Standard Clinical Indices Research Articles

Radiomics of Intrahepatic Cholangiocarcinoma and Peritumoral Tissue Predicts Postoperative Survival: Development of a CT-Based Clinical-Radiomic Model.

For many tumors, radiomics provided a relevant prognostic contribution. This study tested whether the computed tomography (CT)-based textural features of intrahepatic cholangiocarcinoma (ICC) and peritumoral tissue improve the prediction of survival after resection compared with the standard clinical indices. All consecutive patients affected by ICC who underwent hepatectomy at six high-volume centers (2009-2019) were considered for the study. The arterial and portal phases of CT performed fewer than 60days before surgery were analyzed. A manual segmentation of the tumor was performed (Tumor-VOI). A 5-mm volume expansion then was applied to identify the peritumoral tissue (Margin-VOI). The study enrolled 215 patients. After a median follow-up period of 28months, the overall survival (OS) rate was 57.0%, and the progression-free survival (PFS) rate was 34.9% at 3years. The clinical predictive model of OS had a C-index of 0.681. The addition of radiomic features led to a progressive improvement of performances (C-index of 0.71, including the portal Tumor-VOI, C-index of 0.752 including the portal Tumor- and Margin-VOI, C-index of 0.764, including all VOIs of the portal and arterial phases). The latter model combined clinical variables (CA19-9 and tumor pattern), tumor indices (density, homogeneity), margin data (kurtosis, compacity, shape), and GLRLM indices. The model had performance equivalent to that of the postoperative clinical model including the pathology data (C-index of 0.765). The same results were observed for PFS. The radiomics of ICC and peritumoral tissue extracted from preoperative CT improves the prediction of survival. Both the portal and arterial phases should be considered. Radiomic and clinical data are complementary and achieve a preoperative estimation of prognosis equivalent to that achieved in the postoperative setting.

Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure With Pulmonary Hypertension.

Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in patients with heart failure with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. We thus sought to characterize RV myocyte contractile depression in HFrEF-PH, identify those components reflected by clinical RV indices, and uncover underlying biophysical mechanisms. Resting, calcium-, and load-dependent mechanics were prospectively studied in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 patients with HFrEF-PH undergoing cardiac transplantation and 9 organ donor controls. Unsupervised machine learning using myocyte mechanical data with the highest variance yielded 2 HFrEF-PH subgroups that in turn mapped to patients with decompensated or compensated clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in decompensated clinical RV function, whereas surprisingly, many other major myocyte contractile measures including peak power and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick filament defects, myofibrillar structure was assessed by x-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in decompensated clinical RV function, but not compensated clinical RV function, as compared with controls. This corresponded to reduced myosin ATP turnover in decompensated clinical RV function myocytes, indicating less myosin in a crossbridge-ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Last, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human heart failure. Although there are many RV myocyte contractile deficits in HFrEF-PH, commonly used clinical indices only detect reduced isometric calcium-stimulated force, which is related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients.

Abstract 10282: Biventricular Shape Markers in Repaired Tetralogy of Fallot Associate with Pulmonary Valve Replacement Better Than Standard Clinical Indices

Introduction: Current indications for pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (rTOF) rely on global ventricular measurements but are inconsistently applied, lead to mixed outcomes, and are widely debated. Hypothesis: We aimed to test the hypothesis that specific regional markers of biventricular shape can discriminate differences in ventricular remodeling between rTOF patients that were and were not designated for follow-up PVR better than standard clinical indices. Methods: In this cross-sectional retrospective study, biventricular shape models were fit to CMR images from 84 rTOF patients. A statistical atlas of end-diastolic shape was constructed using principal component analysis. Multivariate regression was used to quantify shape marker and clinical index associations with subsequent intervention status (PVR, n=48 vs. No-PVR, n=36) while accounting for confounders. Clustering analysis was then used to test the ability of statistically significant shape markers and clinical indices to discriminate PVR status as evaluated by Matthews correlation coefficient (MCC). Geometric strain analysis was also conducted to assess shape marker associations with systolic function. Results: PVR status correlated with shape markers associated with RV apical dilation and LV dilation (p<0.001), RV basal bulging and LV conicity (p<0.02), and pulmonary valve dilation (p<0.002). PVR status also correlated with RV EF (p<0.03) and non-significantly correlated with LV ESVi (p<0.06). Clustering analysis revealed that shape markers discriminated PVR status better than clinical indices (MCC=0.49 and MCC=0.28, respectively). These shape markers were also significantly associated with RV and LV radial strain. Conclusions: Biventricular shape markers discriminated PVR status better than standard and current use clinical indices for PVR. These specific, regional features of cardiac morphology can provide mechanistic insight into adaptive vs. maladaptive types of ventricular remodeling that provide the foundation for clinical decision-making but may be overlooked when relying solely on global ventricular measurements.

