Congenital cataracts cause approximately one-third of blindness in infants worldwide. If untreated they can cause permanent blindness by interfering with the sharp focus of light onto the retina and thus fail to establish appropriate synaptic connections between the retina and the visual cortex. Between 8 and 30% (see later) of congenital cataracts are inherited, and our understanding of their genetic architecture is increasing. Delineating the relationship between the genes and mutations causing cataracts and their phenotypic presentation can help us to understand the biology of the lens and provide a framework for the clinical approach to diagnosis and treatment.

Among patients who survive over two years post-allo-HSCT, cGVHD and subsequent cancers represent a significant source of morbidity and mortality. Long-term treatment with immunosuppressive agents and cGVHD-related immune dysregulation may promote the development of subsequent cancers. The burden of subsequent cancers has not yet been described in patients with the most severe manifestations of cGVHD, who likely represent a high-risk population. 439 patients were enrolled on the prospective NIH Chronic GVHD Natural History Study from 2004 to 2019, underwent one-week evaluation by subspecialists, and were scored in accordance with 2005 NIH criteria. Follow-up data were collected by annual survey in which patients self-reported cancer diagnoses and provided consent for confirmatory medical records. Cumulative incidence was estimated for non-melanoma skin cancer (NMSC) competing with death, relapse, or cancer other than NMSC and for cancer other than NMSC competing with death or relapse using the method of Gooley. Potential predictors of subsequent cancers including demographics, transplant characteristics, and cGVHD-related factors were assessed using Gray's test in univariable analysis and Cox proportional hazards models in multivariable analysis. Patients must have been free of post-transplant relapse, NMSC (for NMSC analyses only), and cancer other than NMSC at evaluation to be included in analysis. 22 NMSC and 19 cancers other than NMSC were observed among 205 eligible patients, with cumulative incidences at 60 months of 11.2% (95% CI: 6.9-16.7) and 7.3% (95% CI 4.1-11.8), respectively. The most common cancers other than NMSC were oral squamous cell carcinoma and melanoma (n=6 each). Factors associated with NMSC in univariable analysis were older age at transplant, older age at evaluation, having received sirolimus for cGVHD, having received extracorporeal photopheresis or psoralen-ultraviolet therapy for cGVHD as well as higher CRP, higher NK cell count, and greater BMI at evaluation. Only older age at transplant (HR=2.12; 95% CI: 1.35-3.31) and higher CRP (HR=9.61; 95% CI: 1.29-71.73) remained associated in the multivariable model. Factors associated with subsequent cancers other than NMSC in univariable analysis were T-cell depletion, lymphoid malignant indication for transplant, and increasing severity of oral cGVHD by NIH score. Only lymphoid malignant indication for transplant (HR=2.58; 95% CI: 1.31-5.07) remained significant in multivariable analysis. The association of CRP with NMSC may represent an effect of cGVHD-related inflammation, with CRP previously associated with cGVHD severity. Interestingly, sirolimus was associated with increased risk of NMSC despite its purported antineoplastic effects. One study has previously reported increased risk of NMSC in allo-HSCT recipients treated with sirolimus, however, numerous studies have reported that sirolimus reduces risk of NMSC in solid organ recipients. In this study population, sirolimus was often prescribed later in patients already with refractory cGVHD and adjustment for measures of disease severity attenuated this association in multivariable modeling. The association of lymphoid indication with cancers other than NMSC may be attributable to age as patients with lymphoid malignancies were older at transplant than those with other indications. Additionally, differences in pre-transplant therapies for lymphoid vs. other indications may also contribute to this observation. Post-transplant patients with cGVHD are at high risk of developing subsequent cancers, with higher incidence of NMSC than other cancers. This study identifies potential risk groups for subsequent cancers, highlights patients who may benefit from increased surveillance, and reiterates the need for effective cGVHD therapy to mitigate risks associated with long-term immunosuppression and immune dysfunction. Disclosures Cowen: UpToDate: Other: Royalties; Elsevier: Other: Royalties.

