Reliability and Responsiveness of Clinical and Endoscopic Outcome Measures in Crohn's Disease.

BACKGROUND: Regulatory guidance for Crohn's disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. METHODS: Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease trial. Readers scored the Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. RESULTS: Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn's Disease and Crohn's Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn's Disease, Crohn's Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn's Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn's Disease Activity Index score <150 and Crohn's Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). CONCLUSION: Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect.

This study largely supports current regulatory guidance for Crohn's disease trials recommending coprimary efficacy end points evaluating both symptoms and mucosal inflammation. Continuous endoscopic measures are most reliable and improve sensitivity to treatment effect when employed in composite outcomes.

Early Combined Immunosuppression May Be More Effective for Reducing Complications in Isolated Colonic- vs Ileal-Dominant Crohn Disease.

BACKGROUND: We assessed whether differential efficacy of early combined immunosuppression (ECI) in comparison with conventional management (CM) is present in patients with Crohn disease (CD) according to disease location. METHODS: In this posthoc analysis of the Randomized Evaluation of an Algorithm for Crohn's Treatment trial, the effect of ECI vs CM modified by disease location (isolated-colonic vs ileal-dominant) in terms of time to first complication (hospitalization, surgery, or disease-related complications-presence of a new abscess, fistula, or stricture; serious worsening of disease activity; extraintestinal manifestations) was analyzed using a marginal Cox proportional hazard model to account for cluster randomization. Factors adjusted included practice size, country, and other covariates selected in a backward logistic regression analysis with the first composition as outcome and P < 0.10. RESULTS: Of the 1969 patients with CD, 435 had isolated colonic CD (ECI n = 257, CM n = 178) and 1534 had ileal CD (ECI n = 817, CM n = 717). Over 24 months there was a significant differential impact for ECI vs CM for reducing the risk of a CD-related complication between patients with colonic CD and ileal CD (colonic CD hazard ratio [HR] = 0.51; 95% CI, 0.30-0.85 vs ileal CD HR = 0.79; 95% CI, 0.57-1.10; P = 0.033). No difference was identified between ECI vs CM for reducing the risk of surgery (colonic HR = 0.52 vs ileal HR = 0.74; P = 0.468) or hospitalization (colonic HR = 0.77 vs ileal HR = 0.83; P = 0.806). CONCLUSIONS: In this posthoc analysis of the Randomized Evaluation of an Algorithm for Crohn's Treatment trial, symptom-based ECI was associated with greater efficacy for reducing the risk of CD-related complications in patients with colonic disease location relative to ileal disease location.

Reliability of Endoscopic Evaluation of Postoperative Recurrent Crohn's Disease.

Endoscopic evaluation for postoperative recurrence of Crohn's disease (CD) is routinely integrated into clinical practice. The Rutgeerts score (RS) was developed to grade the severity of endoscopic postoperative CD recurrence and has been integrated into clinical practice guidelines and utilized as an endpoint in interventional trials.1,2 However, the operating properties of the RS have not been fully assessed. Furthermore, the RS i2 grade groups purely anastomotic ulcerations with those in the neoterminal ileum, whereas the modified Endoscopic Postoperative Recurrence Score (mEPRS) distinguishes lesions limited to the ileocolic anastomosis (i2a) from those in the neoterminal ileum (i2b). Accurate characterization of endoscopic recurrence is an important determinant for initiating postoperative medical therapy. Therefore, variability in endoscopic scoring may result in inappropriate therapeutic decisions.3 We evaluated the reliability of endoscopic assessment of postoperative CD recurrence among independent blinded central readers.

Discordance Between Patient-Reported Outcomes and Mucosal Inflammation in Patients With Mild to Moderate Ulcerative Colitis.

