Predictor Of Poor Outcome In Patients Research Articles

Bispectral EEG (BSEEG) Algorithm Captures High Mortality Risk Among 1,077 Patients: Its Relationship to Delirium Motor Subtype

Delirium is dangerous and a predictor of poor patient outcomes. We have previously reported the utility of the bispectral EEG (BSEEG) with a novel algorithm for the detection of delirium and prediction of patient outcomes including mortality. The present study employed a normalized BSEEG (nBSEEG) score to integrate the previous cohorts to combine their data to investigate the prediction of patient outcomes. We also aimed to test if the BSEEG method can be applicable regardless of age, and independent of delirium motor subtypes. We calculated nBSEEG score from raw BSEEG data in each cohort and classified patients into BSEEG-positive and BSEEG-negative groups. We used log-rank test and Cox proportional hazards models to predict 90-day and 1-year outcomes for the BSEEG-positive and -negative groups in all subjects and motor subgroups. A total of 1,077 subjects, the BSEEG-positive group showed significantly higher 90-day (hazard ratio 1.33 [95% CI 1.16-1.52] and 1-year (hazard ratio 1.22 [95% CI 1.06-1.40] mortality rates than the negative group after adjustment for covariates such as age, sex, CCI, and delirium status. Among patients with different motor subtypes of delirium, the hypoactive group showed significantly higher 90-day (hazard ratio 1.41 [95% CI 1.12-1.76] and 1-year mortality rates (hazard ratio 1.32 [95% CI 1.05-1.67], which remained significant after adjustment for the same covariates. We found that the BSEEG method is capable of capturing patients at high mortality risk.

Real World Data on the Outcomes of Richter's Transformation of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma in the Australian Population: An Australasian Lymphoma Alliance Study

Real World Data on the Outcomes of Richter's Transformation of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma in the Australian Population: An Australasian Lymphoma Alliance Study

Sustained Low-Efficiency Dialysis is Associated with Worsening Cerebral Edema and Outcomes in Intracerebral Hemorrhage.

We postulated that renal replacement therapy (RRT) in ICH patients with advanced chronic kidney disease (CKD) is associated with increased frequency and size of perihematomal edema (PHE) expansion and worse patient outcomes. The Get With the Guidelines-Stroke Registry was queried for all patients admitted with ICH (N = 1089). Secondary causes, brainstem ICH, and initial HV < 7cc were excluded. We identified patients with advanced CKD with and without RRT following admission for ICH. ABC/2 formula was used to measure hematoma volume (HV) and PHE. Patient outcomes were 30-day mortality, 90-day modified Rankin Scale score, and discharge disposition. We used propensity scores and optimal matching to adjust for multiple covariates. At 48h post-ICH, PHE expansion was a significant predictor of poor patient outcomes in our cohort. Patients with CKD who received sustained low-efficacy dialysis (SLED) treatment had larger 48h PHE growth compared to both untreated CKD group (average treatment effect (ATE), 11.5; 95% CI, 4.9-18.1; p < 0.01) and all untreated patients (ATE, 7.43; 95% CI, 4.7-10.2; p < 0.01). Moreover, patients with RRT had significantly worse functional and mortality outcomes. SLED treatment in ICH patients with CKD was associated with significant increase in rate and frequency of PHE expansion. Absolute increase in PHE during 48-h post-ICH was associated with increased mortality and worse functional outcomes. Further prospective and multicenter evaluation is needed to differentiate the effects of RRT on hematoma dynamics and patient outcomes from those attributed to CKD.

Assessing Diaphragmatic Function.

The diaphragm is vulnerable to injury during mechanical ventilation, and diaphragm dysfunction is both a marker of severity of illness and a predictor of poor patient outcome in the ICU. A combination of factors can result in diaphragm weakness. Both insufficient and excessive diaphragmatic contractile effort can cause atrophy or injury, and recent evidence suggests that targeting an appropriate amount of diaphragm activity during mechanical ventilation has the potential to mitigate diaphragm dysfunction. Several monitoring tools can be used to assess diaphragm activity and function during mechanical ventilation, including pressure-derived parameters, electromyography, and ultrasound. This review details these techniques and presents the rationale for a diaphragm-protective ventilation strategy.

Forkhead box O1 as an indicator of prognosis is inactivated in urothelial carcinoma of the upper urinary tract.