Chronic graft-versus-host disease (cGVHD) reduces relapse risk in patients with hematological malignancies treated with allogeneic hematopoietic stem cell transplant (allo-HSCT). Nevertheless, relapse remains a major barrier to treatment success. Better understanding of factors determining relapse risk in the cGVHD patient population may lead to development of improved strategies for malignancy control. We hypothesized that cGVHD-related factors would contribute to decreased risk of relapse in addition to other well-known transplant related factors. Patients (N=275) were enrolled on the NCI cross-sectional cGVHD natural history study (NCT00092235) and described using NIH criteria for disease severity and organ scoring. Subjects were subsequently followed for malignancy relapse and survival. Potential predictors of relapse were assessed for their association with risk of relapse using Gray's test. Cox proportional hazards modeling was performed to estimate the joint effect of factors on risk of relapse. Seventeen patients experienced relapse at a median follow-up of 85 months. 48-month cumulative incidence of relapse was 5.7% (95% CI 3.3-8.9%). Median progression-free survival was 156 months. Factors associated with increased risk of relapse in multivariable analysis included aggressive malignancy as an indication for transplant (HR 3.93, 95% CI 1.27-9.10), shorter time from transplant to cGVHD evaluation (HR 0.24, 95% CI 0.06-0.88), and higher number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.34, 95% CI 0.12-0.98). Interestingly, conditioning intensity, T-cell depletion, HLA-match, female donor to male recipient, blood vs. marrow stem cell source, or malignancy remission status at transplant were not predictive of relapse in univariate or multivariate analyses. These data suggest an important inverse relationship between cGVHD severity and likelihood of relapse post-transplant. Most classical relapse predictors seem to be abrogated by these effects.

Patients (pts) with chronic graft-versus-host-disease (cGvHD) prospectively enrolled in a natural history study (NCT00092235) from 10/2004 - 11/2016 were evaluated according to 2005 NIH cGvHD Staging Criteria (SC) and followed for survival. Supervised by a physician experienced in cGvHD, two selected team members rescored pts retrospectively using 2014 SC based on the original 2005 NIH cGvHD scoring forms and concurrently obtained medical records. 284 pts were analyzed. Distributions of Organ Scores (OS) and Global Severity Scores (GSS) of 2005 and 2014 NIH cGvHD SC were compared, and their associations to functional and quality of life (QOL) outcome measures were tested: Lee symptom scale (LSS), Short Form 36 (SF36), 2-minute walk test (2MW), grip strength (GS), joint range of motion (ROM), Human Activity Profile (HAP), and Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). Pts had median age of 46 yrs (range 19-71); 37% received moderate and 40% high levels of systemic immunosuppression. Pts scored by 2014 NIH SC had slightly lower GSS in comparison to 2005 NIH SC (72% vs 75% pts with severe cGvHD, P = .0009). cGvHD Liver Score was significantly worse using 2005 NIH SC (score of 0: 89% vs 55%, P < .0001). cGvHD Lung Score, scored exclusively using pulmonary function tests, were significantly lower when scored by 2014 vs 2015 SC (P < .0001). NIH scores for Skin, Mouth, Eye, Gastrointestinal tract, Joints &Fascia, and Genital did not show statistically significant difference. 2005 and 2014 NIH Skin Scores were associated with reduced GS and ROM (both P < .0001) and higher LSS (P = .0001). 2005 and 2014 NIH Lung Scores were associated with impairments in gait speed (2MW), and physical function (SF36 and HAP Maximum Activity Scale (MAS)), (all P < .0001) and a trend towards association with reduced GS (P = .002). Both 2005 and 2014 NIH Global Scores were significantly associated with ROM and GS. Compared to 2005 NIH GSS, weaker associations were seen between the 2014 NIH GSS and patient self-report of symptoms, functional status and quality of life (SF36, HAP MAS, and FACT-BMT) P < .001 and P < .05 respectively. Five-year overall survival in this cohort was 70.9% (95% CI: 64.8-76.1%) with median potential follow-up of 79 months. The final Cox survival model included 2014 NIH Lung Score (3 vs 0-2, HR = 2.67, 95% CI: 1.47-4.84; P = .0012), time from cGvHD diagnosis to consent (≥4 yrs vs <4 yrs, HR = .53, 95% CI: .31-0.94, P = .028), and Karnofsky performance status (80-100% vs <80%, HR = .48, 95% CI: .30-0.77; P = .0020). In conclusion, this cross-sectional cohort of patients severely affected by cGvHD shows the 2014 NIH cGvHD SC OS and GSS being significantly associated with functional and QOL measures. Refinements in grading criteria for lung and liver cGvHD resulted in lower scores for these organs. Implications of these findings need to be elucidated in prospective, large-cohort studies.

