Oral disease profiles in chronic graft versus host disease.

At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth-opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow ≤ 1 mL/5 min, mouth-opening ≤ 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer's tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P < 0.001); salivary dysfunction (11% prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD as 3 separate manifestations will improve clinical diagnosis, observational research data collection, and the definitions of outcome measures in clinical trials.

NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD.

Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported ('Form A') and 8 patient-reported ('Form B') response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient-reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies.

Oral chronic graft-vs.-host disease characterization using the NIH scale.

Chronic graft-vs.-host disease (cGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Oral cGVHD is manifested by mucosal, salivary, and/or sclerotic changes that have been linked to pain and poor quality of life. Our aim was to describe the demographic, clinical, and laboratory markers of oral cGVHD in alloHSCT patients (N = 187) enrolled in a cGVHD cross-sectional study at the NIH (#NCT00331968). We propose a meaningful and reproducible measure of disease defined by a cut-off point reflecting clinical minimally detectable change (0-2 = no oral cGVHD, 3-15 = oral cGVHD) on the 15-point NIH cGVHD clinician assessment scale. Forty-four patients had oral cGVHD. Oral cGVHD was associated with a quiescent or de novo type of cGVHD onset (p = 0.05), higher cGVHD severity (p = 0.033), lower albumin (p = 0.0008), higher total complement (p = 0.012), greater bother from foods or oral ulcers and greater mouth pain, and sensitivity (p < 0.0001). Multivariable logistic regression modeling with albumin, mouth pain, and total complement was 74.3% predictive of oral cGVHD and 80.2% predictive of non-oral cGVHD. We propose the use of >2 points on the NIH scale as a reproducible definition of clinically significant oral cGVHD, which may be useful in clinical settings or as eligibility criterion or as an endpoint in clinical trials.

MRI of the human eye using magnetization transfer contrast enhancement.

PURPOSE: To determine the feasibility of using magnetization transfer contrast-enhanced magnetic resonance imaging (MRI) to track cataractous lens changes. METHODS: A fast spin-echo sequence was modified to include a magnetization transfer contrast (MTC) preparation pulse train. This consisted of twenty 8.5-msec sinc pulses, 1200 Hz upfield from the water resonance and 1.2-Hz power. The MTC preparation pulse was followed by acquisition through fast spin-echo imaging. The imaging parameters were number of excitations (NEX) = 1, echo time (TE) = 14 msec, recovery time (TR) = 2 sec, echo train length of eight echos, and a matrix size of 256 x 160. To reduce motion artifacts, the volunteers were asked to fixate on a blinking LED. Normal and MTC-enhanced images were acquired from normal volunteers and volunteers with nuclear or cortical cataracts. RESULTS: The eye was adequately imaged, with few motion artifacts appearing. The lens was well resolved, despite the short T(2). The cornea and ciliary body were also clearly visible. In the lens, resolution of the epithelium and cortex were enhanced with MTC. In addition, contrast-to-noise ratios were measured for each image. Examination of the contrast-to-noise ratio confirmed that MTC increased the contrast between the nucleus and cortex. Unenhanced MRIs showed significant differences between the cortex of normal volunteers and volunteers with cataracts. MTC-enhanced images improved the sensitivity to changes in the nucleus. CONCLUSIONS: In this preliminary study, we were able to use MTC-enhanced MRI to obtain high-contrast images of the human lens. Regular and enhanced MRIs detected statistically significant differences between normal and cataractous lenses.

An atypical form of alphaB-crystallin is present in high concentration in some human cataractous lenses. Identification and characterization of aberrant N- and C-terminal processing.

Two unique polypeptides, 22.4 and 16.4 kDa, were prominent in some human cataracts. Both proteins were identified as modified forms of the small heat shock protein, alphaB-crystallin. The concentration of total alphaB-crystallin in most of these cataracts was significantly increased. The 22.4-kDa protein was subsequently designated as alphaB(g). Mass spectrometric analyses of tryptic and Asp-N digests showed alphaB(g) is alphaB-crystallin minus the C-terminal lysine. alphaB(g) constituted 10-90% of the total alphaB-crystallin in these cataracts and was preferentially phosphorylated over the typical form of alphaB-crystallin. Human alphaB(g) and alphaB-crystallin were cloned and expressed in Escherichia coli. The differences in electrophoretic mobility and the large difference in native pI values suggest some structural differences exist. The chaperone-like activity of recombinant human alphaB(g) was comparable to that of recombinant human alphaB-crystallin in preventing the aggregation of lactalbumin induced by dithiothreitol. The mechanism involved in generating alphaB(g) is not known, but a premature termination of the alphaB-crystallin gene was ruled out by sequencing the polymerase chain reaction products of the last exon for the alphaB-crystallin gene from lenses containing alphaB(g). The 16.4-kDa protein was an N-terminally truncated fragment of alphaB(g). The high concentration of alphaB-crystallin in these cataracts is the first observation of this kind in human lenses.