The transcription factor forkhead box O1 (FOXO1) can be inactivated via its phosphorylation, resulting in suppression of apoptosis. Using immunohistochemistry, the expression of a phosphorylated form of FOXO1 was assessed in upper urinary tract urothelial carcinoma (UUTUC) specimens. Overall, phospho-FOXO1 (p-FOXO1) was immunoreactive in all 99 UUTUC specimens [12 (12.1%) weak (1+), 46 (46.5%) moderate (2+) and 41 (41.4%) strong (3+)], which was significantly (P=0.018) increased, compared with benign urothelium specimens [77/82 (93.9%): 18 (22.0%) 1+, 41 (50.0%) 2+ and 18 (22.0%) 3+]. Muscle invasion (P=0.031) and lymphovascular invasion (P=0.025) were observed more frequently in p-FOXO1(2+/3+) tumor samples compared with p-FOXO1(1+) tumor samples. No statistically significant associations between p-FOXO1 expression and tumor grade or presence of concurrent carcinoma in situ, hydronephrosis or lymph node metastasis were observed. Furthermore, the levels of p-FOXO1 and estrogen receptor-β expression were significantly (P<0.05) correlated in UUTUC samples [correlation coefficient (CC)=0.244], particularly in tumor samples from male patients (CC=0.330). Additionally, patients with p-FOXO1(3+) tumors had a significantly increased risk of cancer-specific mortality (P=0.043), compared with those with p-FOXO1(1+/2+) tumors. Multivariate analysis further demonstrated a notable, albeit not significant, association between p-FOXO1 expression and cancer-specific survival (hazard ratio=2.204; P=0.053). These findings indicate that FOXO1 is inactivated in UUTUC specimens and p-FOXO1 overexpression may serve as a predictor of poor patient outcomes.

Targeted matrisome analysis identifies thrombospondin-2 and tenascin-C in aligned collagen stroma from invasive breast carcinoma

Increasing evidence demonstrates an important role for the extracellular matrix (ECM) in breast cancer progression. Collagen type I, a core constituent of the fibrous ECM, undergoes a significant set of changes that accompany tumor progression, termed Tumor Associated Collagen Signatures (TACS). Late stages of this progression are characterized by the presence of bundled, straight collagen (TACS-2) that become oriented perpendicular to the tumor-stromal boundary (TACS-3). Importantly, the presence of TACS-3 collagen is an independent predictor of poor patient outcome. At present, it remains unclear whether reorganization of the collagen matrix is the consequence of mechanical or compositional tissue remodeling. Here, we identify compositional changes in ECM correlating to collagen fiber reorganization from nineteen normal and invasive ductal carcinoma (IDC) patient biopsies using matrisome-targeted proteomics. Twenty-seven ECM proteins were significantly altered in IDC samples compared to normal tissue. Further, a set of nineteen matrisome proteins positively correlate and five proteins inversely correlate with IDC tissues containing straightened collagen fibers. Tenascin-C and thrombospondin-2 significantly co-localized with aligned collagen fibers in IDC tissues. This study highlights the compositional change in matrisome proteins accompanying collagen re-organization during breast cancer progression and provides candidate proteins for investigation into cellular and structural influences on collagen alignment.

Abstract TP400: Acute Catecholamine Surge Reflects the Prognosis in Patients With Aneurysmal Subarachnoid Hemorrhage

Objective: We investigated that the characteristics of serum catecholamine concentration at the hyper-acute phase of aneurysmal subarachnoid hemorrhage (SAH) and its relationship between patient outcome and delayed vasospasm. Methods: Patients with aneurysmal SAH (n=170) were prospectively enrolled between 2008 and 2011. Baseline demographic data and physiological parameters, including plasma concentrations of adrenaline (AD), noradrenaline (NA) and dopamine (DP) were evaluated. Results: On admission, plasma AD, NA and DP levels were significantly higher in patients with a poor clinical grade on admission (Hunt and Kosnik: IV-V), compared to those with a good clinical grade on admission (Hunt and Kosnik: I-III). AD showed a significantly high concentration immediately after the onset of SAH and then rapidly decreased. The levels of NA peaked within 6 hours after onset, then significantly decreased. The time course of the elevation of DP showed a similar trend to that of NA. The each catecholamine levels significantly correlated with each other. Multivariate analyses demonstrated age, poor clinical grade, plasma AD and NA levels were predictors of poor patient outcome. Poor clinical grade, Fisher scale and plasma AD level were predictors of the development of delayed vasospasm. Conclusion: The present study suggests that sympathetic activation in patients in the acute phase of SAH reflects the severity of SAH, and is closely related to the development of delayed vasospasm, leading to the subsequent immune response and inflammatory reactions. Suppressing catecholamine surge in hyper-acute phase may contribute to prevention of vasospasm and improvement of patient outcome.

