John Keighley

Defining post-stroke recovery : implications for design and interpretation of drug trials

Measurement of stroke recovery is complex because definition of successful recovery is highly variable across measures and cut-off points for defining successful outcomes vary. The purpose of this paper is to describe patterns of recovery in stroke patients of varying severity when different measures are used and when different cut-off points are selected. 459 individuals enrolled in a prospective cohort study were assessed within 14 days post stroke and re-evaluated at 1, 3, and 6 months. Recovery was assessed using the NIH Stroke Scale, the Fugl-Meyer Assessment of Motor Recovery, the Barthel Index of Activities of Daily Living, the Physical Function Index of the SF-36, and the Modified Rankin Outcome Scale. Subjects also defined their preference (utility) for their current health state with a time-trade off question. We compared patterns of recovery using the different measures and varying the cut-off points for defining successful recovery. The percentage of patients who are believed to have recovered depends on how recovery is defined. If recovery is defined at the disability level (Barthel > 90), the majority 57.3% of stroke survivors experience a full recovery. Fewer individuals are considered to be fully recovered if impairments are measured (NIH </= 1, 44.9% and Fugl-Meyer > 90, 36.8%. Less than 25% of stroke survivors are considered recovered if recovery is defined relative to reported prior function in higher levels of physical activity. Shifting the definition of recovery on the modified Rankin scale from </= 1 to </= 2 shifts the percentage of those deemed recovered from </= 25% to 53.8%. In designing drug trials the methods for defining stroke recovery should be carefully considered. If recovery is defined in terms of disability, a higher proportion of the placebo group will achieve the outcome than if impairments are used to define recovery. The benchmarks for recovery in minor strokes must include measures of higher functioning (e.g. the SF-36 physical functioning index or a Rankin 0 (no symptoms).

High Accuracy of Narrow Band Imaging Without Magnification for the Real-Time Characterization of Polyp Histology and Its Comparison With High-Definition White Light Colonoscopy: A Prospective Study

OBJECTIVES:Standard white light colonoscopy has limited ability to differentiate between polyp types (adenomatous vs. hyperplastic). Narrow band imaging (NBI) highlights the superficial mucosal/vascular patterns on polyps and may facilitate real-time characterization of polyp histology. The aim of this study was to prospectively evaluate and compare the diagnostic characteristics of high-definition white light colonoscopy (HDWL) and NBI without magnification in the real-time prediction of polyp histology (adenomatous vs. hyperplastic) by evaluating the surface mucosal and vascular patterns.METHODS:We conducted a prospective comparative study in a tertiary referral center. A total of 100 patients referred for screening or surveillance colonoscopy were prospectively enrolled and underwent colonoscopy using a high-definition colonoscope with NBI capability. Every polyp detected was initially evaluated with HDWL followed by NBI for the presence of surface mucosal/vascular patterns. Based on these patterns, polyp histology was predicted by both modalities. The main outcome measurements were: (i) diagnostic characteristics of HDWL and NBI in predicting polyp histology and (ii) impact of polyp size and learning effect (first half of study vs. second half) on the ability of NBI to predict adenomas.RESULTS:A total of 236 polyps were detected in 100 patients—143 adenomas, 77 hyperplastic, and 16 others. Surface patterns (type A: hyperplastic; type B: adenomatous) were recognized in all polyps with NBI (100%) compared to 45% with HDWL. For predicting adenomas, NBI had a significantly higher sensitivity and greater accuracy (96 and 93% respectively) compared with HDWL (38 and 61% respectively) (all P<0.0001). Although the accuracy of NBI for predicting adenomas improved with increasing polyp size (≤5 mm; 6–9 mm; ≥10 mm) and in the second half compared with the first half of the study, these differences were not statistically significant.CONCLUSIONS:Using a simple surface mucosal/vascular pattern classification, NBI without magnification was highly accurate and significantly superior to HDWL for the real-time prediction of adenomas.

