanical Thrombectomy for Acute Stroke: Atrial Fibrillation Predicts Single Device Therapy

Background Timely and efficient reperfusion is associated with better outcome from acute cerebral ischemia. The predictors of procedural success in patients treated with multimodal mechanical device strategies (Merci ± Penumbra ± angioplasty and stenting) have not been well delineated. Methods In a prospectively maintained database, we analyzed consecutive patients with acute ICA and M1 occlusions treated with endovascular recanalization following multimodal MRI. We investigated the pretreatment clinical and imaging factors affecting three procedural outcomes: number of passes, single device-type therapy, and presence of SAH after the procedure. We also sought to determine the relationship between these procedural variables with substantial recanalization (TICI≥2b) and clinical outcome. Results Among 105 patients meeting study entry criteria, mean age was 66.6 (±17.8), 65% were female and 34% had history of atrial fibrillation. The median pretreatment NIHSS was 18 (range 2-31), mean baseline DWI volume was 30.6cc (SD±35.1), and mean time to groin puncture was 412min (SD±207.6). The median number of mechanical device passes was 2 (range 0-8). 73 (70%) patients were treated with a single device. IV tPA was used in 43 patients (41%). Substantial recanalization occurred in 43 patients (41%). In the final binary logistic regression multivariate analysis, among all baseline clinical and imaging variables, history of atrial fibrillation was the most significant factor associated with a single device therapy (OR 0.249; p=0.024). Age, gender, baseline DWI volumes, arterial occlusion site and time to recanalization did not correlate with the number of attempts, single or multiple device usage, or presence of SAH after the procedure. None of the procedural or baseline variables correlated with recanalization rates. The strongest predictors of poor outcome (mRS≥3 at discharge) were high baseline NIHSS (OR 0.87; p&lt;0.001) and presence of SAH after the procedure (OR 0.05; p=0.001). However, the presence of SAH did not correlate with the number of attempts or devices used. Conclusions: A history of atrial fibrillation predicts single device usage in mechanical thrombectomy for acute ischemic stroke treatment. This is likely due to the fibrin-rich histological composition of the clot. In contrast to prior studies involving a single type of device, increased number of passes with multiple different mechanical devices was not associated with lower recanalization rates and did not worsen clinical outcome.

Prediction of Outcomes for Emergency Cervical Cerclage in the Presence of Protruding Membranes

The aim of our study is to verify whether some maternal features are related to pregnancy outcomes of emergency cerclage when membranes are protruding through the dilated cervix. We present a retrospective review of 20 cases of emergency cervical cerclage performed over a 3-year period at Al Wasl hospital, a tertiary level centre in Dubai. Analysis shows presence of membrane prolapse with infection causing rupture of membranes, to be the strongest predictor of poor outcome. Analysis also reveals a significant association between initial white blood cell count and perinatal outcome. This information is helpful in decision making and counseling patients regarding the likely outcome.

