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Papers by Katherine Kacena

Research paper thumbnail of Initial Analysis of Viral Dynamics and Circulating Viral Variants During the mRNA-1273 Phase 3 COVE Trial

This analysis assessed the impact of mRNA-1273 vaccination on the viral dynamics of severe acute ... more This analysis assessed the impact of mRNA-1273 vaccination on the viral dynamics of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the ongoing Coronavirus Efficacy (COVE) trial. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval [CI]) by 100-fold on the day of diagnosis (4.1 [3.4-4.8] versus placebo (6.2 [6.0-6.4] log10 copies/ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 for placebo. Vaccination also reduced the burden of disease and infection scores. Vaccine efficacies (95% CI) during the trial against SARS-CoV-2 variants circulating in the US were 82.4% (40.4%-94.8%) for Epsilon and Gamma, and 81.2% (36.1%-94.5%) for the Epsilon variants. The detection of other respiratory viruses during the trial was similar between groups. In those who became SARS-CoV-2 infected, the reduction of viral load after mRNA-1273 vaccination is potentially correlated to the risk of transmission, ...

Research paper thumbnail of Phase 1a/b open-label study of IK-175, an oral AHR inhibitor, alone and in combination with nivolumab in patients with locally advanced or metastatic solid tumors and urothelial carcinoma

Journal of Clinical Oncology

TPS3169 Background: Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor th... more TPS3169 Background: Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activity of multiple innate and adaptive immune cells. Kynurenine, generated from tryptophan by IDO1 and TDO2, is a ligand that binds AHR and leads to a net immunosuppressive tumor microenvironment, making AHR an attractive therapeutic target in multiple cancer types. IK-175 is a selective, small molecule inhibitor of AHR being developed as an oral agent. In preclinical mouse tumor models, IK-175 demonstrates antitumor activity as a single agent or in combination with checkpoint inhibitors. AHR immunohistochemistry (IHC) tumor microarray analysis across 15 different tumor types revealed that bladder cancer has the highest level of AHR protein expression and nuclear localization indicative of ligand-bound and active AHR signaling. Therefore, nuclear AHR in urothelial carcinoma tumors is being investigated for potential predictive clinical benefit with IK-175. Methods: Thi...

Research paper thumbnail of Machine-learning, MRI bone shape and important clinical outcomes in osteoarthritis: data from the Osteoarthritis Initiative

Annals of the Rheumatic Diseases, 2020

ObjectivesOsteoarthritis (OA) structural status is imperfectly classified using radiographic asse... more ObjectivesOsteoarthritis (OA) structural status is imperfectly classified using radiographic assessment. Statistical shape modelling (SSM), a form of machine-learning, provides precise quantification of a characteristic 3D OA bone shape. We aimed to determine the benefits of this novel measure of OA status for assessing risks of clinically important outcomes.MethodsThe study used 4796 individuals from the Osteoarthritis Initiative cohort. SSM-derived femur bone shape (B-score) was measured from all 9433 baseline knee MRIs. We examined the relationship between B-score, radiographic Kellgren-Lawrence grade (KLG) and current and future pain and function as well as total knee replacement (TKR) up to 8 years.ResultsB-score repeatability supported 40 discrete grades. KLG and B-score were both associated with risk of current and future pain, functional limitation and TKR; logistic regression curves were similar. However, each KLG included a wide range of B-scores. For example, for KLG3, ri...

Research paper thumbnail of A novel structural status assessment of oa is strongly associated with all patient important outcomes - an mri study of 9,433 knees from the osteoarthritis initiative

Osteoarthritis and Cartilage, 2020

Research paper thumbnail of Effect of Enzyme Replacement Therapy on Bone Mineral Density in Type 1 Gaucher Disease

Blood, 2005

Objective: To determine the effect of enzyme replacement therapy (ERT; Cerezyme®, imiglucerase fo... more Objective: To determine the effect of enzyme replacement therapy (ERT; Cerezyme®, imiglucerase for injection) on bone mineral density (BMD) in patients with type 1 Gaucher disease (GD). Methods: The GD population included all adults (males 18–70y, females 18–50y) with type 1 GD enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry for whom serial spine BMD measurements were submitted. BMD data with up to 12 years of follow-up were analyzed for 111 patients not on ERT, 218 patients on ERT only and 34 patients on ERT plus bisphosphonates. BMD was measured by dual energy X-ray absorptiometry (DXA) Z-scores (age and sex-adjusted) in the lumbar spine of each patient. All measurements were compared to a reference population (Hologic reference standard). Results: DXA Z-scores for GD patients not on ERT were significantly lower than the reference population and remained approximately one standard deviation below the reference population over time (y intercept = −...

Research paper thumbnail of Pooling of Urine Samples for Screening for Neisseria gonorrhoeae by Ligase Chain Reaction: Accuracy and Application

Journal of Clinical Microbiology, 1998

The accuracy of detection of genital Neisseria gonorrhoeae infection in pooled urine samples by l... more The accuracy of detection of genital Neisseria gonorrhoeae infection in pooled urine samples by ligase chain reaction (LCR) was examined in three populations. Firstly, urine specimens from 300 female military recruits (FMR) were tested by LCR individually and in pools of four and six. Secondly, 300 urine specimens from middle-school students (MSS) were tested individually by LCR, and then the processed specimens were stored frozen for subsequent testing in pools of 4 and 10. Thirdly, 600 frozen urine specimens from high-school students (HSS) were tested by using the LCR pooling algorithm, i.e., testing processed specimens in pools of four in one test unit dose, and retesting individual specimens from positive pools. Finally, the pooling algorithm results were compared to culture results for a subset of 344 students from the original 600 HSS from whom cervical or urethral samples were taken at the discretion of the school nurse practitioners. Compared to individual testing of specime...