Scaling vs Comprehensive Periodontal Therapy in Reducing Serum Lipid Levels in Patients with Hyperlipidemia

Chronic inflammatory conditions, such as periodontitis, have shown adverse lipid profiles. The periodontal bacterial burden can induce systemic levels of inflammatory mediators precipitating dyslipidemia. Several studies have provided convincing data linking periodontitis, metabolic syndrome and obesity. Based on these findings, this study gauged the impact of comprehensive periodontal care with surgical therapy on standard periodontal clinical indices, and parameters such as the Body-Mass Index (BMI), Waist-Hip circumference ratio (WHR), and serum lipid levels. Thirty patients with high lipid levels and chronic periodontitis were allocated randomly to group A, receiving complete periodontal therapy, and group B, with scaling only. Apart from BMI and WHR, plaque, and gingival indices, probing depth, total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were recorded before and after three months of intervention. Data analysis utilized the paired t-test and Pearson’s correlation coefficient. Patients receiving complete periodontal treatment showed significantly reduced post-therapy lipid levels (TC, LDL), standard clinical indices (plaque and gingival indices) and probing depth, Body mass index, and waisthip ratio (p< 0.05) compared to their respective baseline levels. Plaque index, Gingival index and probing depth were observed to correlate with total cholesterol levels. Therefore, alleviating conditions with persistent inflammation is essential to manage borderline hyperlipidemia.

Abstract PR03: Genome-wide 5-hydroxymethylcytosine profiles in circulating cell-free DNA and survival in patients with multiple myeloma

Abstract Background: Biomarkers currently used for prognostic stratification or predicting survival in patients with newly diagnosed multiple myeloma (MM) either lack good sensitivity and specificity or require invasive bone marrow biopsies. Aberrant DNA methylation has been associated with poor prognosis and survival in MM. We recently identified a gene panel modified with 5-hydroxymethylcotosine (5hmC), a mark of gene activation, in circulating cell-free DNA (cfDNA) that is associated with relapse or death in patients with diffuse large B-cell lymphoma, another lymphoproliferative disorder. To date, no study has investigated 5hmC in cfDNA for its prognostic significance in MM. Methods: Starting in 2010, we prospectively enrolled patients who were newly diagnosed with MM at The University of Chicago Medical Center. Blood samples were collected at the time of diagnosis. The current report includes data from 184 MM patients. Mortality was ascertained using medical records and the National Death Index. Follow-up was through December 2017, with an average follow-up length of 41.64 months (deceased, n=31; alive, n=153). We profiled genome-wide 5hmC in cfDNA by first using the nano-hmC-Seal technique to construct DNA libraries, which were subjected to next-generation sequencing, mapped to the human genome, and annotated to ~22,000 gene bodies. Cox proportional hazards model and the elastic net regularization, controlling for age, gender, and population, were used to detect 5hmC marker genes associated with overall survival (OS) after diagnosis. Results: For the 184 patients, median age at diagnosis was 61.7 years and 48% (n=88) were males. The differential 5hmC enrichment levels of a preliminary eight-gene marker panel were used to compute a weighted prognostic score (wp-score). In multivariate Cox models, patients with high wp-score had worse OS (Hazard Ratio [HR] = 8.2; 95% Confidence Interval [CI], 2.9-23.4, p < 0.0001), compared with those in the low risk group. Some of the eight 5hmC-midified marker genes have been previously implicated in MM survival. For example, GTF2I (encoding general transcription factor IIi), a known prosurvival gene in MM, showed a single-gene HR of 0.3 (95% CI, 0.1-0.7, p=0.002). The 5hmC-based wp-score outperformed (sensitivity=0.74, specificity=0.84) standard prognostic indices (e.g., albumin, beta-2 microglobulin, and risk classification by cytogenetics) in predicting patients at risk for inferior survival. We are validating the gene panel in an independent cohort of ~150 MM patients. The results will be presented. Conclusions: These findings suggest that 5hmC in cfDNA at the time of diagnosis correlate with OS and outperform standard clinical prognostic indices. Our novel findings, if confirmed, suggest that a plasma-derived cfDNA 5hmC-modified gene panel holds promise as a noninvasive approach for predicting prognosis in MM and may be integrated in clinical practice to improve precision care of MM. This abstract is also being presented as Poster A40. Citation Format: Brian C.-H. Chiu, Zhou Zhang, Jason Karpus, Benjamin Derman, Chang Zeng, Elizabeth Stepniak, Rudy Chiu, John Spinelli, Andrzej Jakubowiak, Chuan He, Wei Zhang. Genome-wide 5-hydroxymethylcytosine profiles in circulating cell-free DNA and survival in patients with multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR03.