Introduction Chronic Graft-versus-Host Disease (cGvHD) is a complication of allogeneic stem cell transplantation. 2005 NIH Staging Criteria (SC) of cGvHD emerged as result of an international effort to provide uniform standards for clinicians and researchers. In 2014, NIH cGvHD SC were revised based on gathered scientific evidence. This study assessed the impact of 2014 revision of NIH cGvHD SC on Organ and Global Score distributions, and associations to functional and quality of life measures (QOL). Methods Patients (pts) with cGvHD participating in a natural history study of cGvHD (NCT00092235) between October 2004 and November 2016 were evaluated and followed for survival. NIH cGvHD organ and global severity scores (0-3) were prospectively assigned using the 2005 NIH cGvHD SC. Supervised by a physician experienced in cGvHD, two selected team members rescored pts retrospectively with the 2014 SC based on the original 2005 NIH cGvHD scoring forms and data obtained from assessments by clinician subspecialists. A total of 284 pts were evaluated. Distributions of organ-specific and global severity scores measured by the 2005 and 2014 NIH cGvHD SC were compared. 2014 NIH cGvHD SC were tested for associations with functional and QOL measures: Lee symptom scale (LSS), Short Form 36 (SF36), 2-minute walk test (2MW), grip strength (GS), joint range of motion (ROM), Human Activity Profile (HAP), mean Subspecialist Evaluation Score (mSSE), and Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), using the model established by Baird et al. to validate the original 2005 NIH SC in a subset of this cohort (BBMT 2013; 19:632). Survival analysis was performed to determine potential predictors of overall survival. Results Pts had a median age of 46 yrs (range 19-71); 37% were receiving moderate and 40% high levels of systemic immunosuppression. Pts scored by 2014 NIH SC tended to have slightly lower global severity scores in comparison to 2005 NIH SC (75% vs 72% pts with severe cGvHD). Lung and liver scores tended to be lower, 2014 NIH cGvHD organ-specific and global severity scores are shown in Table 1. 2014 NIH skin score was associated with reduced GS and ROM (both p Five-year overall survival in this cohort was 70.9% (95% CI: 64.8-76.1%) with a median potential follow-up of 79 months. The final Cox survival model included 2014 NIH Lung score (3 vs 0-2, HR=2.67, 95% CI: 1.47-4.84; p=0.0012), time from cGvHD diagnosis to consent (4+ yrs vs The associations between NIH Global score and the NIH lung score and patient-reported outcome measures are similar to those in the Baird et al. analysis of 2005 NIH cGvHD SC. In contrast to Baird et al. statistically significant associations are now seen between global severity, skin score and lung scores and performance-based measures including GS and 2MW. This suggests that scoring refinements introduced in 2014 have strengthened the validity of the NIH SC. Conclusions In this cross-sectional cohort severely affected by cGvHD, the 2014 NIH cGvHD SC organ-specific and global scores were associated with functional and QOL measures, and likely reflect cGvHD burden. Refinements in describing lung and liver cGvHD resulted in lower scores for these organs using the 2014 NIH cGvHD SC compared to the 2005 NIH cGvHD SC. These findings illustrate that 2014 NIH cGvHD SC are valid measures for cGvHD-related burden and warrant study within both clinical care and prospective trials. Download : Download high-res image (149KB) Download : Download full-size image Table . Disclosures No relevant conflicts of interest to declare.