BACKGROUND & AIMS: Little is known about the association between rectal bleeding and increased stool frequency with endoscopic findings in patients with mild to moderate ulcerative colitis (UC). We evaluated the associations between rectal bleeding or stool frequency and endoscopic remission in this population. METHODS: We performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 817 adults with mild to moderate UC who received treatment with mesalazine. We obtained information on rectal bleeding, stool frequency, and Mayo endoscopic subscores (MESs) at weeks 0, 8, and 38. The sensitivity, specificity, and positive and negative predictive values with which rectal bleeding and stool frequency identified patients with MESs of 0 and/or 1 were calculated at weeks 8 and 38 of treatment. The associations between change in rectal bleeding and stool frequency and change in MES after treatment were quantified using the Spearman's rank correlation coefficient. RESULTS: Among patients with a MES of 0, 7/82 patients (9%) had a rectal bleeding score of 1 or more and 40/82 patients (49%) had a stool frequency score of 1 or more at week 8; at week 38, 6/167 patients (4%) had a rectal bleeding score of 1 or more and 63/167 patients (38%) had a stool frequency score of 1 or more. Among patients with MESs of 0 or 1, 50/310 patients (16%) had a rectal bleeding score of 1 or more and 162/310 patients (52%) had had a stool frequency score of 1 or more at week 8; at week 38, 18/363 patients (5%) had a rectal bleeding score of 1 or more and 141/363 patients (39%) had a stool frequency score of 1 or more. The Spearman rank correlation coefficients for change in rectal bleeding and stool frequency with change in MES at week 8 were 0.39 (95% CI, 0.32-0.45) and 0.34 (95% CI, 0.27-0.40), respectively. In patients with reduced MESs at week 8, 39/389 patients (10%) had unchanged or worsening rectal bleeding and 81/389 patients (21%) had unchanged or increasing stool frequencies. CONCLUSIONS: In a post-hoc analysis of data from a phase 3 trial of adults with mild to moderate UC treated with mesalazine, we found absence of rectal bleeding to identify patients in endoscopic remission. However, many patients in remission still have increased stool frequency, indicating that it may not be a sensitive marker of disease activity in patients with mild to moderate UC.

Early combined immunosuppression may be effective and safe in older patients with Crohn's disease: post hoc analysis of REACT.

BACKGROUND: Physicians may be reluctant to prescribe combined immunosuppression in older patients with Crohn's disease due to perceived risk of treatment-related complications. AIM: To evaluate the impact of age on risk of Crohn's disease-related complications in patients treated with early combined immunosuppression vs conventional management in a post hoc analysis of the randomised evaluation of an algorithm for Crohn's treatment (REACT), a cluster-randomised trial. METHODS: We compared efficacy (time to major adverse outcome of Crohn's disease-related surgery, hospitalisation or serious complications; corticosteroid-free clinical remission) and safety outcomes at 24 months, between patients aged <60 vs ≥60 years randomised to early combined immunosuppression or conventional management, using Cox proportional hazard analysis or modified Poisson model. In the early combined immunosuppression arm, patients with failure to achieve clinical remission within 4-12 weeks of corticosteroids were treated with a combination of tumour necrosis factor-α antagonist plus anti-metabolite and sequentially escalated in a stepwise algorithm. RESULTS: Of 1981 patients, 311 were ≥60 years (15.7%; 173 randomised to early combined immunosuppression and 138 to conventional management). Over 24 months, 10% of older patients developed Crohn's disease-related complications (early combined immunosuppression vs conventional management: 6.4% vs 14.5%) and 14 patients died (3.5% vs 5.8%). There was no difference between younger and older patients in risk of achieving corticosteroid-free clinical remission (<60 years, early combined immunosuppression (72.6%) vs conventional management (64.4%): relative risk [RR], 1.06 [95% CI, 0.98-1.15] vs ≥60 years, early combined immunosuppression (74.8%) vs conventional management (63.0%): RR, 1.09 [0.90-1.33], P-interaction = 0.78) or time to major adverse outcome (<60 years: hazard ratio [HR], 0.71 [0.53-0.96] vs ≥60 years: HR, 0.69 [0.31-1.51], P-interaction = 0.92) with early combined immunosuppression vs conventional management. CONCLUSIONS: We observed no difference in efficacy and safety of early combined immunosuppression compared to conventional management in older and younger patients. Early combined immunosuppression may be considered as a treatment option in selected older patients with Crohn's disease with suboptimal disease control. Clinical Trial Identifier: NCT01030809.

Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial.

OBJECTIVE: We evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment. DESIGN: Disease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and >2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo. RESULTS: Inter-rater reliability of the histological indices was substantial to almost perfect (ICC>0.61), and responsiveness was moderate to large (SES estimates>0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608-0.649). CONCLUSION: All four existing histological indices were similarly reliable and responsive based on this dataset.

Long-Term Outcomes in the Management of Central Neuropathic Pain Syndromes: A Prospective Observational Cohort Study.

BACKGROUND: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, traumatic spinal cord injury, or multiple sclerosis. These syndromes are distinctly less common than peripheral neuropathic pain, and less is known regarding the underlying pathophysiology, appropriate pharmacotherapy, and long-term outcomes. The objective of this study was to determine the long-term clinical effectiveness of the management of central neuropathic pain relative to peripheral neuropathic pain at tertiary pain centers. METHODS: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified for analysis from a prospective observational cohort study of patients with chronic neuropathic pain recruited from seven Canadian tertiary pain centers. Data regarding patient characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow-up. The primary outcome measure was the composite of a reduction in average pain intensity and pain interference. Secondary outcome measures included assessments of function, mood, quality of life, catastrophizing, and patient satisfaction. RESULTS: At 12-month follow-up, 13.5% (95% confidence interval [CI], 5.6-25.8) of patients with central neuropathic pain and complete data sets (n=52) achieved a ≥30% reduction in pain, whereas 38.5% (95% CI, 25.3-53.0) achieved a reduction of at least 1 point on the Pain Interference Scale. The proportion of patients with central neuropathic pain achieving both these measures, and thus the primary outcome, was 9.6% (95% CI, 3.2-21.0). Patients with peripheral neuropathic pain and complete data sets (n=463) were more likely to achieve this primary outcome at 12 months (25.3% of patients; 95% CI, 21.4-29.5) (p=0.012). CONCLUSION: Patients with central neuropathic pain syndromes managed in tertiary care centers were less likely to achieve a meaningful improvement in pain and function compared with patients with peripheral neuropathic pain at 12-month follow-up.

Development of Reliable, Valid and Responsive Scoring Systems for Endoscopy and Histology in Animal Models for Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Although several endoscopic and histopathologic indices are available for evaluating the severity of inflammation in mouse models of colitis, the reliability of these scoring instruments is unknown. Our aim was to evaluate the reliability of the individual items in the existing indices and develop new scoring systems by selection of the most reliable index items. METHODS: Two observers scored the histological slides [n = 224] and endoscopy videos [n = 201] from treated and untreated Interleukin[IL]-10 knock-out and T-cell transferred SCID mice. Intra-rater and inter-rater reliability for endoscopy and histology scores, and each individual item, were measured using intraclass correlation coefficients [ICCs]. The Mouse Colitis Histology Index [MCHI] and Mouse Colitis Endoscopy Index [MCEI] were developed using the most reliable items. Both were correlated to the colon density and to each other and were evaluated for their ability to detect changes in pathobiology. RESULTS: The intraclass correlation coefficients (ICCs) for inter-rater agreement (95% CIs) for the total histology and endoscopy scores were 0.90 [0.87-0.92] and 0.80 [0.76-0.84], respectively. The MCHI and MCEI were highly correlated with colon density, with a Spearman Rho = 0.81[0.75-0.85] and 0.73 [0.66-0.79], respectively, and with each other, Spearman Rho = 0.71 [0.63-0.77]. The MCHI and MCEI were able to distinguish between the experimental groups within the models, with pairwise differences between the treated and untreated groups being statistically significant [p < 0.001]. CONCLUSIONS: These histological and endoscopic indices are valid and reliable measures of intestinal inflammation in mice, and they are responsive to treatment effects in pre-clinical studies.

