Rachel J Bishop

National Eye Institute, 베서스다, Maryland, United States

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Publications (28)154.58 Total impact

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    ABSTRACT: Purpose: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase 1 protocol. Experimental design: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10mg/m2 intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Results: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n=12), sarcoma (n=17), or other refractory solid tumors (n= 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5mg/kg and 10mg/kg dose levels. Pharmacokinetics revealed a half-life of 8-15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T cell populations. Six subjects had confirmed stable disease for 4-10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). Conclusions: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune related toxicities had an increased overall survival compared to those who showed no evidence of breaking tolerance.
    No preview · Article · Nov 2015 · Clinical Cancer Research
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    Preview · Article · Oct 2015

  • No preview · Article · Aug 2015 · The Journal of allergy and clinical immunology
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    ABSTRACT: Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · The Lancet Infectious Diseases
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    ABSTRACT: Inhibition of heat shock 90 (Hsp90) molecular chaperones allows targeting of multiple proteins involved in tumorigenesis. We investigated the safety, recommended phase 2 dose (RP2D), and pharmacokinetic and pharmacodynamic profile of onalespib (AT13387), a potent synthetic Hsp90 inhibitor, administered on days 1, 2, 8, 9, 15, and 16 of 28 day cycles (QDx2/week) in a phase I trial. This study followed an accelerated titration design with a starting dose of 20 mg/m(2)/dose and a standard 3 + 3 dose escalation design for dose level 4 (120 mg/m(2)/dose) and above. Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis. Thirty-one patients were treated; RP2D was established at 160 mg/m(2)/dose on the QDx2/week schedule. Common toxicities were gastrointestinal, hepatic, and hematologic. Pharmacokinetic profile was linear and plasma levels increased proportionally with dose (T½ ~8 h). No responses were observed; eight patients had stable disease for > 2 cycles with one patient remaining on study for 6 cycles. Target engagement was demonstrated by transcriptional upregulation of Hsp70 and Hsp27 in PBMCs. Statistically significant modulation of client proteins was not achieved in the 9 paired tumor biopsies evaluated; however, hierarchical clustering revealed two subgroups of patients with differential patterns of protein expression. Further combination studies are needed in order to target prospective driver oncoproteins.
    No preview · Article · Jun 2015 · Investigational New Drugs
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    ABSTRACT: Ocular chronic graft-versus-host disease is one of the most bothersome common complications after 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. 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (NCT00092235). 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. 157 (75%) patients were diagnosed with ocular chronic graft-versus-host disease; (133/157; 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. (NCT00092235). Copyright © 2015, Ferrata Storti Foundation.
    Full-text · Article · Jun 2015 · Haematologica

  • No preview · Article · Apr 2015 · Journal of Hepatology
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    ABSTRACT: 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.
    No preview · Article · Feb 2015 · Investigational New Drugs

