Objectives-Cystinosis is a rare autosomal recessive lysosomal storage disorder with developmental and mineralization anomalies as part of its clinical presentation. The objective of this study was to provide the first systematic assessment of the craniofacial and dental characteristics associated with cystinosis.

Introduction and Objective-To characterize enamel defects in patients with methylmalonic acidemia (MMA) and cobalamin metabolic disorders and to examine salivary methylmalonate levels in MMA.

Background- The lack of standardized response criteria has been identified as one of the major obstacles in the development of new therapeutic agents for chronic graft-versus host disease (cGvHD). In 2004, the National Institutes of Health initiated a multidisciplinary consensus project, one aim of which was to develop criteria for measuring response in therapeutic trials for cGvHD (http://palladianpartners.com/GvHD/docs/). This report presents the results of the first pilot study evaluating the feasibility and reproducibility of these new response criteria. Methods- Eight raters (Oncology Fellows and Oncology Nurse Practitioners with limited experience with cGvHD) participated in a 2 ½ hour training session designed to provide an overview of comprehensive response evaluation in cGvHD and an opportunity to practice conducting functional and organ-specific evaluations. Each participant received a syllabus and a photo atlas illustrating common oral, ocular, and dermatologic manifestations of cGvHD. Feasibility and inter-rater agreement between experts in cGvHD (transplantation, dermatology, oral medicine, and rehabilitation medicine) and the panel of 8 novice raters were evaluated using four adult patients with varying manifestations of cGvHD. Percent Agreement was calculated using the following formula: %Agreement = #Agreements/(#Agreements + #Disagreements) x 100 Results Response Criterion Extent of Agreement Between Experts(Es)-Novices (Ns) Agreement Erythematous and/or Papular Skin Rash 62% agreement between Es and Ns Superficial Sclerosis 62% agreement between Es and Ns Deep Sclerosis 83% agreement between Es and Ns Skin Ulcers 97% agreement between Es and Ns Oral Cavity Pearson correlations ranged from 0.43–0.92 Gastrointestinal System Upper GI: 100% agreement; Esophageal: 83% agreement; Lower GI: 86% agreement Functional Performance Measures 2 Minute Walk: 66% of Ns within 95% CI of Es;Grip Strength: 75% of Ns within 95% CI of Es Karnofsky PS All Ns within ± 20% of Es cGvHD Mild, Moderate, Severe? All Ns rated consistently one severity category lower than Es Severity of cGvHD Symptoms (0–10 scale) All Ns scored symptom severity within ± 2 points of Es cGvHD Improving, Stable, Worse? (7-point scale) 50% of Ns in absolute accord with Es; 50% of Ns direction of change consistent with Es Clinical evaluation of a patient with cGVHD by the novice raters lasted a median of 36 minutes (range 19–60). Completion of the five patient self report measures (SF-36, Lee cGVHD Symptom Scale, Human Activity Profile, FACT-BMT, and cGvHD Activity Assessment Patient Self-Report) required a median total of 14 minutes (range 18–22). Conclusions- We are currently improving the clarity of the skin and oral definitions, and refining the photo atlas and training syllabus. Pediatric modifications of these criteria will undergo testing in Fall of 2005. Although limited by small sample size, this pilot study offers preliminary evidence of the reliability and feasibility of these cGvHD response criteria, and supports their use for prospective validation in larger patient cohorts and clinical trials.

Background The lack of standardized response criteria is a major obstacle to the development of therapeutic agents for cGvHD. Consensus criteria for evaluating response in cGvHD have been recently published (BBMT, 2006;12:252). We report on 3 pilot trials evaluating the feasibility and reproducibility of these proposed response criteria. Methods Oncology clinicians (n=27) with limited experience with cGvHD, participated in a 2.5 hour training session and received a syllabus and a photo atlas illustrating common manifestations of cGvHD. Feasibility and inter-rater agreement between experts in cGvHD (transplantation, dermatology, oral medicine, and rehabilitation medicine) and novice raters were evaluated using 15 pediatric and adult patients with varying manifestations of cGvHD. Data from each trial were used to strengthen the criteria and the teaching tools, and these materials were then re-tested. Intraclass correlation coefficients (ICCs) and percent agreement (#Agreements/[#Agreements + #Disagreements] × 100) were used in the analysis. Results Response Criterion Trial 1 (8 novices; 4 adult patients) Trial 2 (10 novices; 6 pediatric patients) Trial 3 (9 novices; 5 adult patients) Oral(Median ICC/Range) .50(−.62–.84) .44(.14–.81) .57(−.06–.74) Erythema(Median ICC/Range) .88(.12–.93) .07(−.01–.97) .47(.08–.82) Movable Sclerosis(Median ICC/Range) .33(−.65–.71) .21(−.38–.81) .60(.11–.91) Non-movable Sclerosis(Median ICC/Range) .23(−.06–.62) .16(−.45–.77) .62(.37–.96) Ulcers(%agreement) 97% 95% 67% Gastrointestinal(%agreement) 83%–100% 57%–93% 68%–100% Functional Performance(% novices within 95% confidence interval of expert) 2 Minute Walk:66%;Grip Strength:75% Not evaluated 2 Minute Walk:60%;Grip Strength:66% Performance Status(novices within +/−20% of expert) 100% 80% 100% The concordance between expert and novices for global ratings of cGvHD severity and disease course was also evaluated. The median time to perform and document the evaluation, which includes a Schirmer test, ranged from 32–36 minutes. In the third trial, the agreement among experts for the dimensions of oral manifestations (ICC=0.7) and skin erythema (ICC=0.54) approached satisfactory values. Overall, interobserver agreement was modest; although in the third trial the median ICCs between novices and experts for movable sclerosis, non-movable sclerosis, and oral findings began to approach the 0.7 level. Conclusions These data provided critical information to guide the successive refinement of the response criteria and training materials resulting in improved reproducibility in specific domains, such as oral and movable and non-movable sclerosis. While these data offer preliminary evidence of feasibility, it was challenging for novices to acquire in a single session the skills necessary to grade these patients reliably. Work is ongoing to refine the training materials, and future efforts will examine whether experienced transplant clinicians who receive this educational program can apply the response criteria with greater reproducibility.