Reliability of Measuring Ileo-Colonic Disease Activity in Crohn's Disease by Magnetic Resonance Enterography.

Background: Magnetic resonance enterography is increasingly utilized for assessment of luminal Crohn's disease activity. The Magnetic Resonance Index of Activity and the London Index are the most commonly used outcome measures in clinical trials. We assessed the reliability of these indices and several additional items. Methods: A consensus process clarified scoring conventions and identified additional items based on face validity. Four experienced radiologists evaluated 50 images in triplicate, in random order, at least 1 month apart, using a central image management system. Intra- and interrater reliability were assessed by calculating and comparing intraclass correlation coefficients. Results: Intrarater intraclass correlation coefficients (95% confidence intervals) for the Magnetic Resonance Index of Activity, London, and London "extended" indices and a visual analogue scale were 0.89 (0.84 to 0.91), 0.87 (0.83 to 0.90), 0.89 (0.85 to 0.92), and 0.86 (0.81 to 0.90). Corresponding interrater intraclass correlation coefficients were 0.71 (0.61 to 0.77), 0.67 (0.55 to 0.75), 0.70 (0.61 to 0.76), and 0.71 (0.62 to 0.77). Reliability for each index was greatest in the terminal ileum and poorest in the rectum. All 3 indices were highly correlated with the visual analogue scale; 0.79 (0.71 to 0.85), 0.78 (0.71 to 0.84), and 0.79 (0.72 to 0.85) for the Magnetic Resonance Index of Activity, London, and the London "extended" indices, respectively. Conclusions: "Substantial" interrater reliability was observed for all 3 indices. Future studies should assess responsiveness to treatment in order to confirm their utility as evaluative indices in clinical trials and clinical practice.

Long-Term Outcomes in the Management of Painful Diabetic Neuropathy.

BACKGROUND: Painful diabetic neuropathy (PDN) is a frequent complication of diabetes mellitus. Current treatment recommendations are based on short-term trials, generally of ≤3 months' duration. Limited data are available on the long-term outcomes of this chronic disease. The objective of this study was to determine the long-term clinical effectiveness of the management of chronic PDN at tertiary pain centres. METHODS: From a prospective observational cohort study of patients with chronic neuropathic non-cancer pain recruited from seven Canadian tertiary pain centres, 60 patients diagnosed with PDN were identified for analysis. Data were collected according to Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials guidelines including the Brief Pain Inventory. RESULTS: At 12-month follow-up, 37.2% (95% confidence interval [CI], 23.0-53.3) of 43 patients with complete data achieved pain reduction of ≥30%, 51.2% (95% CI, 35.5-66.7) achieved functional improvement with a reduction of ≥1 on the Pain Interference Scale (0-10, Brief Pain Inventory) and 30.2% (95% CI, 17.2-46.1) had achieved both these measures. Symptom management included at least two medication classes in 55.3% and three medication classes in 25.5% (opioids, antidepressants, anticonvulsants). CONCLUSIONS: Almost one-third of patients being managed for PDN in a tertiary care setting achieve meaningful improvements in pain and function in the long term. Polypharmacy including analgesic antidepressants and anticonvulsants were the mainstays of effective symptom management.

Development and validation of a histological index for UC.

OBJECTIVE: Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument. DESIGN: Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt's responsiveness statistic (GRS) using data from a clinical trial of an effective therapy. RESULTS: Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively. CONCLUSIONS: The RHI is a new histopathological index with favourable operating properties.

Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial.

BACKGROUND: Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. METHODS: In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. FINDINGS: This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. INTERPRETATION: Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. FUNDING: AbbVie Pharmaceuticals.