  • No preview · Article · Feb 2015 · Biology of Blood and Marrow Transplantation
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    ABSTRACT: Objective To study efficacy and safety of escalating doses of canakinumab, a fully human anti-IL-1β monoclonal antibody in the severe cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease (NOMID). Methods 6 patients were enrolled in this 24-month, open-label phase I/II study. All underwent anakinra withdrawal. The initial subcutaneous canakinumab dose was 150 mg (or 2 mg/kg in patients ≤40 kg) or 300 mg (or 4 mg/kg) with escalation up to 600 mg (or 8 mg/kg) every 4 weeks. Full remission was remission of patient-reported clinical components and measures of systemic inflammation and CNS inflammation. Hearing, vision and safety were assessed. Primary endpoint was full remission at month 6. Results All patients flared after anakinra withdrawal, and symptoms and serum inflammatory markers improved with canakinumab. All patients required dose escalation to the maximum dose. At month 6, none had full remission, although 4/6 achieved inflammatory remission, based on disease activity diary scores and normal C-reactive proteins. None had CNS remission; 5/6 due to persistent CNS leucocytosis. At the last study visit, 5/6 patients achieved inflammatory remission and 4/6 had continued CNS leucocytosis. Visual acuity and field were stable in all patients, progressive hearing loss occurred in 1/10 ears. Adverse events (AEs) were rare. One serious AE (abscess due to a methicillin-resistant Staphylococcus aureus infection) occurred. Conclusions Canakinumab at the studied doses improves symptoms and serum inflammatory features of NOMID, although low-grade CNS leukocytosis in four patients and headaches in one additional patient persisted. Whether further dose intensifications are beneficial in these cases remains to be assessed. ClinicalTrials.gov identifier NCT00770601.
    Full-text · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Neonatal onset multisystem inflammatory disease (NOMID) is the most severe subset of patients (pts) with cryopyrin associated periodic syndromes (CAPS). IL-1 inhibitors are the mainstay of therapy for CAPS, however, the efficacy of longer acting IL-1 inhibitors in NOMID is not known. Objectives To study the efficacy and safety of a long acting IL-1β inhibitor, canakinumab in NOMID. (ClinicalTrials.gov number, NCT00770601) Methods 6 pts ages 11 to 34 with rash, systemic inflammation and CNS disease and typical arthrophathy (n=5) were enrolled in this 24-month, open label phase III study. Pts were previously treated with anakinra and underwent a one day withdrawal. The initial dose was 150 mg (or 2 mg/kg) or 300 mg (or 4 mg/kg in children) sc with repeat doses of 300 mg (or 4 mg/kg) sc every 4 to 8 weeks with dose escalation up to 600 mg (or 8 mg/kg) sc if evidence of disease activity persisted. Complete disease remission was defined based on patient-reported weekly clinical components (global diary score ≤2 and headache score <0.5) and measures of systemic inflammation (serum CRP ≤10 mg/L) and CNS inflammation (WBC count in CSF ≤15 cells/mm3). Hearing, vision and safety were also assessed. Results Although some pts flared after anakinra withdrawal, symptoms and serum inflammatory markers improved with canakinumab. At Month 6, 5/6 pts achieved remission based on diary scores, but no pt achieved complete remission due to CRP elevation (1/6) and persistent CNS leukocytosis (5/6). Two of the 6 pts had the lumbar puncture at 8 rather than 6 months. At the last available data point (range 195-750 days, median 550.5 days), 5/6 pts achieved remission based on diary scores and CRPs ≤10 mg/L, but 4/6 pts continued to have CNS leukocytosis. From time 0, visual acuity and visual field were stable in all 6 pts and a hearing loss from 15 to 30db in three consecutive frequencies (500 – 2000Hz) was observed in 1/10 ears that could reliably be tested. All pts required dose escalation to the maximum allowable dose of 600 mg (or 8 mg/kg) sc every 4-6 weeks. Adverse events (AEs) were mainly related to infections – during this study twelve infection-related AEs were reported by a total of 6 pts. One Serious AE (an abscess due to a methicillin-resistant Staphylococcus aureus infection) was considered to be study drug related. Conclusions Canakinumab at the studied doses improves symptoms and serum inflammatory features of NOMID, although low grade CNS leukocytosis in four pts and headaches in one additional patient persisted. The question of whether further dose intensifications could be beneficial in these cases remains to be assessed. Canakinumab at doses up to 600 mg (or 8 mg/kg in children) sc every 4-6 weeks was overall well tolerated. Disclosure of Interest R. Goldbach-Mansky Grant/Research support from: Regeneron, Novartis and Biovitrum, C. Sibley: None Declared, S. Felix Employee of: Novartis Pharma AG, C. Brewer: None Declared, K. King: None Declared, C. Zalewski: None Declared, H. Kim: None Declared, R. Bishop: None Declared, A. Chakraborty Employee of: Novartis Pharmaceuticals Corporation, L. Colin Employee of: Novartis Pharma AG, A. Chioato Employee of: Novartis Pharma AG