Prediction of Functional Outcome After Stroke: Comparison of the Orpington Prognostic Scale and the NIH Stroke Scale

BACKGROUND AND PURPOSE This study compared the ability of 2 stroke impairment scales, Orpington Prognostic Scale and National Institutes of Health (NIH) Stroke Scale, to predict disability as measured by the Barthel activities of daily living (ADL) Index and higher level of self-reported physical functioning as measured by the SF-36 physical functioning index (PFI) at 1, 3, and 6 months after stroke. METHODS The participants in this ongoing study are 184 individuals who sustained an eligible stroke and were recruited for the Kansas City Stroke Study. All patients were prospectively evaluated using standardized assessments at enrollment (within 14 days of stroke onset) and followed at 1, 3, and 6 months after stroke. Coefficient of determination (R2) was used to assess the ability of the 2 stroke scales to prognosticate outcomes. RESULTS Means and SDs of the Orpington Prognostic Scale and NIH Stroke Scale measured at baseline were 3.6+/-1.31 and 5.5+/-4.58, respectively. The Spearmans rank correlation between the 2 baseline measures was 0.83 (P=0.0001). The Orpington Prognostic Scale and the NIH Stroke Scale explained well the variance in Barthel ADL Index (P<0.001). However, the Orpington Prognostic Scale explained more variance than did the NIH Stroke Scale. Similarly, the Orpington Prognostic Score explained more variance in higher level of physical function than did the NIH Stroke Scale. The amount of variance in Barthel ADL Index and SF-36 PFI, which were explained by both stroke severity measures, decreased over time. CONCLUSIONS Our results demonstrate that in a sample of mostly mild and moderate strokes, the Orpington Prognostic Scale compared with the NIH Stroke Scale is simpler to use and is a slightly better predictor of ADL and higher levels of physical function.

Recognition of surface mucosal and vascular patterns of colon polyps by using narrow-band imaging: interobserver and intraobserver agreement and prediction of polyp histology

BACKGROUND The 2 main types of colon polyps are adenomas and hyperplastic. Pit patterns on the surface of polyps have been described by using magnification chromoendoscopy, which can help differentiate between polyp types. Narrow band imaging (NBI) is a novel technology that enhances the visualization of surface mucosal and vascular patterns on the polyp surface. Earlier we described, in a pilot study, patterns seen on the polyp surface with NBI that can help differentiate between adenomas and hyperplastic polyps with a high degree of accuracy. OBJECTIVE The aim of this study was to evaluate the interobserver and intraobserver agreement (among endoscopists) for the NBI surface mucosal and vascular patterns and prediction of polyp histology and the accuracy of the investigators to predict polyp histology based on these patterns. SETTING Kansas City Veterans Affairs Medical Center. METHODS NBI images of the polyp surface mucosal and vascular patterns obtained in our pilot trial were retrieved. A teaching set of 20 images was selected to educate and demonstrate the polyp patterns to 4 endoscopists. Subsequently, the test set of images was evaluated by the 4 endoscopists for quality, polyp pattern, and prediction of polyp type. Interobserver agreement (k value) was calculated among the 4 assessors for the polyp patterns and predicted histology. By using the final histology as the criterion standard, the accuracy of polyp-type prediction was calculated for each assessor. After a period of 2 months, all polyp images were reevaluated by the assessors (as before), and all findings were recorded in a similar fashion. These results were used for calculation of intraobserver agreement (k value) and the accuracy of the assessors in predicting polyp type. RESULTS Photographs of 65 polyps were included in the test set and were evaluated by the 4 assessors. Thirty-eight polyps were adenomatous, and 27 were hyperplastic. The kappa value for the interobserver agreement for polyp surface pattern was 0.57 (moderate) and for prediction of polyp type was 0.63 (substantial). The kappa value for the intraobserver agreement of the 4 assessors for the surface patterns was 0.70, 0.65, 0.60, and 0.79, and for the prediction of polyp type was 0.87, 0.71, 0.61, 0.81. The accuracy to predict polyp type ranged from 80% to 86% for the 4 assessors in the first reading and from 85% to 91% in the second reading, with every assessor showing an improvement in accuracy in the second reading. LIMITATIONS A single-center study, with a limited number of polyps. CONCLUSIONS This initial evaluation showed that the NBI polyp patterns described in our pilot study are reproducible, easy to learn, reasonably accurate, and have the potential for use in daily clinical practice for the real-time differentiation of colon polyps.