Use of dynamic light scattering and Scheimpflug imaging for the early detection of cataracts.

Cataract is a leading cause of blindness. Diabetes and glycemic conditions enhance the chances of developing cataracts early. At clinical stage cataracts are detected and documented by slit-lamp biomicroscopy and Scheimpflug photography. A compact fiber optic probe, developed for space experiments, was mounted on a Scheimpflug imaging system. The probe detects and documents cataracts at pre-clinical stage noninvasively and quantitatively. The early detection at the molecular level may lead to medical treatment of cataracts, better control of glycemia, and diabetes mellitus.

Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas.

PURPOSE: To evaluate long-term survivors of high-grade non-Hodgkin's lymphomas (NHLs) for late effects and to attempt to assess the relative contributions of the primary treatment modalities to these late effects. PATIENTS AND METHODS: Of 103 young survivors followed up for 1 to 20 years, 74 patients were interviewed and underwent various investigations, and an additional 12 patients were interviewed only. Of the 86 patients, 65 had previously suffered from small non-cleaved-cell lymphoma, 16 from lymphoblastic lymphoma, and five from large-cell lymphoma. RESULTS: Left ventricular dysfunction was identified in eight of 57 (14.0%) patients who had received doxorubicin (DOX) in doses greater than 200 mg/m2, of whom four were symptomatic and four were asymptomatic. A ninth patient required a pacemaker. Of the 86 patients, 23 (26.7%) reported pregnancies, 18 of whom had 30 children. Two of the 86 (2.3%) patients developed second cancers. Other major late effects included posttransfusion viral hepatitis, eight patients; CNS toxicity, two patients; endocrine impairment, 14 patients; vitamin B12 deficiency, two patients; esophageal stricture, one patient; urinary tract problems, two patients; and musculoskeletal defects, three patients. Major late effects occurred in 11 of 21 (52.4%) patients who had received radiation as well as chemotherapy, eight of 22 (36.4%) patients who had surgical resections as well as chemotherapy, and 17 of 74 (23.0%) patients who had received chemotherapy alone. CONCLUSION: The predominant major late effects observed were late cardiac toxicity related to DOX therapy and hepatitis C virus infection that presumably resulted from blood product transfusions administered before the introduction of screening for the hepatitis C virus. Fertility was not greatly impaired, and second malignancies were uncommon. No patient had clinically significant impairment of growth. Radiation appeared to increase the likelihood of late effects.

Evaluation of visual function following neodymium:YAG laser posterior capsulotomy.

PURPOSE: Improvement in visual acuity is the primary endpoint for successful neodymium:YAG (Nd:YAG) laser posterior capsulotomy for posterior capsule opacification. There is limited information on related parameters of visual function that may also improve after laser treatment. The authors evaluate changes in contrast sensitivity and glare disability, aside from visual acuity, following Nd:YAG laser posterior capsulotomy. METHODS: Measurements of visual acuity, contrast sensitivity (using the Pelli-Robson chart), and glare disability (using the Brightness Acuity Tester [Mentor O & O, Inc., Norwell, MA]) were obtained from 24 consecutive patients before and after Nd:YAG laser posterior capsulotomy. Glare testing was done with both the Pelli-Robson and Early Treatment Diabetic Retinopathy Study (ETDRS) charts. The degree of glare disability was indicated by the difference between visual function with glare (at medium and high settings) and without glare. Prelaser measurements were taken within 2 weeks prior to treatment, and postlaser measurements were obtained within 3 months after treatment. Only one eye per patient was evaluated. RESULTS: Mean differences between prelaser and postlaser measurements were significantly different from zero: (1) Contrast sensitivity, mean difference = 0.24 log units (P < 0.0001); (2) High glare disability using Pelli-Robson chart, mean difference = 0.15 log units (P = 0.004); (3) Visual acuity using ETDRS chart, mean difference = 11 letters (P < 0.0001); 4) High glare disability using ETDRS chart, mean difference = 7 letters (P = 0.005). CONCLUSIONS: Using the above methods for visual function testing, Nd:YAG laser capsulotomy is shown to significantly improve visual acuity, contrast sensitivity, and glare disability measurements as compared with prelaser values. The ophthalmologist may find it helpful to document the last two measurements prior to Nd:YAG laser capsulotomy, especially in patients who have good visual acuity but complain of glare sensitivity.