Glasgow prognostic score predicts therapeutic outcome after hepatic resection for hepatocellular carcinoma

Systemic inflammation, as evidenced by the Glasgow prognostic score (GPS), predicts cancer-specific survival in various cancer types. The aim of this study was to evaluate the significance of the GPS in the therapeutic outcome of the patient following surgical resection for hepatocellular carcinoma. In total, 144 patients underwent surgical resection for hepatocellular carcinoma. For the assessment of systemic inflammatory response using the GPS, patients were classified into three groups: Patients with normal serum albumin (<3.5 g/dl) and normal serum C-reactive protein (CRP) (≤1.0 mg/dl) were classified as GPS 0 (n=76), those with low serum albumin (<3.5 g/dl) or elevated serum CRP (>1.0 mg/dl) were classified as GPS 1 (n=58), and those with low serum albumin (<3.5 g/dl) and elevated serum CRP (>1.0 mg/dl) were classified as GPS 2 (n=10). Retrospectively, the relationship between patient characteristics including GPS, disease-free as well as overall survival were investigated. In disease-free survival, GPS 2 (P=0.019), with a tumor number ≥3 (P=0.004), and positive portal or venous invasion (P=0.034) were independent predictors of cancer recurrence in multivariate analysis. In overall survival, GPS 1 (P=0.042), GPS 2 (P<0.001) and positive portal or venous invasion (P<0.001) were independent predictors of poor patient outcome according to multivariate analysis. To conclude, the GPS in patients with hepatocellular carcinoma is an independent prognostic predictor after hepatic resection.

GATA3 immunohistochemistry in urothelial carcinoma of the upper urinary tract as a urothelial marker and a prognosticator

Immunohistochemistry of a transcription factor, GATA3, has been widely used as a promising urothelial marker in diagnostic surgical pathology practice. However, the expression status of GATA3 in upper urinary tract urothelial carcinomas (UUTUCs) and its prognostic significance have not been fully investigated. We immunohistochemically stained for GATA3 in 99 UUTUC samples and paired nonneoplastic urothelial tissues. GATA3 was positive in 51 (51.5%; 32 [32.3%] weak, 11 [11.1%] moderate, 8 [8.1%] strong) of 99 UUTUCs, which was significantly lower than in benign urothelium (79 [96.3%] of 82; 33 [40.2%] weak, 35 [42.7%] moderate, 11 [13.4%] strong; P<.001). However, there were no statistically significant associations between GATA3 expression and tumor grade, pT stage, lymph node involvement, or distant metastasis. Meanwhile, the rate of GATA3 positivity was significantly higher (P=.004) in ureteral tumors (66.0%) than in renal pelvic tumors (35.6%). Kaplan-Meier and log-rank tests revealed that GATA3 negativity was significantly associated with lower recurrence-free survival (P=.037 for all cases, P=.026 for muscle-invasive tumors) and cancer-specific survival (P=.007 for all cases, P=.012 for muscle-invasive tumors, P=.035 for cases with adjuvant chemotherapy) rates. Multivariate analysis further identified strong correlations of GATA3 expression with tumor progression (all cases: hazard ratio [HR], 0.479 [95% confidence interval {CI},0.229-1.003; P=.051]; muscle-invasive tumors: HR, 0.387 [95% CI, 0.166-0.903; P=.028) or cancer-specific mortality (all cases: HR, 0.354 [95% CI, 0.135-0.925; P=.034]; muscle-invasive tumors: HR, 0.402 [95% CI, 0.149-1.086; P=.072]). Thus, compared with nonneoplastic urothelium, a significant decrease in the expression of GATA3 in UUTUC was seen. Moreover, loss of GATA3 expression was found to be an independent predictor of poor patient outcomes. Of note was that only roughly half of high-grade and/or muscle-invasive UUTUCs were immunoreactive for GATA3.