Switching From Originator Adalimumab to the Biosimilar SB5 in Patients With Inflammatory Bowel Disease: Short-term Experience From a Single Tertiary Clinical Centre.

Patients' perspectives after switching from originator to biosimilar adalimumab have yet to be assessed. We evaluated the efficacy of switching from the originator adalimumab to a biosimilar compound [SB5] in patients with inflammatory bowel disease [IBD]. Data on IBD patients who were switched from the originator to biosimilar adalimumab [SB5] at IBD Center ISCARE were analysed. Disease activity was assessed using standard clinical indices (Harvey-Bradshaw index [HBI] for Crohn's disease [CD] and partial Mayo score for ulcerative colitis [UC]), and laboratory parameters (C-reactive protein [CRP] and faecal calprotectin [FC]). Trough levels and anti-drug antibodies were measured. Patients were evaluated 10 weeks [W10] after the switch, and results were compared with the control group of patients on originator compound. A total of 93 patients switched to biosimilar adalimumab were included [CD 86%] and were matched to 93 controls for age, gender, diagnosis, and disease activity. There was no difference in the disease activity in either SWITCH or ORIGINATOR cohorts between Weeks 0 and 10. Similarly, no difference was found between cohorts at both prespecified time points. Moreover, no significant differences in CRP or FC concentrations were seen between W0 and W10 either in the SWITCH, or in the ORIGINATOR cohort [p >0.05]. Adalimumab serum trough levels remained stable after the switch. No new safety signals were detected. Our study confirmed that switching IBD patients from the originator adalimumab to a biosimilar compound [SB5] does not affect treatment efficacy.

Power-law scaling behavior of A-phase events during sleep: Normal and pathologic conditions

ObjectiveA-phases are short-time cortical events during sleep that repeatedly disrupt the basal fluctuations of electrical brain activity. They are the basic units of the cyclic alternating pattern (CAP), which is related to the instability and consolidation of the sleep process. The main purpose of this study is to evaluate the temporal occurrence of A-phases (TOAP) under normal and pathologic sleep conditions. MethodsTo derive a quantitative description of TOAP, we have applied detrended fluctuation analysis (DFA), to unveil scale-free behavior from non-stationary time series. Data from sleep recordings of 15 healthy subjects (H), 37 with nocturnal frontal lobe epilepsy (NFLE), 9 with periodic leg movement (PLM), and 22 with REM Sleep Behavior Disorder (RBD) from the Physionet database were used. TOAP was computed from binary time series constructed from A-phase annotations, where symbols 1 and −1, represent the presence or absence of an A-phase, respectively. These time series were analyzed through DFA and characterized by the scaling exponent. ResultsIn all cases, numerical results show evidence that a statistical fractal structure is embedded in TOAP, where persistent scaling behavior is observed with scaling exponent close to 1. ConclusionThe sleep process maintains a similar structure from the A-phase perspective despite of internal or external factors that could affect the sleep process, suggesting that sleep may be a resilient process. SignificanceThe scaling exponent of the A-phase occurrence provides new information about the sleep process that may have clinical relevance and complementary to standard clinical indices such as the CAP-rate.

5-Hydroxymethylcytosines of Circulating Cell-Free DNA and Prognosis in Diffuse Large B-Cell Lymphoma