Purpose: To conduct a longitudinal study on age-related nuclear cataracts using dynamic light scattering (DLS) to determine if cataract progression is associated with loss of the unbound form of the lens molecular chaperone protein, a-crystallin.Design: Natural history and cohort study.Participants: Patients 30 years of age or older of either gender seeking treatment at the Wilmer Eye Institute Cornea-Cataract Department.Methods: All patients underwent a comprehensive dilated eye examination every 6 months, including slit-lamp grading of their lenses using the Age-Related Eye Disease Study (AREDS) clinical lens grading system and obtaining an estimate of unbound alpha-crystallin level in the nucleus, the alpha-crystallin index (ACI), using the National Aeronautics and Space Administration-National Eye Institute DLS device. We used a random effects statistical model to examine the relationship of lens opacity changes over time with ACI changes.Main Outcome Measures: a-Crystallin Index (ACI) and AREDS nuclear cataract grade.Results: Forty-five patients (66 eyes) 34 to 79 years of age with AREDS nuclear lens grades of 0 to 3.0 were followed up every 6 months for a mean of 19 months (range, 6-36 months). We found that lenses with the lowest baseline levels of ACI had the most rapid progression of cataracts, whereas lenses with higher ACI at baseline had no or slower cataract progression. Lenses that lost a-crystallin at the highest rates during the study also had faster progression of nuclear cataracts than lenses with a slower rate of ACI loss. Kaplan-Meier survival curves showed that lenses with the lowest initial ACI had the highest risk of undergoing cataract surgery.Conclusions: This longitudinal study corroborates our previous cross-sectional study finding that higher levels of unbound a-crystallin as assessed by ACI are associated with lower risk of cataract formation and that loss of ACI over time is associated with cataract formation and progression. This study suggested that assessment of ACI with the DLS device could be used as a surrogate for lens opacity risk in clinical studies, and for assessing nuclear cataract events in studies where cataract development may be a side effect of a drug or device. (C) 2016 Published by Elsevier on behalf of the American Academy of Ophthalmology.

Purpose To conduct a longitudinal study on age-related nuclear cataracts using dynamic light scattering (DLS) to determine if cataract progression is associated with loss of the unbound form of the lens molecular chaperone protein, α-crystallin. Design Natural history and cohort study. Participants Patients 30 years of age or older of either gender seeking treatment at the Wilmer Eye Institute Cornea–Cataract Department. Methods All patients underwent a comprehensive dilated eye examination every 6 months, including slit-lamp grading of their lenses using the Age-Related Eye Disease Study (AREDS) clinical lens grading system and obtaining an estimate of unbound α-crystallin level in the nucleus, the α-crystallin index (ACI), using the National Aeronautics and Space Administration–National Eye Institute DLS device. We used a random effects statistical model to examine the relationship of lens opacity changes over time with ACI changes. Main Outcome Measures α-Crystallin Index (ACI) and AREDS nuclear cataract grade. Results Forty-five patients (66 eyes) 34 to 79 years of age with AREDS nuclear lens grades of 0 to 3.0 were followed up every 6 months for a mean of 19 months (range, 6–36 months). We found that lenses with the lowest baseline levels of ACI had the most rapid progression of cataracts, whereas lenses with higher ACI at baseline had no or slower cataract progression. Lenses that lost α-crystallin at the highest rates during the study also had faster progression of nuclear cataracts than lenses with a slower rate of ACI loss. Kaplan-Meier survival curves showed that lenses with the lowest initial ACI had the highest risk of undergoing cataract surgery. Conclusions This longitudinal study corroborates our previous cross-sectional study finding that higher levels of unbound α-crystallin as assessed by ACI are associated with lower risk of cataract formation and that loss of ACI over time is associated with cataract formation and progression. This study suggested that assessment of ACI with the DLS device could be used as a surrogate for lens opacity risk in clinical studies, and for assessing nuclear cataract events in studies where cataract development may be a side effect of a drug or device.