MP71-04 GATA3 IMMUNOHISTOCHEMISTRY IN UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT AS A UROTHELIAL MARKER AS WELL AS A PROGNOSTICATOR

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma I1 Apr 2017MP71-04 GATA3 IMMUNOHISTOCHEMISTRY IN UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT AS A UROTHELIAL MARKER AS WELL AS A PROGNOSTICATOR Satoshi Inoue, Kazutoshi Fujita, Hiroki Ide, Seiji Yamaguchi, Hiroaki Fushimi, George Netto, Norio Nonomura, and Hiroshi Miyamoto Satoshi InoueSatoshi Inoue More articles by this author , Kazutoshi FujitaKazutoshi Fujita More articles by this author , Hiroki IdeHiroki Ide More articles by this author , Seiji YamaguchiSeiji Yamaguchi More articles by this author , Hiroaki FushimiHiroaki Fushimi More articles by this author , George NettoGeorge Netto More articles by this author , Norio NonomuraNorio Nonomura More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2260AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES A transcription factor, GATA3, has been one of the most useful urothelial markers in diagnostic surgical pathology practice. However, previous studies have assessed the utility of GATA3 immunohistochemistry often in bladder specimens. Moreover, the prognostic significance of GATA3 expression in upper urinary tract urothelial carcinomas (UUTUCs) has not been fully investigated. Meanwhile, using cell line and animal models, we have demonstrated that GATA3 functions as a tumor suppressor for urothelial cancer. The current study aims to determine the expression status of GATA3 in UUTUC and its prognostic significance. METHODS We immunohistochemically stained for GATA3 in the tissue microarrays consisting of 99 UUTUC samples and paired non-neoplastic urothelium from each case. We then evaluated the associations between GATA3 expression and clinicopathologic features available for our patient cohort. RESULTS GATA3 was positive in 51 [52%; 32 (32%) weak, 11 (11%) moderate, 8 (8%) strong] of 99 UUTUCs, which was significantly lower than in benign urothelium [79 (96%) of 82; 33 (40%) weak, 35 (43%) moderate, 11 (13%) strong] (P < 0.001). Ten (67%) of 15 low-grade versus 41 (48%) of 84 high-grade UUTUCs (P = 0.266) and 20 (54%) of 37 non-muscle-invasive versus 31 (50%) of 62 muscle-invasive UUTUCs (P = 0.836) were immunoreactive for GATA3. There were also no statistically significant associations between GATA3 expression and pN status, distant metastasis, gender of the patients, or the side of UUTUC. However, the rate of GATA3 positivity was significantly higher (P = 0.004) in ureteral tumors (66%) than in renal pelvic tumors (36%). Kaplan-Meier and log-rank tests revealed that GATA3 negativity significantly correlated with lower recurrence-free survival (P = 0.040 for all cases; P = 0.030 for muscle-invasive tumors) and cancer-specific survival (P = 0.007 for all cases; P = 0.012 for muscle-invasive tumors) rates. Multivariate analysis further identified strong correlations of GATA3 expression with cancer-specific mortality of all cases [hazard ratio (HR) = 0.399, 95% confidence interval (CI) = 0.179-0.890, P = 0.025] or muscle-invasive tumors (HR = 0.374, 95% CI = 0.169-0.831, P = 0.016). CONCLUSIONS Compared with non-neoplastic urothelium, a significant decrease in the expression of GATA3 in UUTUC was seen. Of note was that GATA3 was immunohistochemically detected only in roughly half of high-grade and/or muscle-invasive UUTUCs. In addition, loss of GATA3 expression was found to be an independent predictor of poor patient outcomes. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e945-e946 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Satoshi Inoue More articles by this author Kazutoshi Fujita More articles by this author Hiroki Ide More articles by this author Seiji Yamaguchi More articles by this author Hiroaki Fushimi More articles by this author George Netto More articles by this author Norio Nonomura More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract WP386: Acute Catecholamine Surge in Patients with Aneurysmal Subarachnoid Hemorrhage: Characteristics and Prognostic Value