Background: Elevated levels of circulating cell-free DNA (cfDNA) have been associated with poor prognosis and relapse in patients with diffuse large B-cell lymphoma (DLBCL). However, the tumor-specific molecular targets in cfDNA that have prognostic significance remain unclear. We investigated the association between 5-hydroxymethylcytosine (5hmC), a mark of active demethylation and gene activation, in cfDNA from plasma and prognosis in DLBCL.Methods: We used the 5hmC-Seal, a highly sensitive chemical labeling technique integrated with next-generation sequencing (NGS), to profile 5hmC in plasma cfDNA samples from Caucasian patients at the University of Chicago who were newly diagnosed with DLBCL (n=43) or follicular lymphoma (FL, n=28), the two most common histological subtypes of non-Hodgkin lymphoma (NHL), in 2011-13. Baseline clinical, laboratory, and vital status data were abstracted from medical records. Patients were followed through December 31, 2017 and those who relapsed after completion of treatment, lost to follow-up, or died were censored. We profiled 5hmC with 1-2 ng of cfDNA extracted from ~2 ml of plasma for library construction and the NGS. We obtained ~25 million reads per sample, providing a depth of coverage ~600X in terms of gene bodies. We normalized read counts and identified differential 5hmC markers using DESeq2. Cox proportional hazards model were used to estimate the association between 5hmC markers and overall survival.Results: We found that in cfDNA from DLBCL patients, 5hmC markers were enriched within gene bodies and depleted in CpG islands. The cfDNA-based 5hmC profiles at diagnosis differed between DLBCL and FL, and in DLBCL, the 5hmC profiles differed between Ann Arbor stage (stage 1/2 vs stage 3/4), lactate dehydrogenase (LDH) level (normal vs elevated), and cell-of-origin (germinal center B-like and activated B-cell-like DLBCL). In addition, genome-wide 5hmC distribution patterns in cfDNA samples are highly correlated with those found in cfDNA-paired tumor tissues, supporting the tumor relevance of cfDNA in a patient. Next, we evaluated the prognostic significance of cfDNA-based 5hmC in DLBCL using a two-step approach. In the discovery phase (7 DLBCL patients with relapse and 12 age- and sex-matched patients without relapse within two years following treatment), a substantial number of 5hmC markers were associated with relapse (449 gene bodies at 5% false discovery rate [FDR]). These relapse-associated 5hmC signatures showed high sensitivity, specificity, and overall accuracy (area under curve [AUC]=0.91) in predicting relapse in the independent validation set (relapse=5, no relapse=13). Finally, we identified a panel of 128 5hmC markers (fold change >20% and p-value <0.05) that were associated with 4-year overall survival.Conclusion: These findings suggest that 5hmC signatures in cfDNA at the time of DLBCL diagnosis correlate with standard clinical prognostic indices and hold promise as non-invasive markers for prognosis and survival. DisclosuresSmith:BMS: Consultancy; Portola: Honoraria.

Angiotensin-converting enzyme-inhibitor therapy in adolescents with type 1 diabetes in a regional cohort: Auckland, New Zealand from 2006 to 2016.

To review indications and use of angiotensin-converting enzyme-inhibitor (ACEI) therapy for the treatment of persistent microalbuminuria (MA) and/or hypertension (HTN) in adolescents with type 1 diabetes mellitus (T1DM). Retrospective chart review of adolescent patients with T1DM seen within the paediatric diabetes service in Auckland, New Zealand, from 2006 to 2016. MA, HTN, patient demographic characteristics and ACEI prescribing and monitoring indices were examined. Five hundred adolescents with T1DM were included. There were 26 patients (5%) with MA and/or HTN. MA alone was present in 16, HTN alone in 3 and both HTN and MA in 7. The 5-year MA/HTN-free rate was 98%, and the 10-year MA/HTN-free rate was 93%. Longer disease duration and earlier diagnosis were predictors of MA/HTN. There was no significant difference in standard clinical indices between study patients and others. ACEI was prescribed for 17 of 26 patients for either HTN or MA. Within 6 weeks of ACEI commencement, less than half of the subjects had repeat serum creatinine and MA screens and no record of repeat blood pressure measurement. Despite this, all patients had 3-monthly reviews within outpatient clinics where adjustments of ACEI doses were made. In our regional adolescent population with T1DM, there were low rates of both MA and/or HTN. In those who required treatment with ACEI, clinical monitoring post-commencement of therapy was inconsistent. Local consensus guidelines for the management of persistent MA in children and adolescents with diabetes mellitus were developed in response to this study.

Sudden cardiac death and pump failure death prediction in chronic heart failure by combining ECG and clinical markers in an integrated risk model.