Constructing retinal fundus photomontages. A new computer-based method.

PURPOSE: To develop computer algorithms for reconstructing 24-bit color, wide-angle composite retinal fundus images from a set of adjacent 45 degrees fundus slides. The authors present the description, technical details, and results of the image reconstruction technique. METHODS: Patients with retinal degeneration underwent fundus photography with a 45 degrees field-of-view fundus camera. Individual photographic slides were digitized for creating fundus montages. Background variations in individual 45 degrees images were modeled to first- or second-order two-dimensional polynomial functions to generate a background image. The background image was subtracted from the original image to obtain background corrected image. Background corrected images were registered and spatially transformed using a first- or second-order two-dimensional polynomial warp model to reconstruct a composite retinal fundus montage. RESULTS: The authors successfully reconstructed 24-bit color, 100 degrees field-of-view, composite retinal fundus images. The computer-reconstructed montages are an improvement over manually generated montages because computer analysis can be performed on the computer-based montages. In addition, background variations and discontinuities between individual photographs observed in manually generated montages are reduced greatly in computer-generated montages. Most important, the computer-generated montages are better aligned than the manually generated photomontages. CONCLUSIONS: This method of reconstructing a wide-angle composite retinal fundus image from a set of adjacent small- and wide-angle fundus slides is a new tool for creating montages as large as 100 degrees field of view. The computer-generated montages may be used for documenting and quantifying retinal findings. This can greatly assist studies of retinal manifestations of diseases, such as gyrate atrophy, retinitis pigmentosa, sickle cell disease, and acquired immune deficiency syndrome.

The nucleus of the human lens: demonstration of a highly characteristic protein pattern by two-dimensional electrophoresis and introduction of a new method of lens dissection.

A practical method for dissection of human lenses is described. The method utilizes the suture patterns as a guide to identify the developmental stage in which fiber cells were formed. Lenses were separated into cortex and adult, infantile, fetal and embryonic nuclear regions. Analysis of the proteins in each of these regions in adult lenses shows that the lens nucleus has a highly characteristic two-dimensional protein pattern distinct from that of the cortex. Each of the nuclear regions has essentially the same protein pattern. The data suggest that the conversion of cortical fibers to mature nuclear fibers involves well controlled processes.

A longitudinal study of cortical cataracts using retroillumination photographs.

The National Eye Institute (NEI) computer planimetry system has been shown to have good reproducibility in assessing the size of cortical cataracts from retroilluminatin photographs. In this study, we determined the usefulness of this system in monitoring cortical cataract changes over time. Using the Neitz Kawara retroillumination camera, retroillumination photographs of cortical cataracts in 81 eyes were obtained every six months for an average of 31 months. As previously described, the cortical cataract outlines were traced in a masked fashion onto transparent plastic overlays, and the tracings then digitized into a Macintosh Quadra computer using a computer scanner. Cortical cataract area was then determined using a specially developed software program. For each eye, the rate of cortical area change was determined by the slope of the regression line fitted to the follow-up measurements. Cataract progression was classified to be significant if the slope exceeded a critical value. Of the 81 eyes, 24 (30%) had significant cataract progression, while 57 (70%) did not progress. This study presents data on progression of the area of cortical cataracts and suggests the usefulness of the NEI computer planimetry system for monitoring such changes from retroillumination photographs. The slope-based test can also play a useful part in longitudinal studies with irregular time intervals and variable number of visits.

Potential vision tests in patients with cataracts.