(99m)Tc-Annexin A5 quantification of apoptotic tumor response: a systematic review and meta-analysis of clinical imaging trials.

PURPOSE: (99m)Tc-Annexin A5 has been used as a molecular imaging probe for the visualization, characterization and measurement of apoptosis. In an effort to define the quantitative (99m)Tc-annexin A5 uptake criteria that best predict tumor response to treatment, we performed a systematic review and meta-analysis of the results of all clinical imaging trials found in the literature or publicly available databases. METHODS: Included in this review were 17 clinical trials investigating quantitative (99m)Tc-annexin A5 (qAnx5) imaging using different parameters in cancer patients before and after the first course of chemotherapy and/or radiation therapy. Qualitative assessment of the clinical studies for diagnostic accuracy was performed using the QUADAS-2 criteria. Of these studies, five prospective single-center clinical trials (92 patients in total) were included in the meta-analysis after exclusion of one multicenter clinical trial due to heterogeneity. Pooled positive predictive values (PPV) and pooled negative predictive values (NPV) (with 95% CI) were calculated using Meta-Disc software version 1.4. RESULTS: Absolute quantification and/or relative quantification of (99m)Tc-annexin A5 uptake were performed at baseline and after the start of treatment. Various quantitative parameters have been used for the calculation of (99m)Tc-annexin A5 tumor uptake and delta (Δ) tumor changes post-treatment compared to baseline including: tumor-to-background ratio (TBR), ΔTBR, tumor-to-noise ratio, relative tumor ratio (TR), ΔTR, standardized tumor uptake ratio (STU), ΔSTU, maximum count per pixel within the tumor volume (Cmax), Cmax%, absolute ΔU and percentage (ΔU%), maximum ΔU counts, semiquantitative visual scoring, percent injected dose (%ID) and %ID/cm(3). Clinical trials investigating qAnx5 imaging have included patients with lung cancer, lymphoma, breast cancer, head and neck cancer and other less common tumor types. In two phase I/II single-center clinical trials, an increase of ≥25% in uptake following treatment was considered a significant threshold for an apoptotic tumor response (partial response, complete response). In three other phase I/II clinical trials, increases of ≥28%, ≥42% and ≥47% in uptake following treatment were found to be the mean cut-off levels in responders. In a phase II/III multicenter clinical trial, an increase of ≥23% in uptake following treatment was found to be the minimum cut-off level for a tumor response. In one clinical trial, no significant difference in (99m)Tc-annexin A5 uptake in terms of %ID was found in healthy tissues after chemotherapy compared to baseline. In two other clinical trials, intraobserver and interobserver measurements of (99m)Tc-annexin A5 tumor uptake were found to be reproducible (mean difference <5%, kappa = 0.90 and 0.82, respectively) and to be highly correlated with treatment outcome (Spearman r = 0.99, p < 0.0001). The meta-analysis demonstrated a pooled positive PPV of 100% (95% CI 92 - 100%) and a pooled NPV of 70% (95% CI 55 - 82%) for prediction of a tumor response after the first course of chemotherapy and/or radiotherapy in terms of ΔU%. In a symmetric sROC analysis, the AUC was 0.919 and the Q* index was 85.21 %. CONCLUSION: Quantitative (99m)Tc-annexin A5 imaging has been investigated in clinical trials for the assessment of apoptotic tumor responses. This meta-analysis showed a high pooled PPV and a moderate pooled NPV with ΔU cut-off values ranging between 20% and 30%. Standardization of quantification and harmonization of results are required for high-quality clinical research. A standardized uptake value score (SUV, ΔSUV) using quantitative SPECT/CT imaging may be a promising approach to the simple, reproducible and semiquantitative assessment of apoptotic tumor changes.

Role of plasma osteopontin as a biomarker in locally advanced breast cancer.