BackgroundSudden cardiac death (SCD) and pump failure death (PFD) are common endpoints in chronic heart failure (CHF) patients, but prevention strategies are different. Currently used tools to specifically predict these endpoints are limited. We developed risk models to specifically assess SCD and PFD risk in CHF by combining ECG markers and clinical variables.MethodsThe relation of clinical and ECG markers with SCD and PFD risk was assessed in 597 patients enrolled in the MUSIC (MUerte Súbita en Insuficiencia Cardiaca) study. ECG indices included: turbulence slope (TS), reflecting autonomic dysfunction; T-wave alternans (TWA), reflecting ventricular repolarization instability; and T-peak-to-end restitution (ΔαTpe) and T-wave morphology restitution (TMR), both reflecting changes in dispersion of repolarization due to heart rate changes. Standard clinical indices were also included.ResultsThe indices with the greatest SCD prognostic impact were gender, New York Heart Association (NYHA) class, left ventricular ejection fraction, TWA, ΔαTpe and TMR. For PFD, the indices were diabetes, NYHA class, ΔαTpe and TS. Using a model with only clinical variables, the hazard ratios (HRs) for SCD and PFD for patients in the high-risk group (fifth quintile of risk score) with respect to patients in the low-risk group (first and second quintiles of risk score) were both greater than 4. HRs for SCD and PFD increased to 9 and 11 when using a model including only ECG markers, and to 14 and 13, when combining clinical and ECG markers.ConclusionThe inclusion of ECG markers capturing complementary pro-arrhythmic and pump failure mechanisms into risk models based only on standard clinical variables substantially improves prediction of SCD and PFD in CHF patients.

Relative Abundance of Streptococcus spp. and its Association with Disease Activity in Inflammatory Bowel Disease Patients Compared with Controls

Background: Some studies show that the gut microbiota is an essential risk factor in driving inflammatory bowel disease (IBD). There are some evidences regarding the involvement of Streptococcus spp. in the pathogenesis of IBD. In this study we compared proportions of Streptococcus spp. in feces of IBD patients and control volunteers. Methods: The freshly prepared stool samples were collected from 29 patients with IBD and 29 healthy volunteers. Disease activity was measured by means of standard clinical indices. Total DNA was extracted from the stool samples and used for relative quantification of Streptococcus spp. based on the real-time PCR method in the patient’s and control’s groups. Results: Results showed a relative increase in abundance of Streptococcus spp. (0.0006 to 34.2 fold increase) and greater population diversity among IBD patients compared with the control group (mean ± standard deviation 2.94 ± 0.37 versus 1.07 ± 0.31). Patients with increased Streptococcus spp. levels represent a higher rate of neutrophil and lymphocyte infiltration than those with the lower levels; however, this increase was not statistically significant. Analysis of body mass index indicated a significant difference between IBD patients and healthy people (P value 0.02). Conclusions: The determined correlation between increases in abundance of Streptococcus spp. and IBD suggests possible involvement of this bacterial genus in promotion or severity of the disease.

Infliximab Biosimilar (Remsima™) in Therapy of Inflammatory Bowel Diseases Patients: Experience from One Tertiary Inflammatory Bowel Diseases Centre

Background: The evidence on the efficacy and safety of biosimilar infliximab (IFX) in patients with inflammatory bowel diseases (IBD) is sparse. Methods: Consecutive IBD patients visiting our centre were included. One cohort composed of prospectively followed patients who were switched from original to biosimilar IFX between January and March 2015. The second cohort included retrospectively assessed anti-tumor necrosis factor α-naïve patients who started therapy between January 2015 and January 2016. Disease activity was assessed using standard clinical indices, endoscopic evaluation, and laboratory parameters (blood count, C-reactive protein (CRP) and fecal calprotectin (FC)). Trough levels and anti-drug antibodies (ATIs) were also measured. Patients were evaluated 56 weeks (W56) after switch and at week 14 (W14) and week 46 (W46) in the naïve cohort. Results: Seventy-four IBD patients were switched to biosimilar IFX and 119 naïve patients newly initiated therapy with the preparation. Disease activity remained stable in a majority of switched patients (remission at week 0 (W0) vs. W56: 72.2 vs. 77.8%; median difference of both Harvey-Bradshaw index and Simple Clinical Colitis Activity Index between W0 and W56 was 0). When W0 and W56 were compared, no significant difference in CRP (4.3 ± 8.0 vs. 3.3 ± 3.8 mg/l; p = 0.89) and FC (135 ± 153 vs. 199 ± 225 µg/g; p = 0.17) was observed. In total, 92% of Crohn's disease (CD) and 83% of ulcerative colitis (UC) patients responded to induction therapy (W14) with biosimilar IFX. At W46, the response rate was 86% in CD and 64% in UC. Moreover, half of UC patients experienced mucosal healing at W14 and improvement of perianal disease occurred in 95% of CD at W46. In this cohort, clear steroid-sparing effect was observed. No increase in immunogenicity was found in switched patients (ATI positivity: 9.5 vs. 6.0%, p = 0.54) and the type and frequency of adverse events were comparable to the original preparation in both cohorts. Conclusion: Switching of IBD patients from original to biosimilar IFX is effective and safe.