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background In severe forms of the rare monogenic autoinflammatory syndrome CAPS (NOMID, also denoted CINCA), persistent systemic and organ specific inflammation includes rash, central nervous system, and eye and cochlear inflammation leading to progressive hearing and vision loss. CAPS is caused by an uncontrolled IL-1β release, demonstrated by the often complete response after treatment with the IL-1 blocker anakinra (Kineret®) in all three entities of CAPS1,2,3 Objectives To characterize the long-term efficacy and safety of Kineret® in patients with severe CAPS. Methods A prospective, open-label withdrawal design study with long-term extension including 43 patients (7 adult and 36 pediatric) was conducted at the NIH (study 03-AR-0298). Diary disease sum scores (DSSS), inflammatory serum markers, CNS inflammation, hearing, vision, joint status, quality of life, and safety were evaluated for up to 5 years, and the pharmacokinetics and dosing of Kineret® in CAPS patients were evaluated. Results The median follow up time for the 43 patients was 4.9 years (range <0.1 to 5.4 years); 40 patients completed 3 or 6 months follow up and22/43 (51.2%) patients completed 60 months of treatment or more. Age at recruitment was 0.7 - 46.3 years (mean [SD] 10.3 [10.4]). Key symptoms (DSSS), decreased within 3 days of Kineret® initiation, from a mean baseline value of 4.5 to 0.8. At Month 3-6 (n=29), the estimated change was -3.5 (95% CI -3.7 to -3.3; p <0.0001). Median SAA and hsCRP levels decreased from 149 mg/L and 51 mg/L to 6 mg/L and 4 mg/L, respectively. Treatment withdrawal resulted in a clinical and laboratory relapse within a few days3. The DSSS and inflammatory serum marker improvement was sustained for up to 5 years of Kineret® treatment. Active inflammatory CNS disease (headache, MRI, and LP data) sustainably improved, and hearing and vision remained stable during treatment. The number of affected joints sustainably decreased, and bone mineral density gradually increased. The overall CHAQ score and other QoL assessments improved progressively over 5 years. The pharmacokinetics of Kineret® in CAPS patients was similar to that in RA patients. Body-weight adjusted dosage was a safe and effective approach for treatment of CAPS. Initial doses were optimized to maintain remission; the maintenance dose range at 5 years was 3.2-3.6 mg/kg. Conclusions Kineret® treatment for up to 5 years in severe CAPS patients was safe and resulted in the control of disease symptoms, inflammatory markers, CNS inflammation, and stabilized organ function. Careful monitoring with rapid individual dosing adjustments is important to achieve optimal control of organ inflammation. References References Disclosure of Interest H. Olivecrona Employee of: Swedish Orphan Biovitrum AB, M. Aldén Raboisson Employee of: Swedish Orphan Biovitrum AB, K. Söderberg Employee of: Swedish Orphan Biovitrum AB, B. Hallén Employee of: Swedish Orphan Biovitrum AB, M. Leinonen Consultant for: Swedish Orphan Biovitrum AB, C. Sibley: None Declared, N. Plass: None Declared, C. Brewer: None Declared, K. King: None Declared, C. Zalewski: None Declared, J. Kim: None Declared, R. Bishop: None Declared, S. Hill: None Declared, S. Paul: None Declared, D. Stone: None Declared, D. Chapelle: None Declared, J. Butman: None Declared, R. Goldbach-Mansky Grant/research support from: Swedish Orphan Biovitrum AB, Regeneron, and Novartis
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Purpose: Chronic granulomatous disease (CGD) is an inherited disorder characterized by defects in phagocyte-derived nicotinamide adenine dinucleotide phosphate oxidase. It is typically diagnosed in childhood and leads to severe, recurrent bacterial or fungal infections. Chorioretinal lesions are the most common ocular manifestation. We sought to determine whether there are infectious agents in CGD-associated chorioretinopathy. Methods: Medical records and ocular histopathology from CGD cases from January 1983 to January 2012 at the National Institutes of Health were retrospectively reviewed. Chorioretinal cells from normal and lesional tissues of the same eye were microdissected. Primers for Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia sp., and a panbacterial 16S ribosomal DNA were used for polymerase chain reaction. Results: Seventeen CGD patients had ocular tissues (16 autopsied cases and 1 chorioretinal biopsy) examined. Of these 17, 8 demonstrated CGD-associated chorioretinal lesions in at least one eye on histopathology. Of these 8, 7 showed amplification of 16S ribosomal DNA within the lesion; of these 7, two also amplified S. epidermidis and one P. aeruginosa. One had no bacterial DNA amplified. Importantly, no microbial DNA was amplified from the normal, non-lesional ocular tissues of these 8 cases. Furthermore, only 1 of the 9 eyes without chorioretinopathy had amplified Burkholderia DNA, that patient had a history of Burkholderia infection. Conclusions: We detected bacterial DNA in 7 of 8 (88%) cases with CGD-associated chorioretinopathy and only in 1 normal ocular tissue of 17 CGD cases. Bacterial infection may play a role in the pathogenesis of CGD-associated chorioretinal lesions.
    Full-text · Article · May 2013 · Journal of Clinical Immunology
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    ABSTRACT: OBJECTIVE: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. METHODS: Complete age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. RESULTS: Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. CONCLUSIONS: Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
    Full-text · Article · Apr 2013 · Ophthalmology
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    ABSTRACT: Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute (NCI) cross-sectional chronic Graft-versus-Host disease (cGVHD) natural history study. Patients were evaluated by multiple disease scales and outcome measures including the 2005 NIH Consensus Project cGVHD severity score. The purpose of this study is to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in order to standardize clinician evaluation and staging of cGVHD. 125 of 189 patients met criteria for severe cGVHD on the NIH global score and 62 had moderate disease, with a median of 4 (range 1-8) involved organs. Clinician average NIH organ score and the corresponding organ scores performed by subspecialists were highly correlated (r=0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures including Lee Scale, SF-36 Physical Component Scale (PCS), 2 minutes walk, grip strength, range of motion and Human Activity Profile (HAP). Joints/fascia, skin, and lung involvement impacted function and quality of life most significantly and showed highest number of correlations with outcome measures. The final Cox model showing factors jointly predictive for survival contained the time from cGVHD diagnosis (>49 vs. ≤49 months, HR=0.23; p=0.0011), absolute eosinophil count of (0-0.5 vs. >0.5 cells/μL, HR=3.95; p=0.0006) at the time of NIH evaluation, and NIH lung score (3 vs. 0-2, HR= 11.02; p <0.0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. Strong association with subspecialist evaluation suggests that NIH organs and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex sub-specialist exams. In this population of severely affected patients, NIH lung score is the strongest predictor of poor overall survival, both alone and after adjustment for other important factors.