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogren's syndrome. Xerostomia was reported by 77% of the patients and was associated with xerophthalmia in all but I case. The salivary flow rate was <= 0.2 mL/min in 27%, and <= 0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD. Biol Blood Marrow Transplant 16: 1362-1369 (2010) Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation

In the above mentioned article, the authors have noted an error in the abstract and Results sections. The original text of the abstract reads "Xerostomia was reported by 77% of the patients and was associated with xerophthalmia in all but 1 case." The correct text should read "Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints."

OBJECTIVE:Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype-phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious. METHODS:We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1. RESULTS:In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed not only prominent spastic paraparesis but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material. CONCLUSIONS:Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders.

The American Academy of Ophthalmology and Otolaryngology (later the American Academy of Ophthalmology/AAO) published a manual, titled ‘‘Cataract Types,’’ by Frederick C. Cordes, MD, as part of its Continuing Education Program in 1961, which served as a practical guide for the classification of congenital cataracts for generations of AAO members. It contained a complex and confusing scheme to describe myriad types of congenital cataract that was difficult to apply clinically. Jules Francois published in 1963 a monumental textbook on congenital cataracts, which contained similar descriptions of myriad types of congenital cataracts. More recently, Amaya et al., Reddy et al., and Hejtmancik published excellent reviews on correlating the lens phenotype with known molecular genetic abnormalities of congenital and childhood cataracts. The lens phenotypes were quite varied and were categorized based on a combination of anatomic location, etiology, and descriptions of the shapes of the lenses, which were still complex and cumbersome to use in the clinic. In this issue of IOVS, Lin et al. propose a simplified clinical classification based on anatomic location with correlation to coexisting anterior segment abnormalities discovered using Scheimpflug imaging, performed under chloral hydrate sedation, of 598 eyes of 428 patients. These findings suggest that genetic and other factors that caused the cataracts may also affect the cornea, iris, and other anterior segment tissues. Hence a more thorough eye examination using newly available technology should be conducted to allow correlation of genetic abnormalities, not only to the lens but also to abnormalities of the cornea and iris. This is a pilot use of this classification system, and further development of a simple but comprehensive clinical classification system for congenital cataracts that is easy to use in practice should be undertaken. Perhaps it would be useful to have a Consensus Conference on this issue at some point.

Ocular chronic GVHD (cGVHD) is one of the most bothersome and common long-term complications after allogeneic HCT. The 2005 NIH cGVHD Consensus Project provided expert recommendations for diagnosis: dry, gritty, or painful eyes, cicatricial conjunctivitis, keratoconjunctivitis sicca or confluent areas of punctate keratopathy in conjunction with abnormally low Schirmer’s tear test. However these have not been prospectively validated in patients. The goal of this analysis was to identify predictive models for ocular cGVHD diagnosis, disease activity and clinical correlates that could be feasibly employed by transplant clinicians to assess outcomes in clinical practice and therapeutic trials. Between 2004 and 2013, 210 patients with moderate (n=57) or severe (n=151) cGVHD were enrolled on the NIH/NCI cGVHD cross-sectional observational study (NCT00092235). Median time from cGVHD diagnosis to enrollment was 765 (20-6670) days. Patient-reported outcomes (PROs) and transplant-clinician-reported outcomes (ClinROs) were gathered: Schirmer’s, NIH eye score (0-3), Lee cGVHD symptom scale (dry eye, needs eye drops frequently, and difficulty seeing clearly) (each 0-4) and chief eye symptom intensity scale (0-10). Participants were examined by ophthalmologists experienced in diagnosing and treating ocular cGVHD (MBD, RJB), who confirmed the diagnosis and classified patients as active vs. inactive. Univariate analyses and logistic models were developed to examine the associations among ophthalmologist assessment, PRO and ClinRO measures. Based on ophthalmology evaluation, 157 (75%) patients were diagnosed with ocular cGVHD; a majority (133/157; 85%) had active disease. In a multivariable model, the NIH eye score (3 vs. 2 vs. 1) (p<0.0001) and lower Schirmer’s (p<0.0001) were significant independent predictors of ocular cGVHD (sensitivity 93.0%, specificity 92.2%). The Lee dry eye was the strongest predictor of active ocular cGVHD (p<0.0001) (sensitivity 68.5%, specificity 82.6%). The following risk factors for ocular cGVHD were identified: related donor (p=0.0029) and HLA matched (p=0.0095) HCT. Oral cGVHD was strongly associated with the diagnosis of ocular cGVHD (p<0.0001). NIH eye score and Schirmer’s test are ClinRO measures that are strongly predictive for diagnosis of ocular cGVHD, while a single PRO item assessing dry eye symptom bother had 82.6% specificity for ocular cGVHD activity. Results support the use of these items for routine screening and ocular triage when providing long-term care to allogeneic HCT survivors. Prospective studies are needed to determine if a single PRO item assessing dry eye is sufficient for use as a trial outcome and to guide therapeutic decision-making in clinical practice. We confirm observations of others that HLA-matched and related donor transplants are associated with an increased risk of ocular cGVHD.