Objectives: The characteristics of serum catecholamine concentration at the hyper-acute phase of aneurysmal subarachnoid hemorrhage (SAH) and its relationship between patient outcome and delayed vasospasm were investigated. Methods: Patients with aneurysmal SAH (170) were prospectively studied between August 2008 and June 2011. Baseline demographic data and physiological parameters, including plasma concentrations of adrenaline (AD), noradrenaline (NA) and dopamine (DP) were evaluated for all patients. Results: On admission, plasma AD, NA and DP levels were significantly higher in patients with a poor clinical grade on admission (Hunt &amp; Kosnik: IV-V), compared to those with a good clinical grade on admission (Hunt &amp; Kosnik: I-III). AD showed a markedly high concentration immediately after the onset of SAH and then rapidly decreased. NA levels peaked within 6 hours after onset, then significantly decreased. The increase of DP with time was not significant, but showed a similar trend to that of NA. The level of each catecholamine showed significant mutual correlation. Multivariate analyses demonstrated age, poor clinical grade, plasma AD and NA levels were predictors of poor patient outcome, and.poor clinical grade, Fisher scale and plasma AD level were predictors of the development of delayed vasospasm. Conclusions: The present findings suggest that sympathetic activation in patients in the acute phase of SAH reflects the severity of SAH, and is closely related to the development of delayed vasospasm, leading to the subsequent immune response and inflammatory reactions. Strategies for suppressing catecholamine at the hyperacute phase may contribute to vasospasm prevention and improve patient outcome.

The Combination of DNA Ploidy Status and PTEN/6q15 Deletions Provides Strong and Independent Prognostic Information in Prostate Cancer.

Aberrant DNA content has been discussed as a potential prognostic feature in prostate cancer. We analyzed the clinical significance of DNA ploidy in combination with prognostic relevant deletions of PTEN and 6q15 in 3,845 prostate cancers. The DNA status was diploid in 67.8%, tetraploid in 25.6%, and aneuploid in 6.8% of tumors, and deletions of PTEN and 6q15 occurred in 17.8% and 20.3% of tumors. Abnormal DNA content and deletions were linked to high Gleason score, advanced tumor stage, and positive nodal stage (P < 0.0001 each). The risk of PSA recurrence increased from diploid to tetraploid and from tetraploid to aneuploid DNA status (P < 0.0001 each). However, 40% of patients with Gleason score ≥4+4 and 55% of patients with PSA recurrence had diploid cancers. This fraction decreased to 21% (Gleason ≥4+4) and 29% (PSA recurrence) if PTEN and/or 6q deletion data were added to ploidy data to identify cancers with an aberrant DNA status. The significance of combining both deletions and ploidy was further demonstrated in a combined recurrence analysis. Presence of deletions increased the risk of PSA recurrence in diploid (P < 0.0001), tetraploid (P < 0.0001), and aneuploid cancers (P = 0.0049), and the combination of ploidy data and deletions provided clinically relevant information beyond the CAPRA-S nomogram. Multivariate modeling including preoperatively and postoperatively available parameters identified the "combined DNA status" as a strong independent predictor of poor patient outcome. The combinatorial DNA content analysis involving general (ploidy) and specific events (deletions) has the potential for clinical utility in prostate cancer. Clin Cancer Res; 22(11); 2802-11. ©2016 AACR.

The C-reactive Protein to Albumin Ratio Predicts Long-Term Outcomes in Patients with Pancreatic Cancer After Pancreatic Resection.

The C-reactive protein to albumin (CRP/Alb) ratio, a novel inflammation-based prognostic score, is associated with outcomes in septic patients. The prognostic value of CRP/Alb ratio has not been established in cancer patients. The aim of this study is to evaluate the significance of CRP/Alb ratio in therapeutic outcome after pancreatic resection for pancreatic cancer. The study comprised 113 patients who had undergone pancreatic resection for pancreatic cancer between April 2001 and December 2011. We retrospectively investigated the relation between CRP/Alb ratio and disease-free as well as overall survival. The optimal cut-off level of the CRP/Alb ratio was 0.03. For disease-free survival, preoperative biliary drainage (p=0.011), advanced tumor-node-metastasis (TNM) classification (p=0.002), and higher CRP/Alb ratio (p=0.049) by univariate analysis, and advanced TNM classification (p=0.003) by multivariate analysis, were independent and significant predictors of cancer recurrence. For overall survival, preoperative biliary drainage (p=0.012), advanced TNM classification (p=0.001), and higher CRP/Alb ratio (p=0.023) by univariate analysis, and advanced TNM classification (p=0.003) and higher CRP/Alb ratio (p=0.035) by multivariate analysis, were independent and significant predictors of poor patient outcome. The CRP/Alb ratio may be an independent and significant indicator of poor long-term outcomes in patients with pancreatic cancer after pancreatic resection.