PURPOSE: To determine the limits of usefulness of the potential acuity meter (PAM) and the laser interferometer (LI) in determining potential visual acuity in various severities and types of cataracts. METHODS: The study included 48 patients (67 eyes) who were undergoing cataract surgery and who had PAM and LI tests. The 67 eyes were grouped into (1) eyes with cataracts only (45 eyes) and (2) eyes with cataracts and other ocular diseases (22 eyes). Group 1 eyes were subdivided into two groups according to their Lens Opacities Classification System II (LOCS II) grading: 1a eyes (moderate cataracts) had an LOCS II grade of nuclear opalescence (NO) < 4 and cortical opacity (C) < 5 and posterior sub-capsularcataract (P) < 4, and group 1b eyes (severe cataracts) had an LOCS II grade of NO = 4 or C = 5 or P = 4. The accuracy of the PAM and LI was estimated separately for each group. RESULTS: For moderate cataracts, the accuracy of the PAM was 100% and of the LI was 92%. For severe cataracts, the accuracy of the PAM was 52% and of the LI was 79%. Both instruments tended to underestimate visual outcome more in eyes with posterior subcapsular cataracts. For eyes with other ocular diseases, the LI tends to overestimate the probable visual outcome more than the PAM, especially in patients with poor retinal function. CONCLUSIONS: Several factors such as preoperative visual acuity of 20/200 or worse, the type and severity of the cataract, and coexisting retinal disorders may affect the accuracy of the PAM and LI tests, and these should be considered when interpreting predicted vision, especially in preoperative counseling of patients.

Longitudinal study of posterior subcapsular opacities using the National Eye Institute computer planimetry system.

BACKGROUND: The National Eye Institute (NEI) computer planimetry system has proved to be helpful in cross sectional studies by providing clinically useful area measurements of posterior subcapsular cataracts (PSC) and other opacities from retroillumination photographs. In this study, we evaluated the worth of this system in detecting PSC area changes over time. METHODS: Using the Neitz-Kawara camera, retroillumination photographs of the PSCs of 51 eyes were obtained every 6 months for an average of 25 months. The PSCs were outlined in a masked fashion on plastic overlays. Their tracings were then digitised on to a computer using a scanner. PSC area was determined using a special software program. For each eye, the rate of PSC area change was estimated by the slope of the regression line fitted to the follow up measurements. Cataract progression was classified as significant if the slope exceeded a critical value. RESULTS: These showed that 14 of the 51 eyes had PSC progression, while 37 did not change. CONCLUSION: This study suggests the system is useful for longitudinally monitoring PSC area changes from retroillumination photographs. This system would serve in natural history studies of PSCs and in clinical trials of anticataract drugs. The slope based test can play a part in longitudinal studies with irregular time intervals and variable number of visits.

Study of nuclear cataract progression using the National Eye Institute Scheimpflug system.

AIMS: A study was conducted to determine the capability of the recently developed National Eye Institute (NEI) Scheimpflug cataract imaging system in detecting changes in the nuclear region of the lens over a 1 year period. METHODS: Twenty five eyes with pure nuclear cataracts with mean nuclear densities < or = 0.30 optical density units (ODU) as well as 30 normal control eyes were each examined at baseline and 12 months later. Computerised densitometry using the NEI Scheimpflug cataract imaging system was performed. Clinical grading of the lenses was also done using the Lens Opacities Classification System II (LOCS II). For densitometry, a change of plus or minus 0.023 ODU (the 99% range) in mean density in the nuclear area was considered a progression or regression at 1 year. RESULTS: Using the Scheimpflug densitometry, 14 of the 25 cataractous eyes showed significant progression at 1 year. In the normal control group, only three of the 30 eyes showed significant progression. In contrast, using the LOCS II clinical grading, only two of the 25 cataractous eyes showed a one step increase, two of the 30 controls progressed at 1 year, and none regressed. There was no significant difference in visual acuity. CONCLUSION: This study suggests the value of the NEI Scheimpflug cataract imaging system in detecting nuclear change within 1 year. However, clinically significant changes may require longer follow up periods. These data will be useful in planning future longitudinal studies of nuclear cataracts, such as for clinical trials of anticataract drugs.

Scheimpflug photography and postcataract surgery posterior capsule opacification.