Radiotracer imaging of peripheral vascular disease.

Peripheral vascular disease (PVD) is an atherosclerotic disease affecting the lower extremities, resulting in skeletal muscle ischemia, intermittent claudication, and, in more severe stages of disease, limb amputation and death. The evaluation of therapy in this patient population can be challenging, as the standard clinical indices are insensitive to assessment of regional alterations in skeletal muscle physiology. Radiotracer imaging of the lower extremities with techniques such as PET and SPECT can provide a noninvasive quantitative technique for the evaluation of the pathophysiology associated with PVD and may complement clinical indices and other imaging approaches. This review discusses the progress in radiotracer-based evaluation of PVD and highlights recent advancements in molecular imaging with potential for clinical application.

Multimodality imaging of the effects of a novel dentifrice on oral biofilm.

Oral biofilm formation and progression on the surface of the tooth can lead to advanced oral disease such as gingivitis. The purpose of this randomized, controlled, double-blinded study was to evaluate the effects of a novel dental gel on oral plaque biofilm using multimodal imaging techniques. Twenty-five subjects with moderate gingival inflammation (Löe and Silness Gingival Index ≥2) and pocket depths <4 were randomly assigned to brush twice daily for 21 days with the test or the control dental gel. In vivo multimodality in situ imaging was performed over a 3-week period using in vivo Optical Coherence Tomography (OCT) and Non-Linear Optical microscopy (NLOM). Plaque levels, gingival inflammation and gingival bleeding were also charted on days 0, 7, 14, and 21 using standard clinical indices. After 3 weeks, OCT and NLOM images showed a macroscopic break-up of the plaque layer and smaller, fragmented residual deposits in the test group with no apparent changes in the pellicle. Biofilm was also reduced in the control group, but to a lesser degree with regard to thickness, continuity and surface area. Paralleling these imaging results, clinical indices were significantly improved in both groups (P < 0.05) and significantly lower in the test group (P < 0.05). Both dental gels reduced oral biofilm with the test gel showing greater efficacy (P < 0.05) as determined by clinical and imaging parameters.

Analysis of prognostic factors in locally advanced and metastatic pancreatic cancer treated with gemcitabine or gemcitabine and S-1 chemotherapy using individual patient data from three randomized studies.

223 Background: Both gemcitabine (GEM) and S-1, an oral fluoropyrimidine, are shown efficacy for advanced and resected pancreatic cancer (PC). However PC has one of the poorest outcomes in various cancers. In this pooled analysis, the prognostic factors in locally advanced and metastatic PC were evaluated using individual patient data from three randomized studies (Phase III: GEST, randomized phase II: JACCRO PC-01 and GEMSAP). Methods: Patients (pts) were treated with GEM alone or GEM and S-1 (GS) chemotherapy for advanced PC. Evaluated prognostic factors were standard laboratory data, tumor marker (CA19-9, CEA), clinical and pathological indices and treatment related outcomes e.g. efficacy and safety. To identify the optimal cutoff value to divide continuous data into binomial data, maximized log likelihood value for the model were evaluated and the validity of the model was evaluated by the martingale residuals. The Cox proportional hazards model was performed for overall survival. Results: 770 pts were included in this analysis (389 pts were treated by GEM and 381 pts were GS) and 738 events for survival were observed (95.8%). In continuous data, baseline WBC, AST, CA19-9 and CRP were detected as independent prognostic factors and the cutoff values were identified. The results of multivariate analysis and cutoff value were shown in the table. Conclusions: In our analysis, treatment, extent of disease, target lesion, WBC, AST, CA19-9 and CRP were detected as independent prognostic factors and cutoff values were estimated in continuous data. The further examination is necessary, but these data may help future studies. [Table: see text]

Prognostic features and outcomes in primary liver sarcoma.