Validation of a modified Frailty Index to predict mortality in vascular surgery patients

Patient frailty has been implicated as a predictor of poor patient outcomes; however, there is no consensus on how to define or quantify frailty to assess perioperative risk. A previously described modified Frailty Index (mFI) has been shown to predict adverse outcomes after selected vascular surgical procedures, but no studies to date have compared its utility against other recognized risk indices in specific populations of vascular surgery patients. National Surgical Quality Improvement Program data were reviewed for all patients undergoing carotid revascularization, abdominal aortic aneurysm (AAA) repair, and lower extremity revascularization for peripheral arterial disease (PAD) from 2006 to 2012. Patients were then further stratified into "open" and "endovascular" cohorts. The mFI was compared with the Lee Cardiac Risk Index (LCRI) and the American Society of Anesthesiologists (ASA) Physical Status Classification using a receiver operating characteristic area under curve (AUC). The primary end point was 30-day mortality, with a secondary end point of Clavien-Dindo class IV complications. A total of 72,106 patients were identified in the study period, with 40,931 (56.8%), 20,975 (29.1%), and 10,200 (14.1%) in the carotid, AAA, and PAD populations, respectively. For carotid endarterectomy, mFI demonstrated better discrimination regarding mortality than LCRI and ASA, with an AUC of 0.66 (95% confidence interval [CI], 0.63-0.70; P< .01 vs P= .65 and P= .60, respectively). The open AAA cohort had similar findings, with an AUC of 0.63 (95% CI, 0.59-0.67; P= .02 vs P= .58, and P= .58, respectively). In open PAD patients, mFI was comparable to ASA (AUC, 0.64 [95% CI 0.60-0.69] vs 0.65), with a trend toward better discrimination compared with the 0.60 AUC of LCRI (P= .08). The mFI was a better discriminator of class IV complications than LCRI and ASA after open AAA (AUC for mFI, 0.59 vs 0.56 and 0.55; 95% CI, 0.57-0.61; P< .01) andendovascular AAA repair (AUC for mFI, 0.60 vs 0.59 and 0.57; 95% CI, 0.58-0.62; P= .01). There were no significant differences in discrimination of class IV complications after open or endovascular PAD or carotid endarterectomy. The mFI was a better discriminator of mortality than other risk indices; however this was only significant for the open cohort. The mFI was also a better discriminator of class IV complications for the open and endovascular AAA repair groups. These data suggest that mFI should be used in place of previously recognized risk indices to define perioperative mortality after open vascular surgery and risk of major complications after aneurysm repair.

ATPS-49RESULTS OF A PHASE 0 CLINICAL TRIAL IN CANINE BRAIN CANCER EVALUATING SAFETY AND ACTIVITY OF OMX-4.80P, A PROTEIN OXYGEN CARRIER IND CANDIDATE FOR TREATMENT OF GLIOBLASTOMA

BACKGROUND: Hypoxia in solid tumors blunts the tumor cytotoxicity of radiotherapy (RT) and is a major independent predictor of poor patient outcomes in glioblastoma (GB). To increase tumor oxygenation, Omniox has engineered a novel oxygen delivery protein, OMX-4.80P (OMX), tuned to release oxygen specifically in hypoxic tumor tissue. When given with radiotherapy, OMX significantly enhances RT efficacy in rodent tumor models. Since spontaneous canine brain cancers, including GB, share similarities with human brain cancers in terms of morphology, disease progression, and response to approved therapies, a Phase 0 clinical trial was conducted in patient dogs to assess OMX safety, PK/PD and signs of efficacy to inform human clinical strategy. METHODS: Dogs with presumed brain cancers (MRI) underwent either resection surgery with radiotherapy (Sx + RT) or stereotactic radiosurgery (SRS). In the Sx + RT group, OMX was administered once before surgery (4–48 hours pre-Sx) and twice weekly in conjunction with RT (20x2.5Gy). In the SRS group, OMX was dosed on 2 consecutive days in combination with SRS (3x8Gy). PK, CBC, blood chemistry, coagulation, and immune responses were assessed. Additionally, resected tumors were analyzed for OMX accumulation and hypoxia levels (ELISA, IHC). RESULTS: To date, 14 dogs have completed the trial (10 Sx, 5 Sx + RT, 4 SRS): Five dogs show no signs of tumor regrowth at 3 months and 2 dogs had no visible tumors at 6 months. OMX induced no dose-limiting adverse events and median T1/2 is 35h. Resected tumors show a strong correlation between OMX concentration in tumor tissue and reduced hypoxia with OMX penetrating deep into tumor tissue. CONCLUSIONS: When given in conjunction with RT regimens equivalent to human standard of care, OMX is safe and well-tolerated. Tumor tissue analysis suggests that OMX-4.80P decreases tumor hypoxia, thus supporting its further clinical development for the enhancement of radiotherapy efficacy in GB patients.