Osteopontin (OPN), a malignancy-associated secreted phosphoprotein, is a prognostic plasma biomarker for survival in metastatic breast cancer patients. We evaluated the role of OPN in Locally Advanced Breast Cancer (LABC) patients in predicting response to neoadjuvant chemotherapy and association with survival. Fifty-three patients with non-metastatic LABC were enrolled in this study and monitored serially for plasma OPN levels by ELISA during neoadjuvant chemotherapy prior to surgery. For fifty patients who had baseline OPN levels available for analysis, the median baseline OPN level was 63.6 ng/ml. Median patient follow up was 45 months and thirteen patients died from metastatic disease. Patients with baseline OPN levels ≥ 63.6 ng/ml were significantly more likely to die of their disease than those with baseline OPN < 63.6 ng/mL (Hazard Ratio = 3.4; 95% confidence interval 1.4-11.3; P = 0.011), and overall, baseline OPN level was significantly associated with survival (P = 0.002). There was little support for value of serial OPN determination in monitoring response to therapy in this patient population. Although the percentage of patients with baseline OPN levels < 63.6 ng/ml was higher in patients with pathological complete response than in those with no response, the difference was not statistically significant (64% and 14%, respectively (P = 0.066)). Thus, baseline plasma OPN level is a prognostic biomarker in this group of LABC patients, and could also be helpful in identifying LABC patients who will respond to neoadjuvant chemotherapy. Our results call for validation of our findings in large prospective trial data sets.

Physical Functioning and Opioid use in Patients with Neuropathic Pain.

OBJECTIVE: To evaluate the association between opioid dosage and ongoing therapy with physical function and disability in patients with neuropathic pain (NeP). DESIGN: Secondary analysis of a prospective cohort. SETTING: Multicenter clinical NeP registry. SUBJECTS: Seven hundred eighty-nine patients treated for various NeP diagnoses. METHODS: The following measures were included: dependent variables. 12-month self-reported physical function (pain disability index [PDI] and medical outcomes study short form-12 physical function [PCSS-12]); independent variables: baseline opioid dose (none, ≤200 mg and >200 mg of morphine equivalent), ongoing opioid use; potential confounding variables: age, sex, baseline pain intensity, and psychological distress (profile of mood states). Analysis of covariance models was created to examine the relationship between opioid therapy and both physical functioning outcomes with adjustment for confounding. RESULTS: Complete data was available for 535 patients (68%). Compared with the lower and high dose opioid groups, NeP patients not taking opioids had statistically lower disability and higher physical functioning scores, after adjusting for disease severity. Compared with patients prescribed opioid therapy on an ongoing basis, NeP patients who were not prescribed had statistically lower disability and higher physical functioning scores, after adjusting for disease severity. Improvements in disability and physical functioning scores from baseline and 12-months in all groups were modest and may not be clinically significant. CONCLUSIONS: Physical functioning and disability did not improve in patients with NeP who were prescribed opioids compared with those who are not prescribed, even after adjusting for disease severity.

Postoperative atrial fibrillation is not pulmonary vein dependent: results from a randomized trial.

BACKGROUND: Although often short-lived and self-limiting, postoperative atrial fibrillation (POAF) is a well-recognized postoperative complication of cardiac surgery and is associated with a 2-fold increase in cardiovascular mortality and morbidity. OBJECTIVE: Our aim was to determine whether intraoperative bilateral pulmonary vein radiofrequency ablation decreases the incidence of POAF in patients undergoing coronary artery bypass grafting (CABG). METHODS: A total of 175 patients undergoing CABG was prospectively randomized to undergo adjuvant bilateral radiofrequency pulmonary vein ablation in addition to CABG (group A; n = 89) or CABG alone (group B; n = 86). Intraoperative pulmonary vein isolation was confirmed by the inability to pace the heart via the pulmonary veins after ablation. All patients received postoperative ß-blocker. RESULTS: There was no difference in the incidence of POAF in the treatment group who underwent adjuvant pulmonary vein ablation (group A; 37.1%) compared with the control group who did not (group B; 36.1%) (P = .887). There were no differences in postoperative inotropic support, antiarrhythmic drug use, need for oral anticoagulation, and complication rates. The mean length of postoperative hospital stay was 8.2 ± 6.5 days in the ablation group and 6.7 ± 4.6 days in the control group (P < .001). CONCLUSION: Adjuvant pulmonary vein isolation does not decrease the incidence of POAF or its clinical impact but increases the mean length of stay in the hospital. The mechanism of POAF does not appear to depend on the pulmonary veins.