DNA Microarray Analysis in DLBCL Dependent on Skp2 Expression,

Abstract 3695 BackgroundThe heterogeneity of diffuse large B-cell lymphoma (DLBCL) has prompted the search for new markers that can accurately separate prognostic risk groups. We previously reported in multivariate analysis that Skp2 high expression by immunohistochemical method was a strong predictor of poor outcome in DLBCL patient treatment with CHOP and CHOP-R. (Ann of Oncology, 2010 21:833). However the precise mechanisms that regulate Skp2 expression in lymphoma are not fully understood. To better characterize the molecular mechanisms, we performed the DNA microarray study on uniformly treated DLBCL patients. Material and MethodsTotal RNA was extracted from fresh tumor samples. All patients were diagnosis of de novo DLBCL. We compared with high(n=12) and low-Skp2(n=10) groups. Gene expression profiling was performed with the use of Illumina Human WG-6 array. The raw signal intensities of all samples were log2-transformed and normalized by rsn algorithm with □elumi’ library package on Bioconductor software. We selected the probes, excluding the control probes, where the detection p-values of all samples were less than 0.01 and use them to identify differentially expressed genes.Then we applied Linear Models for Microarray Analysis (limma) package of Bioconductor software. To identify up or down-regulated genes between high and low Skp2, we calculated Z-scores and ratios (non-log scaled fold-change) from the normalized signal intensities of each probe. ResultsWe selected 633 genes, 311 upregulated and 322 downregulated, which showed significant differences with a P-value of <0.01. Heat map of the differentally expressed genes between high and low-Skp2 groups (Figure 1). In addition, IPA (Ingenuity pathway analysis) showed clearly the network composed of cell cycle regulators, which mediate cell cycle progression during the G1/S checkpoint. A computer-assisted approach was used to procure specific molecular signalling pathways that were aberrantly expressed in DLBCL cells. Several genes related to cyclins and cell cycle regulation and to the MAPK, WNT, NF-kƒÀ and Myc mediated apoptosis signalling pathways were altered in DLBCL cells when compared with Skp2 levels. Gene highly expressed in high Skp2 included CDKN2A, MTA3, and TUBB2A. CDKN2A is known as a gene encoding a CDK inhibitor which functions in cell cycle regulator and the regulator of Myc pathway, and TUBB2A is known as a regulatory gene of the Mitosis. Recent studies have revealed that Skp2 is a transcriptional coactivator of Myc. MTA3 (Metastasis –associated protein 3), which was direct corepressor WNT4 pathway, was a high average increase (1.16-limma/log-fold change, respectively) in high Skp2 DLBCL. Although the basis for differentiation blockade is unkown in DLBCL, recent data suggest that BCL6 binding to the MTA3 corepressormight be involved. Additional biochemicaland functional studies are needed to determine whether MTA3 is a transcriptional factor of the Skp2 oncogene. The synergistic interaction of Myc, MTA3, and Skp2 may enhance the aggressiveness of Skp2-overexpressing lymphoma cells. [Display omitted] ConclusionsThese genes may play a significant role in the pathogenesis of DLBCL anddeserve further investigation as candidates for new therapeutic targets. Disclosures:No relevant conflicts of interest to declare.

Gain of 1q21 Is a Cytogenetic Independent Risk Factor in Light Chain Amyloidosis Patients Treated with Melphalan / Dexamethasone As First-Line Therapy,