RR27. Validation of a Modified Frailty Index to Predict Mortality in Vascular Surgery Patients

Patient frailty has been implicated as a predictor of poor patient outcomes; however, there is no consensus on how to define or quantify frailty to assess perioperative risk. Although a previously described modified Frailty Index (mFI) was shown to predict adverse outcomes after selected vascular surgical procedures, no studies to date have compared its utility against other recognized risk indices in vascular surgery patient populations. National Surgical Quality Improvement Program (NSQIP) data were reviewed for all patients undergoing carotid revascularization, aortic aneurysm repair (AAA), and lower extremity revascularization from 2006 to 2013. Patients were then further stratified into open and endovascular cohorts. The mFI was compared with the Lee Cardiac Risk Index (LCRI) and American Society of Anesthesiologists (ASA) classification using an area under the receiver operating characteristic curve (AUC). The primary end point was 30-day mortality, with a secondary end point of Clavien-Dindo class IV complications. A total of 72,106 patients were identified in the study period, with 40,931 (56.8%), 20,975 (29.1%), and 10,200 (14.1%) in the carotid, AAA, and peripheral vascular disease (PVD) populations, respectively. For carotid endarterectomy, mFI demonstrated better discrimination regarding mortality compared with LCRI and ASA with an AUC of 0.67 (95% confidence interval [CI] 0.63-0.70; P < .01 vs 0.65 and 0.61, respectively). The open AAA cohort had similar findings with an AUC of 0.63 (95% CI, 0.59-0.67; P = .02 vs 0.58 and 0.58, respectively). In open PVD patients, mFI was comparable to ASA, with an AUC of 0.64 (95% CI, 0.60-0.69) vs 0.65 with a trend toward better discrimination compared with the 0.60 AUC of LCRI (P = .08). The mFI was a better discriminator of class IV complications than LCRI and ASA after open AAA (AUC, 0.59 vs 0.56 and 0.55 mFI; 95% CI, 0.57-0.61; P < .01) and EVAR (AUC 0.60 vs 0.59 and 0.57, mFI; 95% CI, 0.58-0.62; P = .01). There were no significant differences in discrimination among any of the other groups. The mFI was a better discriminator of mortality than other risk indices; however, this was only significant for the open cohort. The mFI was also a better discriminator of class IV complications for both the open AAA and endovascular groups. These data suggest that mFI should be utilized to define perioperative risk in an effort to improve both resource utilization and patient outcomes.

Comparison of amyloid deposition in human kidney biopsies as predictor of poor patient outcome.

BackgroundAmyloidosis leads to deposition of abnormal protein with beta-pleated sheet structure in specific compartments of the affected organs. The histological localization of these amyloid deposits determines the overall survival of the patient.MethodsIn this study we have assessed the histological localization and severity of amyloid deposition in 35 patients with biopsy-proven renal amyloidosis and have compared those to clinical parameters, histo-pathological injury criteria and respective patient outcome. Comparisons were statistically analyzed using thus comparison between the different study groups, which was done using Student t-test and analysis of variance.ResultsWe find that the glomerulus is by far the most commonly and most severely affected renal compartment and patients with severe glomerular amyloidosis advance faster towards end stage renal disease (ESRD) and death, compared to those patients without glomerular amyloid deposits. Patients with severe glomerular amyloidosis showed higher serum creatinine and urine protein levels, while patients with severe vascular amyloidosis showed higher levels of interstitial inflammatory infiltrate.ConclusionIn kidneys affected by amyloidosis, the amyloid proteins are predominantly deposited along vessels, especially the small vessels including glomerular capillary loops. The severity of glomerular amyloid deposition enhances the risk of developing ESRD and increases the risk for premature death.