150 Background: Primary liver sarcoma (PLS) is a rare and aggressive hepatic malignancy. Due to the low incidence of PLS, prognostic factors have not been well characterized. The purpose of our study was to evaluate survival outcomes in primary hepatic sarcomas and determine which factors predict survival. Methods: The Surveillance Epidemiology and End Results registry was used to identify patients with PLS from 1988-2009. Patients were evaluated by standard clinical and pathological indices including: age, gender, race, tumor size, tumor grade, histology, and extent of disease. Treatment related factors included surgery and radiation. Overall survival was assessed by Kaplan-Meier method. Univariate and stepwise multivariate Cox proportional hazards analyses were performed to identify prognostic factors. Results: 541 patients with PLS were identified. The mean age was 52 and most patients were male (55%) and white (75%). The most common histology type was blood vessel tumors (50.1%) followed by soft tissue neoplasms (17.7%) and complex mixed-stromal neoplasms (14.6%). Only 33% of patients underwent surgery and most (93%) did not receive radiation. When assessing outcomes, we observed median overall survival (OS) and cancer specific survival (CSS) of 6 months for the entire cohort. When stratified by treatment type, those who received surgery + radiation had the best survival (MS=97mos, p&lt;.001) compared to those who received either radiation alone (MS=5mos) or no treatment (MS=2mos). Stepwise multivariate analysis showed that age, male gender, tumor size, advanced stage, and no surgery were independent predictors of worse survival, all p-values &lt; .005. Conclusions: Primary liver sarcoma is an aggressive hepatic malignancy with low median OS of 6 months. Patients treated with surgery + radiation had the best outcome with a median survival of 97 months. Independent predictors for decreased survival included age, gender, tumor size, advanced stage, and no surgery.

Pyrroloquinoline Quinone (PQQ) and Indicators of Antioxidant Potential, Inflammation and Metabolism in Humans

Pyrroloquinoline quinone (PQQ) improves parameters related to energy metabolism in animals, which involve interactions with cell signaling important to mitochondrial function. However, little is known about responses to PQQ in humans. Using a crossover study design, 10 subjects ingested PQQ and were examined in two studies at 2 to 3 daily intervals. Plasma antioxidant potential (TBARS and TRAP measurements), inflammation (plasma C‐reactive protein and IL‐6), and standard clinical indices were measured, including urinary metabolites. In addition, PQQ clearance was investigated. Data suggested that PQQ is absorbed in the upper intestine with a relatively slow clearance from the plasma pool. Measurement of plasma antioxidant activity was highly correlated with plasma PQQ concentrations. Decreased levels of plasma C‐reactive protein and IL‐6 were also observed (~ 20 mg PQQ/day X 3 d; p &lt;0.01). No changes in clinical indices were observed. However, exposure to PQQ (10–20 mg PQQ/day X 3 d) altered the distribution of mitochondrial‐related urinary metabolites in urine using as assessed by the NMR. It was concluded that the effects of PQQ in humans could be observed with a short‐term exposure at levels easily obtained in commercial supplements. Supported by Mitsubishi Gas and Chemical Co. and the Center for Health Related Research at UCD.

The prognostic significance of extra-intestinal tumor location for primary nonmetastatic gastrointestinal stromal tumors.

2 Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the GI tract. Tumor size, tumor location, and mitotic index are established factors that risk stratify recurrence and survival. Extra-intestinal GISTs are infrequently observed and our objective was to investigate the outcomes of patients with primary GISTs found outside the GI tract. Methods: The Surveillance Epidemiology and End Results registry was used to identify patients with GIST treated with surgery between 1996 and 2008. Patients were evaluated by standard clinical and pathological indices including: age, primary tumor location (extra−intestinal vs. GI tract), tumor size, tumor grade, and extent of disease. Overall survival differences between primary site groups were assessed by Kaplan-Meier method. Univariate and stepwise multivariate Cox proportional hazards analyses were performed. Results: Of the 2812 patients with surgically treated GIST, 2489 (88.5%) had a primary tumor location in the GI tract and 323 (11.5%) were located in extra-intestinal sites. Comparison of patients by primary tumor location demonstrated more locally advanced cancers with lymph node involvement (40.2% vs. 18.4%; p&lt;.0001) and a higher occurrence of distant metastatic disease (22.3% vs. 16.6%; p&lt;.0001) among the extra-intestinal GISTs. When comparing overall survival, patients with extra-intestinal GISTs had significantly worse 5 year survival (62% vs. 70%, respectively; p=0.002) than patients with primary tumors within the GI tract. Stepwise multivariate analysis showed that non-intestinal site was an independent predictor of poorer survival (HR 1.29, 95% CI [1.05-1.59], p=0.015). Conclusions: Our data indicates that extra-intestinal location for primary non-metastatic GIST is an independent poor prognostic factor, with worse overall survival, compared to GISTs located within the GI tract. Risk stratification for prognosis should account for these rare GIST locations.