Identifying incident oral and pharyngeal cancer cases using Medicare claims.

BackgroundBaseline and trend data for oral and pharyngeal cancer incidence is limited. A new algorithm was derived using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to create an algorithm to identify incident cases of oral and pharyngeal cancer using Medicare claims.MethodsUsing a split-sample approach, Medicare claims’ procedure and diagnosis codes were used to generate a new algorithm to identify oral and pharyngeal cancer cases and validate its operating characteristics.ResultsThe algorithm had high sensitivity (95%) and specificity (97%), which varied little by age group, sex, and race and ethnicity.ConclusionExamples of the utility of this algorithm and its operating characteristics include using it to derive baseline and trend estimates of oral and pharyngeal cancer incidence. Such measures could be used to provide incidence estimates where they are lacking or to serve as comparator estimates for tumor registries.

Observer agreement in the assessment of narrowband imaging system surface patterns in Barrett’s esophagus: a multicenter study

BACKGROUND AND STUDY AIMS The clinical utility of narrow-band imaging (NBI) for Barretts esophagus is limited by the multiplicity of classification schemes. We evaluated the interobserver agreement and accuracy of a new consensus-driven simplified binary classification of NBI surface patterns.

Effect of 25-hydroxyvitamin D3 and 1 α,25 dihydroxyvitamin D3 on differentiation and apoptosis of human osteosarcoma cell lines

Osteosarcoma (OS) is a malignant bone tumor predominantly affecting children and adolescents. OS has a 60% survival rate with current treatments; hence, there is a need to identify novel adjuncts to chemotherapeutic regimens. In this pilot study, we investigated the dose‐response to 1α,25‐dihdroxyvitamin D3 (1,α 25(OH)2D3) and 25‐hydroxyvitamin D3 (25(OH)D3) by human OS cell lines, SaOS‐2, and 143B. We hypothesized that 1,α 25(OH)2D3 and 25(OH)D3 would stimulate differentiation and induce apoptosis in OS cells in a dose‐dependent manner. Human OS cell lines, SaOS‐2, and 143B, were treated with 1,α 25(OH)2D3 or 25(OH)D3 or an ethanol control, respectively, at concentrations ranging from 1 to 1,000 nM. Ki67 (a marker of cellular proliferation) immunocytochemistry revealed no significant changes in the expression of Ki‐67 or MIB‐1 in 1α,25(OH)2D3 or 25(OH)D3 treated SaOS‐2 or 143B cells. Both control and 1α,25(OH)2D3 treated SaOS‐2 and 143B cells expressed vitamin D receptor (VDR). Markers of osteoblastic differentiation in 143B cells and SaOS‐2 cells were induced by both 25(OH)D3 and 1α,25(OH)2D, and evident by increases in alkaline phosphatase (ALP) activity, osteocalcin (OCN) mRNA expression, and mineralization of extra‐cellular matrix (ECM) by alizarin red staining. An increasing trend in apoptosis in response to 25(OH)D3, in both SaOS‐2 and 143B cells was detected by terminal deoxynucleotidyl transferase (TdT)‐mediated dUTP nick end labeling (TUNEL) staining. With 1α,25(OH)2D3 treatment, apoptosis was evident at higher concentrations only. These preliminary findings suggest that OS cells express VDR and respond to 25(OH)D3 and 1α,25(OH)2D3 by undergoing differentiation and apoptosis.

Effect of acid-suppressive therapy on narrow band imaging findings in gastroesophageal reflux disease: a pilot study