Reproducibility of histological assessments of disease activity in UC.

OBJECTIVE: Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA. DESIGN: Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated. RESULTS: Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61. CONCLUSIONS: Although 'substantial' to 'almost perfect' ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument.

An adaptive role for negative expected pain in patients with neuropathic pain.

OBJECTIVES: To study the relationship between expected pain and future outcomes along with the moderating effects of expected pain in neuropathic pain patients. METHODS: Study participants were recruited for the Canadian Neuropathic Pain Database. To examine the relationship between expected pain and 6-month pain intensity, pain-related disability, and catastrophizing, multiple regressions were performed. These relationships were adjusted for potential confounding (age, sex, baseline pain intensity, and psychological distress). To evaluate the moderating effect of expected pain on the relationship between baseline pain intensity and 6-month outcomes, pain intensity×expected pain interaction terms were created. RESULTS: Complete data for analysis was available for 560 patients (71%). Expected pain was positively correlated with pain intensity and pain-related disability scores at 6 months. The relationship between baseline pain intensity and 6-month catastrophizing scores was moderated by expected pain (however, despite a similar trend, expected pain did not statistically moderate the relationship between baseline pain intensity and 6-month pain intensity or disability). At higher levels of pain, predicted catastrophizing scores were higher for those with low levels of expected pain than those with high levels of expected pain. An opposite relationship was observed for patients with the lower levels of pain. DISCUSSION: In neuropathic pain patients whose pain does not respond to therapy, high levels of expected pain may relate to relatively lower catastrophizing scores by shifting focus away from futile attempts at "curing" pain toward focusing on achievement of more realistic personal goals.

Added-value of SPECT/CT to lymphatic mapping and sentinel lymphadenectomy in gynaecological cancers.

Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been successfully used in pre-treatment nodal staging of gynaecological cancers. We hypothesised the added-value of LM/SL plus SPECT/CT in patients with early stage of cervical cancer and vulvar cancer. A prospective, single-center, diagnostic, open label, active control, non-randomized clinical trial has been conducted in 7 patients with FIGO IA-IB1 cervical cancer and 7 patients with FIGO stage I-II-IIIcN0 vulvar cancer. All patients underwent LM/SL plus SPECT/low-dose CT and complete lymph node dissection (CLND) according to the standard of care. In case of negative hematoxylin-eosin staining, serial sections of the SLNs were analysed by immunohistochemistry and high molecular weight cytokeratin. Primary outcome measures were the detection rate, the sensitivity (SV), the negative predictive value (NPV), the diagnostic accuracy (DA) for anatomic localisation of SLNs, and the impact on management of SPECT/CT guided LM/SL versus CLND. The secondary outcome measure was the patient tolerability and operating time of LM/SL guided SPECT/CT versus CLND. http://clinicaltrials.gov/show/NCT00773071 All 14 patients were enrolled into the 1-day research protocol with dual-tracer LM/SL and SPECT/CT. Additional SLNs were detected on SPECT/CT compared to conventional planar imaging. Hot and cold > 1cm SLNs were detected on SPECT/CT. Detection rate, SV, NPV, DA were 100% in both groups; false negative rate was 0%. Rate of SLN metastases was 28.5% in cervical cancer and 42.9% in vulvar cancer. Impact on treatment was 28.5% and 14.3% in cervical cancer and vulvar cancer patients, respectively. SPECT/CT was well tolerated by all patients and operating time for LM/SL was within 30 min. No adverse events were reported with a time frame of 1-to-3 years. In early stage of gynaecological cancers, SPECT/low-dose CT is technically feasible and of clinical added-value for LM/SL.