    Full-text · Article · Jan 2013 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID. We conducted a cohort study of 26 NOMID patients ages 0.80-42.17 years who were followed up at the NIH and treated with anakinra 1-5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated. Sustained improvements in diary scores, parent's/patient's and physician's global scores of disease activity, parent's/patient's pain scores, and inflammatory markers were observed (all P<0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P=0.0026 and P=0.0076, respectively), albumin levels, and opening pressures (P=0.0012 and P<0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication. These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall.
    Full-text · Article · Jul 2012 · Arthritis & Rheumatology
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    ABSTRACT: This study reports a case of bilateral rifabutin-associated uveitis in a child with a history of acute myeloid leukemia. We utilized a clinical case description and brief discussion. A 17-year-old girl presented with acute bilateral anterior uveitis, a hypopyon in the left eye, and moderate bilateral vitritis. She had a history of acute myeloid leukemia status post-allogeneic hematopoietic stem cell transplant 5 years earlier. She was receiving rifabutin for a biopsy-proven Mycobacterium avium complex pulmonary infection. Work up for infectious and neoplastic etiologies was negative. The uveitis initially responded to topical corticosteroids, but recurred when the drops were tapered. Fluorescein angiography demonstrated diffuse vasculitis of small retinal vessels and cystoid macular edema. After rifabutin was discontinued, the uveitis and vasculitis slowly resolved. Fluorescein angiography demonstrated widespread retinal vasculitis which is a rare manifestation of rifabutin-associated uveitis.
    Full-text · Article · Feb 2012 · Journal of Ophthalmic Inflammation and Infection
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    Full-text · Article · Sep 2010 · Clinical Immunology
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    ABSTRACT: Three patients with aplastic anemia were evaluated by the ophthalmology service within 2 months of the aplastic anemia diagnosis for bilateral visual loss. The mean age of diagnosis of aplastic anemia was 14.3 years (range: 5 to 19 years) and the mean follow-up was 25 months (range: 15 to 44 months). All 6 eyes demonstrated choroidal ischemia and vitreous hemorrhage. Pars plana vitrectomy was performed in four eyes of two patients for non-clearing vitreous hemorrhage; one patient was observed. Successful anatomic outcomes were achieved in 3 of 4 eyes that underwent vitrectomy. Initial visual acuity ranged from 20/80 to bare light perception and final visual acuity ranged from 20/20 to no light perception. All patients received immunosuppressive therapy including cyclosporine and anti-thymocyte globulin, and two underwent hematopoietic stem cell transplantation. All patients received perioperative platelet and blood transfusions. Pars plana vitrectomy resulted in functional and anatomic success in the majority of eyes in this series. Coordination of medical and surgical care with the hematology service is advisable to stabilize hematologic parameters prior to undertaking a vitreoretinal procedure.
    No preview · Article · Jun 2010 · Ophthalmic Surgery Lasers and Imaging
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    ABSTRACT: Biomarkers could be useful in evaluating immune reconstitution inflammatory syndrome (IRIS). A cohort of 45 HIV-1-infected, antiretroviral treatment (ART)-naive patients with baseline CD4 T cell counts <or=100 cells/microL who were started on ART, suppressed HIV-RNA to <50 copies/mL, and seen every 1-3 months for 1 year were retrospectively evaluated for suspected or confirmed IRIS. d-Dimer, C-reactive protein (CRP), and selected autoantibodies were analyzed at baseline, 1 and 3 months post-ART in cryopreserved plasma. Median differences between cases and controls were compared with Mann-Whitney and Fisher's exact tests. Sixteen patients (35.6%) developed IRIS (median of 35 days post-ART initiation): unmasking=8, paradoxical=7, autoimmune=1. Pre-ART d-dimer and CRP were higher in IRIS cases versus controls (d-dimer: 0.89 mg/L versus 0.66 mg /L, p=0.037; CRP: 0.74 mg/L versus 0.39 mg/L, p=0.022), while d-dimer was higher in unmasking cases at IRIS onset (2.04 mg/L versus 0.36 mg /L, p=0.05). These biomarkers may be useful in identifying patients at risk for IRIS.
    Full-text · Article · Mar 2010 · Clinical Immunology

Publication Stats

771 Citations
154.58 Total Impact Points

Institutions

  • 2010-2015
    • National Eye Institute
      베서스다, Maryland, United States
  • 2009-2015
    • NEI Corporation
      Сомерсет, New Jersey, United States
  • 2007-2014
    • National Institutes of Health
      • • Laboratory of Immunology
      • • Branch of Clinical Trails
      • • Branch of Surgery
      Maryland, United States