We describe a method to objectively document postcataract surgery posterior capsule opacification using Zeiss Scheimpflug photography and computerized image analysis. We examined 42 eyes with clear capsules (group A) and 27 with posterior capsule opacities (group B). The group A eyes had significantly better visual acuity (P < .05), lower mean capsular densitometry readings (0.03 +/- 0.03 optical density units versus 0.15 +/- 0.11 optical density units; P < .0001), and thinner capsules (0.03 +/- 0.4 mm versus 0.10 +/- 0.05 mm) than the group B eyes. This new objective method of documenting postoperative capsular haze may be useful for clinical studies such as clinical trials of drugs or surgical techniques being developed to prevent or minimize capsule opacification.

Progression of lens opacities in cataract patients after one year.

We used the Lens Opacities Classification System II to clinically grade the lenses of 57 patients with age-related cataracts in at least one eye. Progression or regression in each lens region was defined as a one or more step change in the Lens Opacities Classification System II grading noted at 1 year and maintained at the 1 1/2 to 2 year visit (the validation visit). A validated change in a lens region in one eye of a patient was considered a change in that region for that patient. Person-specific rates of cataract progression at 1 year were 42% for nuclear, 32% for cortical and 10% for posterior subcapsular opacities. Corresponding regression rates were 5%, 4%, and 2% for nuclear, cortical and posterior subcapsular opacities, respectively. Progression rates were significantly greater than the regression rates only for nuclear and cortical opacities (p < 0.0005). These findings show the applicability of the clinical Lens Opacities Classification System II method in documenting and monitoring lens changes over time. The usefulness of person-specific analysis was also shown.

Quantitative analysis of retroillumination images.

We have developed a semi-automated image processing system for analysis and evaluation of retroillumination images. This paper describes methods used to compensate for illumination variations in the images, separation of data into cataractous and non-cataractous portions, how quantitative measurements are made and how they assess the pathological condition. In addition to the traditional area measurement, this system computes the net integral of density and several measurements involving the location of the opacity in relation to the pupillary margin. The computer measures of area, integral of density, area centrality, weighted area, density centrality and weighted density provide more data than previously described systems. Data produced by this interactive and automated system can be used in studies of posterior subcapsular and cortical cataracts, and to study the effect of these opacities on vision.

Measurement error in assessing the size of cortical cataracts from retroillumination photographs.

This study describes a new method of quantifying anteriorly located cortical cataracts using retroillumination photographs and computer planimetry. Cortical cataracts were graded clinically and then photographed using the Neitz retroillumination camera twice by each of 2 photographers. The cataract outlines were traced onto a transparent overlay, and computer planimetry was performed using a Scan Maker 600ZS, a MAC II Computer and specially developed software. We estimated the measurement error of the method and its associated effect on sample size estimates for clinical studies. We calculated that the variability in this technique would contribute about 21 additional subjects to overall sample size estimates in studies comparing the mean areas of cortical opacities. In many studies this would be a small addition to total sample size requirements. This technique provides clinically useful measurements of the size of a cortical opacity as seen on a retroillumination photograph. This may be useful for future clinical studies on natural progression of cortical cataracts as well as for clinical trials of anticataract drugs.

Comparison of linear, multilinear and mask microdensitometric analyses of Scheimpflug images of the lens nucleus.

We wanted to determine the agreement among three methods currently used to measure the average density of the nucleus from a Scheimpflug video image of the lens, namely, the multilinear, linear and mask techniques. Using the NEI Scheimpflug Cataract Imaging System, video images of the lens were obtained from 49 eyes of 31 consecutive patients with predominantly nuclear opacities of varying severities. For each image, 3 separate determinations of the average nuclear density [in optical density units (odu)] were obtained by one analyst sequentially applying each of the three methods. Repeat measurements were obtained by the same analyst one week apart to evaluate reproducibility (using 95% error range), of each of the methods. Pairwise comparisons of the 3 methods were also done. Only the error due to outlining of the nucleus was assessed. Reproducibility of each method was excellent. The 95% error ranges were +/- 0.015 odu for the linear, +/- 0.013 odu for the multilinear, and +/- 0.017 odu for the mask methods. Very strong linear relationships were observed between the linear and multilinear methods (R2 = 0.99), between the linear and mask methods (R2 = 0.97), and between the multilinear and mask methods (R2 = 0.98). Simple linear regressions calibrating these three methods against each other would facilitate comparison of density measurements using any of these methods for analysis of Scheimpflug images of the lens nucleus.