Combining Early Coagulation and Inflammatory Status Improves Prediction of Mortality in Burned and Nonburned Trauma Patients

After injury, there is a synergistic response between inflammation and coagulation systems. We hypothesized that combining markers of these processes and standard clinical indices would improve early prediction of in- hospital mortality in burned and nonburned trauma patients. Patients admitted to the surgical or burn intensive care unit within 24 hours of injury with an anticipated stay >or=3 days were enrolled during a one year period. Upon admission, blood was drawn for thromboelastography, plasma-based clotting assays, and cytokine levels. Clinical indices and multiple organ dysfunction syndrome (MODS) scores were recorded. Candidate variables evaluated included age, percentage third degree burns, inhalation injury, percentage total body surface area burns, interleukin-6, tumor necrosis factor alpha, interleukin-8, prothrombin time, partial thromboplastin time (PTT), maximal amplitude reflective of clot strength, group (burn or nonburn) and admission MODS. Multiple logistic regression with stepwise selection and likelihood ratio test was performed to identify predictors for mortality. A receiver operating characteristic (ROC) curve was constructed to assess the diagnostic performance of identified predictors. Validation of the model with an additional cohort was performed. For model development, we enrolled 25 burned and 33 nonburned trauma patients (20 blunt and 13 penetrating injuries). Fifteen deaths occurred. Multiple logistic regression analysis identified six independent risk factors for death: age, percentage third degree burns, inhalation injury, tumor necrosis factor alpha level, maximal amplitude, and MODS score with an area under ROC curve of 0.961 (95% confidence interval: 0.891, 1.000, p < 0.05). The area under the ROC curve for the validation cohort (n = 66) was 0.936 (95% confidence interval: 0.875, 0.997, p < 0.001). Our model improves prediction of in-hospital mortality in comparison to previous methods for burn and nonburn trauma patients. Furthermore, our model is equally applicable to all patients regardless of type of traumatic injury (nonburn or burn). This improvement is because of the inclusion of patient's early coagulation and inflammatory status in addition to standard clinical indices. These data provide a baseline within which to measure incremental improvements in care.

Additional Evidence of Association Between Exposure to Lead and Cadmium and Renal Disease in Children

ISEE-127 Objective: Two studies presented by us to the ISEE Conferences 17 and 18 demonstrated that moderate body burdens of cadmium and lead increased incipient renal damage probability in children. Our animal experimental study confirmed the combined nephrotoxicity of these metals, which was inhibited by a bioprotective combination comprising pectin, glutamate, a multivitamin-multimineral medicine, and a calcium supplement. Now we explored the effectiveness of this intervention on a group of children. Material and Methods: We examined 38 children aged 3 to 7 in Krasnouralsk (Russia) polluted by a big copper smelter. Concentrations of cadmium, lead, and β-2-microglobulin (B2μ) were measured in the morning urine, along with liquid crystallography and standard clinical laboratory indices. All the tests were performed before and after the 5-week period during which the children were given (with the informed consent of parents) the above-mentioned bioprotective complex. Results: The initial B2μ levels in the cohort ranged from 20 to 3180 μg/L. Only 5 children had levels >300 μg/L. However, many children had other renal abnormalities: microurolithiasis seen with the polarization microscopy (in 86.8% of children), which also revealed formation of birefringent lipoprotein crystals characteristic of renal membranolysis (in 100%) and an albuminous ring around the microscopy preparation (in 65.7%). In 34.2% of children the urine specific gravity was >1025. After the bioprotective intervention, all these indices have statistically significantly (P < 0.05) diminished. The mean (SE) concentrations of B2μ, Cd, and Pb were initially 216.6 (85.7), 0.22 (0.20), and 15.23 (1.18), whereas after the intervention 94.5 (16.7), 0.11 (0.01), and 10.20(1.35) μg/L, respectively. Conclusions: A beneficial renal effect produced by bioprotectors previously proven, in an animal experiment, to be inhibitors of cadmium/lead nephrotoxicity may be considered as additional circumstantial evidence of the association, at least in part, between incipient renal disease in children who dwell under environmental exposure to these metals and this exposure.