Safety and efficiency assessment of training Canadian cardiac surgery residents to perform aortic valve surgery.

BACKGROUND: Research has demonstrated equivalent patient safety outcomes for various cardiac procedures when the primary surgeon was a supervised trainee. However, cardiac surgery cases have become more complex, and the Canadian cardiac surgery education model has undergone some changes. We sought to compare patient safety and efficiency of aortic valve replacement (AVR) between Canadian patients treated by senior cardiac trainees and those treated by certified cardiac surgeons. METHODS: We completed a single-centre, case-matched, prospectively collected and retrospectively analyzed study of AVR. Patients were matched between trainees and consultants for age, sex, New York Heart Association and Canadian Cardiovascular Society status, urgency of operation and diabetes status. RESULTS: We analyzed 1102 procedures: 624 isolated AVRs and 478 AVRs with coronary artery bypass graft (CABG). For isolated AVR, there was no significant difference in 30-d mortality (p = 0.13) or in major adverse events (p = 0.38) between the groups. In the AVR+CABG group, there was no significant difference in 30-day mortality (p = 0.10) or in the rates of major adverse events (p = 0.37) between the groups. Secondary outcomes (hospital and intensive care unit lengths of stay, valve size and type) did not differ significantly between the groups for isolated AVR or AVR+CABG. CONCLUSION: Despite a higher-risk patient population and changes in the cardiac surgery training model, it appears that outcomes are not negatively affected when a senior trainee acts as the primary surgeon in cases of AVR.

CONTEXTE: La recherche a fait état de résultats équivalents au plan de la sécurité des patients lors de diverses interventions cardiaques lorsque le chirurgien principal était un résident supervisé. Toutefois, la chirurgie cardiaque se complexifie et le modèle de formation canadien en chirurgie cardiaque a subi quelques transformations. Nous avons voulu comparer la sécurité de patients canadiens et l'efficience du remplacement de la valvule aortique (RVA) selon que les patients étaient traités par des résidents séniors en chirurgie cardiaque ou par des chirurgiens certifiés. MÉTHODES: Nous avons procédé à une collecte prospective de cas assortis, dans 1 seul centre, puis à une analyse rétrospective des cas de RVA. Les patients ont été répartis entre résidents et experts et assortis selon l'âge, le sexe, la classification de la NYHA (New York Heart Association) et de la Société canadienne de cardiologie, le caractère urgent de l'intervention et le statut à l'égard du diabète. RÉSULTANTS: Nous avons analysé 1102 interventions : 624 RVA isolés et 478 RVA avec pontage aorto-coronarien (PAC). Dans les cas de RVA isolés, on n'a noté aucune différence significative pour ce qui est de la mortalité à 30 jours (p = 0,13) ou des effets indésirables majeurs (p = 0,38) entre les groupes. Pour ce qui est du groupe RVA+PAC, on n'a noté aucune différence significative quant à la mortalité à 30 jours (p = 0,10) ou quant aux taux d'effets indésirables majeurs (p = 0,37) entre les groupes. Les paramètres secondaires (durée du séjour à l'hôpital et à l'unité des soins intensifs, taille et type de valvule) n'ont pas été significativement différents entre les groupes qu'il s'agisse de RVA isolé ou de RVA+PAC. CONCLUSIONS: Malgré une population de patients à risque plus élevé et les transformations apportées au modèle de formation en chirurgie cardiaque, il semble que les résultats ne soient pas affectés négativement lorsqu'un résident sénior agit à titre de chirurgien principal dans les cas de RVA.