Impact of the revised International Prognostic Scoring System, cytogenetics and monosomal karyotype on outcome after allogeneic stem cell transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia evolving from myelodysplastic syndromes: a retrospective multicenter study of the European Society of Blood and Marrow Transplantation.

The aim of this study was to determine the impact of the revised 5-group International Prognostic Scoring System cytogenetic classification on outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia who were reported to the European Society for Blood and Marrow Transplantation database. A total of 903 patients had sufficient cytogenetic information available at stem cell transplantation to be classified according to the 5-group classification. Poor and very poor risk according to this classification was an independent predictor of shorter relapse-free survival (hazard ratio 1.40 and 2.14), overall survival (hazard ratio 1.38 and 2.14), and significantly higher cumulative incidence of relapse (hazard ratio 1.64 and 2.76), compared to patients with very good, good or intermediate risk. When comparing the predictive performance of a series of Cox models both for relapse-free survival and for overall survival, a model with simplified 5-group cytogenetics (merging very good, good and intermediate cytogenetics) performed best. Furthermore, monosomal karyotype is an additional negative predictor for outcome within patients of the poor, but not the very poor risk group of the 5-group classification. The revised International Prognostic Scoring System cytogenetic classification allows patients with myelodysplastic syndromes to be separated into three groups with clearly different outcomes after stem cell transplantation. Poor and very poor risk cytogenetics were strong predictors of poor patient outcome. The new cytogenetic classification added value to prediction of patient outcome compared to prediction models using only traditional risk factors or the 3-group International Prognostic Scoring System cytogenetic classification.

Glasgow prognostic score predicts outcome after surgical resection of gallbladder cancer.

Systemic inflammation as evidenced by the Glasgow prognostic score (GPS) predicts cancer-specific survival in various types of cancer. The aim of this study was to evaluate the significance of GPS in therapeutic outcome after surgical resection of gallbladder cancer. The subjects were 51 patients who underwent surgical resection for gallbladder cancer. For the assessment of systemic inflammatory response using the GPS, patients were classified into three groups: patients with normal albumin (≥3.5 g/dl) and normal C-reactive protein (CRP) (≤1.0 mg/dl) as GPS 0 (n = 38), those with low albumin (<3.5 g/dl) or elevated CRP (>1.0 mg/dl) as GPS 1 (n = 8), and those with low albumin (<3.5 g/dl) and elevated CRP (>1.0 mg/dl) as GPS 2 (n = 5). We retrospectively investigated the relation between patient characteristics including GPS, and disease-free as well as overall survival. In disease-free survival, advanced tumor stage based on pathology (p = 0.006), positive lymph node metastasis (p = 0.001), and GPS 1 or 2 (p = 0.006) were independent predictors of cancer recurrence in multivariate analysis. In overall survival, positive lymph node metastasis (p = 0.002) and GPS 1 or 2 (p = 0.032) were independent predictors of poor patient outcome in multivariate analyses. The GPS in patients with gallbladder cancer is an independent prognostic predictor after surgical resection.

UPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies

Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease involved in cancer invasion and metastasis, interacting with plasminogen activator inhibitor-1 (PAI-1), which was originally identified as a blood-derived endogenous fast-acting inhibitor of uPA. At concentrations found in tumor tissue, however, both PAI-1 and uPA promote tumor progression and metastasis. Consistent with the causative role of uPA and PAI-1 in cancer dissemination, several retrospective and prospective studies have shown that elevated levels of uPA and PAI-1 in breast tumor tissue are statistically independent and potent predictors of poor patient outcome, including adverse outcome in the subset of breast cancer patients with lymph node-negative disease. In addition to being prognostic, high levels of uPA and PAI-1 have been shown to predict benefit from adjuvant chemotherapy in patients with early breast cancer. The unique clinical utility of uPA/PAI-1 as prognostic biomarkers in lymph node-negative breast cancer has been confirmed in two independent level-of-evidence-1 studies (that is, in a randomized prospective clinical trial in which the biomarker evaluation was the primary purpose of the trial and in a pooled analysis of individual data from retrospective and prospective studies). Thus, uPA and PAI-1 are among the best validated prognostic biomarkers currently available for lymph node-negative breast cancer, their main utility being the identification of lymph node-negative patients who have HER-2-negative tumors and who can be safely spared the toxicity and costs of adjuvant chemotherapy. Recently, a phase II clinical trial using the low-molecular-weight uPA inhibitor WX-671 reported activity in metastatic breast cancer.