Purpose PI3K/AKT/mTOR and RAS/RAF/MEK pathways are frequently dysregulated in colorectal cancer (CRC). We conducted a biomarker-driven trial of the combination of MK-2206, an allosteric AKT 1/2/3 inhibitor, and selumetinib, a MEK 1/2 inhibitor, in patients with CRC to evaluate inhibition of phosphorylated ERK (pERK) and AKT (pAKT) in paired tumor biopsies. Patients and Methods Adult patients with advanced CRC were enrolled in successive cohorts stratified by KRAS mutation status. Initially, 12 patients received oral MK-2206 90 mg weekly with oral selumetinib 75 mg daily in 28-day cycles. Following an interim analysis, the doses of MK-2206 and selumetinib were increased to 135 mg weekly and 100 mg daily, respectively. Paired tumor biopsies were evaluated for target modulation. Results Common toxicities were gastrointestinal, hepatic, dermatologic, and hematologic. Of 21 patients enrolled, there were no objective responses. Target modulation did not achieve the pre-specified criteria of dual 70 % inhibition of pERK and pAKT levels in paired tumor biopsies. Conclusion Despite strong scientific rationale and preclinical data, clinical activity was not observed. The desired level of target inhibition was not achieved. Overlapping toxicities limited the ability to dose escalate to achieve exposures likely needed for clinical activity, highlighting the challenges in developing optimal combinations of targeted agents.

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.

Ocular chronic graft-versus-host disease is one of the most bothersome common complications following allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring. However, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. A total of 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (clinicaltrials.gov identifier: 00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease, diagnosis and activity. Measures gathered by the transplant clinician included Schirmer's tear test and National Institutes of Health 0-3 Eye Score. Patient-reported outcome measures were the ocular subscale of the Lee Chronic Graft-versus-Host Disease Symptom Scale and Chief Eye Symptom Intensity Score. Altogether, 157 (75%) patients were diagnosed with ocular chronic graft-versus-host disease; 133 of 157 patients (85%) had active disease. In a multivariable model, the National Institutes of Health Eye Score (P<0.0001) and Schirmer's tear test (P<0.0001) were independent predictors of ocular chronic graft-versus-host disease (sensitivity 93.0%, specificity 92.2%). The Lee ocular subscale was the strongest predictor of active ocular chronic graft-versus-host disease (P<0.0001) (sensitivity 68.5%, specificity 82.6%). Ophthalmology specialist measures that were most strongly predictive of diagnosis in a multivariate model were Oxford grand total staining (P<0.0001) and meibomian score (P=0.027). These results support the use of selected transplant clinician- and patient-reported outcome measures for ocular chronic graft-versus-host disease screening when providing care to allogeneic hematopoietic stem cell transplantation survivors with moderate to severe chronic graft-versus-host disease. Prospective studies are needed to determine if the Lee ocular subscale demonstrates adequate responsiveness as a disease activity outcome measure.

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.

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.