Abstract 3946▪▪This icon denotes a clinically relevant abstractThe aim of the current study was to identify cytogenetic risk factors as detected by iFISH in light chain (AL) amyloidosis. We analyzed a cohort of 91 consecutive patients receiving first-line chemotherapy according to the melphalan / dexamethasone protocol (M-Dex) (Palladini et al., Blood 2004, Dietrich et al., Blood 2010). Our study population consisted of patients not eligible for high dose chemotherapy due to age, reduced general health and the severity of heart involvement. Accordingly, the median age was 67 years (range 40 – 77 years), the median Karnofsky index 80% (50% – 90%), the median number of involved organs 2 (range: 1 – 6). 71/91 (78%) patients had cardiac involvement, among them 45 with NYHA stage III/IV. The median NTproBNP values were 4004 ng/l (range 71–48.292) ng/l, the median dFLC – designating the differential between the involved minus the uninvolved serum free light chain – was 204 mg/l (range 1 – 3.888 mg/l). The estimated median follow-up since start of M-Dex was 38 months.Translocation t(4;14) and deletion del17p13, which have been established as indicators of poor prognosis in multiple myeloma, are very rarely detected in AL amyloidosis (Bochtler et al., Blood 2008). In this study cohort we could only detect 4 out of 91 patients (4%) with at least one of these two cytogenetic aberrations. We therefore focused on gain of 1q21, which has also been described as an adverse prognostic factor in multiple myeloma and is more prevalent in AL amyloidosis (Bochtler et al., Blood 2011). Accordingly, 21/91 patients (23%) in our study cohort tested positive for gain of 1q21. The patient groups with and without gain of 1q21 were comparable regarding age, Karnofsky index, number of involved organs and the NTproBNP values to account for cardiac involvement. However, dFLC was higher in gain of 1q21 positive patients (table 1).Table 1Factor (median)Gain 1q21No gain 1q21pAge69660.17Karnofsky Index75800.70Number of involved organs230.30NT-proBNP425140040.81dFLC2801540.01In univariate analysis, gain of 1q21 was associated with a statistically significant inferior overall survival (OS, p=0.001, figure 1). The median OS was 12.5 months in patients with gain of 1q21 as compared to 38.3 months in those without. Statistical significance was also reached for hematologic event free survival (EFS, 2.8 months versus 4.1 months, p=0.04, figure 2) Hereby, failure to achieve at least a partial hematologic remission to the first 3 M-Dex cycles was counted as an event along with death, hematologic relapse or progression and initiation of an alternative chemotherapy regimen in order to account for patients initially unresponsive to M-Dex. [Display omitted] [Display omitted] In multivariate analysis we tested the prognostic significance of gain of 1q21 in comparison with established hematologic and clinical parameters including age, gender, kappa versus lambda light chain restriction, the detection of an intact immunoglobulin, dFLC values, Karnofsky index, number of involved organs and NTproBNP values using the proportional hazards model of Cox. Markedly, gain of 1q21 was confirmed as a strong predictor of poor outcome for OS (p<0.001), along with Karnofsky index, NTproBNP and age (p=0.03, p<0.001 and p=0.05, respectively). Again, statistical significance for gain of 1q21 and NTproBNP was also observed for EFS (p=0.04 and p=0.03, resp.).In conclusion, we have identified gain of 1q21 for the first time as an independent adverse risk factor in AL amyloidosis in a patient cohort with advanced disease uniformly treated with the standard therapy M-Dex. The poor outcome in these patients seems to be attributable to a worse responsiveness of the plasma cell clone to M-Dex. Further studies are required to test whether the poor prognosis conferred by gain of 1q21 is inherent with this cytogenetic aberration irrespective of the chosen therapy regimen or whether the poor prognosis can be overcome by alternative treatment strategies in these high risk patients. Disclosures:No relevant conflicts of interest to declare.

Predictors of survival among older adults with ependymoma

The biological process of aging encompasses a multitude of complex physiological and lifestyle changes that may alter the way typical prognostic factors affect survival among older ependymoma patients. Because very little is known about the clinical significance of traditional prognostic factors and the magnitude of their effects among older individuals, the purpose of this study was to evaluate the associations between survival and demographic and tumor characteristics among patients with ependymoma who were 60 years of age or older. Using the 1973-2007 dataset from the Surveillance, Epidemiology and End Results (SEER) program, we evaluated the impact of several factors on both overall and ependymoma-specific survival, utilizing multivariable Cox proportional hazards regression. We identified 367 ependymoma cases who were 60 years of age or older at diagnosis and had complete data from SEER. Of these, 19 (5.2%) had anaplastic tumors; all others were low-grade tumors. Age, tumor site, extent of surgery, and tumor histology were found to be significant predictors of ependymoma prognosis. The strongest predictor of poor outcome was supratentorial tumor location (adjusted HR: 6.94, 95% CI: 3.19-15.08, compared to spinal cord tumors). Our study suggests that tumor location, tumor histology, and surgical margin may be key predictors of survival among older ependymoma patients. We believe our study is one of the first to assess the prognostic value of these factors for ependymoma survival exclusively in an older patient population.

Predictors of outcome in patients consulting their general practitioners for headache: A prospective study

Headache is the most common neurological symptom presenting to general practitioners (GPs). Identifying factors predicting outcome in patients consulting their GPs for headache may help GPs with prognosis and choose management strategies which would improve patient care. We followed up a cohort of patients receiving standard medical care, recruited from 18 general practices in the South Thames region of England, approximately 9 months after their initial participation in the study. Of the baseline sample (N = 255), 134 provided both full baseline and follow-up data on measures of interest. We determined associations between patients’ follow-up scores on the Headache Impact Test-6 and baseline characteristics (including headache impact and frequency scores, mood, attributions about psychological/medical causes of their headaches, satisfaction with GP care and illness perceptions). Greater impact and stronger beliefs about the negative consequences of headaches at baseline were the strongest predictors of poor outcome at follow-up.