Standard endoscopy is an insensitive test for gastroesophageal reflux disease (GERD). Narrow band imaging (NBI) endoscopy enhances visualization of the distal esophagus. NBI patterns like intrapapillary capillary loop (IPCL) dilatation, tortuosity, and increased number; microerosions; increased vascularity at the squamocolumnar junction (SCJ); ridge-villous pattern below the SCJ; and presence of columnar islands in the distal esophagus have been suggested as features of GERD. We evaluated the effect of proton pump inhibitor (PPI) therapy on NBI findings in GERD patients. Patients prospectively underwent NBI upper endoscopy before and after PPI therapy. NBI findings were recorded at each endoscopy. Twenty-one patients with GERD symptoms (mean age 60.0 years; males 90.5%; white 90.5%) were studied. After PPI therapy, there was a significant reduction in the proportion of patients with the following NBI features: IPCL tortuosity (90% vs. 4.8%, P < 0.0001), dilated IPCLs (86% vs. 9.5%, P < 0.0001), and increased vascularity at the SCJ (43% vs. 9.5%, P= 0.0082). PPI led to healing of all microerosions (71% vs. 0%, P < 0.0001) and disappearance of ridge-villous patterns below the SCJ (14% vs. 0%, P < 0.0001). There was no significant change in the proportion of patients with increased numbers of IPCLs pre- and post-PPI therapy (71% vs. 48%, P= 0.09) or columnar islands in the distal esophagus (38% vs. 29%, P= 0.31). In patients with GERD symptoms, NBI features suggestive of GERD respond to PPI; suggesting these features are truly acid-mediated. These findings need to be confirmed by randomized controlled trials.

Clinicopathologic correlation of vitamin D receptor expression with retinoid X receptor and MIB-1 expression in primary and metastatic osteosarcoma.

Vitamin D, in addition to its effects on bone, is important in cell cycle regulation. Vitamin D receptor (VDR) has been identified in breast, prostate, and colon cancers, as well as in canine and human osteosarcoma (OS) cell lines; however, it has not been well investigated in human OS-archived specimens. We correlated VDR, retinoid X receptor (RXR), and MIB-1 (Ki-67) expression in 110 archived OS cases with several clinicopathologic parameters including patients age, sex, tumor location, tumor grade, and type and metastatic status. The expression of VDR and RXR was identified in human OS tissue obtained from primary and metastatic OS archival tissue. No statistically significant difference was found in VDR expression in relation with tumor grade, type, age, sex, or location. The expression of RXR was highest in higher-grade (P = .0006) and metastatic tumors but remained unchanged when correlated with tumor type, age, sex, or location. The expression of MIB-1 was statistically elevated in higher-grade tumors (P = .001), patients 25 years or younger (P = .04), tumors located in extremities (P = .005), and metastatic lesions, but was not impacted by tumor type or patients sex. Proliferative activity was significantly reduced after treatment, as the mean MIB-1 expression dropped from 11% in primary biopsy samples to 6% in resection specimens. There appears to be a relationship between proliferative tumor activity and tumor grade, location, and metastasis. Additional studies on the analysis of the effects of vitamin D and RXR on OS proliferation, apoptosis, and differentiation are critical to further evaluate their potential role in OS treatment.

Effect of the staging schema on melanoma cancer reporting, 1999 to 2006

BACKGROUND Staging schemas have changed multiple times over the past 10 years. OBJECTIVE We sought to examine the impact of staging schemas on the distribution of stages at diagnosis over time. METHODS We examined the stage at diagnosis for melanoma cancer cases diagnosed between 1999 and 2006 using data provided by the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries (NPCR) programs. The staging schemas were summary staging 1977 (SS1977), summary staging 2000 (SS2000), derived SS2000, and SEER historic staging systems. RESULTS Melanoma was predominantly staged as a localized disease in all schemas. Using SEER data, the proportion of localized melanomas diagnosed in 2001 to 2003 using SS2000 was about 2.5% lower than the proportion diagnosed in 1999 to 2000 using SS1977, whereas the proportion of cases staged as regional was 2.7% higher using the SS2000 than SS1977. The distribution of stages for cases diagnosed in 2001 to 2003 using SS2000 was similar to that for cases diagnosed in 2004 to 2006 using a derived SS2000. Shift in stage distribution among SS1977, SS2000, and SEER historic staging was found to be about 6% (localized to regional) and about 17.5% (unknown to regional stage). The distribution of changes in stage observed for the SEER cases was not evident for cases from NPCR. LIMITATIONS SEER historic staging was not available for NPCR cases. CONCLUSION Changes in staging rules resulted in cases being moved from the localized to the regional stage and from unknown to the regional stage. Without staging rules that have been consistently applied to melanomas over many years, surveillance of prevention, treatment, and control of this condition is difficult.