Research paper thumbnail of Pooling Urine Samples for Ligase Chain Reaction Screening for Genital Chlamydia trachomatis Infection in Asymptomatic Women

Journal of Clinical Microbiology, 1998

The accuracy of pooling urine samples for the detection of genital Chlamydia trachomatis infectio... more The accuracy of pooling urine samples for the detection of genital Chlamydia trachomatis infection by ligase chain reaction (LCR) was examined. A model was also developed to determine the number of samples to be pooled for optimal cost savings at various population prevalences. Estimated costs included technician time, laboratory consumables, and assay costs of testing pooled samples and retesting individual specimens from presumptive positive pools. Estimation of population prevalence based on the pooled LCR results was also applied. After individual urine specimens were processed, 568 specimens were pooled by 4 into 142 pools and another 520 specimens were pooled by 10 into 52 pools. For comparison, all 1,088 urine specimens were tested individually. The sample-to-cut-off ratio was lowered from 1.0 to 0.2 for pooled samples, after a pilot study which tested 148 samples pooled by 4 was conducted. The pooling algorithm was 100% (48 of 48) sensitive when samples were pooled by 4 and ...

Research paper thumbnail of Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, asc...

Neuromuscular Disorders, 2018

Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel e... more Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatmentnaïve and alglucosidase alfa-treated patients with late-onset Pompe disease A phase 1, open-label, multicenter, multinational, ascending dose study NEO1 Investigator Group

Research paper thumbnail of Long-term efficacy of alglucosidase alfa in late-onset Pompe disease

Molecular Genetics and Metabolism, 2017

enriched for genes that were deregulated in four different phenotypes-Gba1 mutant mouse model (Gb... more enriched for genes that were deregulated in four different phenotypes-Gba1 mutant mouse model (Gba1 m), Gba1 m treated with Velaglucerase-alfa or with Imiglucerase and patient fibroblast (N370S/L444P mutations). Microarray datasets were acquired from the Gene Expression Omnibus database: GSE14520, GSE45436, GSE44647, GSE44569 and GSE21899. We hypothesized that up-and downstream deregulated genes/pathways depend on tissue differential expression (DEG), which makes patient's fibroblast phenotype not comparable to any output obtained from master regulator (MR) and gene set enrichment analysis (GSEA) using liver tissue datasets. MR found in patient's fibroblast were HOXC8, DUX1, CDX1, FEV, NKX3-1, CREBL2, ZNF444, ATF1, CNOT8; whereas Gba1 m showed common MR/DEG, including E2F2, PSMD10, RNF4, SMAD4, TRIM22, TSC22D1 between phenotype Gba1 m and the one treated either with Velaglucerase alfa and with Imiglucerase using and stringency threshold of p-value = 0.05. In conclusion, these results do not only provide new insights into the pathogenetic relationship between sphingolipidosis and cancer, but also propose a novel methodology to analyze differential molecular impact of the GBA1 mutation in mice and human, the effect of two similar biopharmaceuticals for GD treatment and the most promising candidates for future experimental validation for targeted metabolic pathways using signature drug-profiling.

Research paper thumbnail of 36. Dose–response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type I

Molecular Genetics and Metabolism, 2008

Introduction: Gaucher disease (GD)-related bone disease puts children at risk for developing irre... more Introduction: Gaucher disease (GD)-related bone disease puts children at risk for developing irreversible complications and interferes with the achievement of optimal bone mass. Appropriate disease management includes an initial assessment and ongoing monitoring of the bone marrow and mineral components, and guidelines addressing the clinical and technical challenges of these evaluations are needed. Methods: A working group met in October 2006 to develop evidenceand consensus-based guidelines to facilitate the assessment and monitoring of bone disease in children with GD. Results: Magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) are recommended for the evaluation of bone marrow infiltration and bone mineral density, respectively. Assessments should be performed at centers with expertise in children. MRI measurements (T1-weighted and STIR sequences) of the femur, pelvis and spine should be made at baseline and at least every 2 years thereafter, preferably annually. DXA measurements of the lumbar spine, proximal femur, and entire body should be made at baseline and annually thereafter, with serial scans performed on the same DXA machine. DXA measurements must be analyzed with the appropriate pediatric software option and reported as Zscores with respect to the best available databases of age-matched controls. Conclusions: These guidelines will facilitate the assessment of GDrelated bone disease needed to tailor clinical management in order to achieve the therapeutic goals of eliminating bone marrow infiltration and achieving optimal bone density in children with GD.

Research paper thumbnail of Chlamydia, Gonorrhea, and HIV-1 Prevalence Among Five Populations of Women in the Czech and Slovak Republics

Sex Transm Dis, 2001

Background: Five populations at risk for sexually transmitted diseases (STDs) in the Czech and Sl... more Background: Five populations at risk for sexually transmitted diseases (STDs) in the Czech and Slovak Republics were sampled. Goal: To estimate prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, and HIV-1 infections. Study Design: Urine specimens were collected serially from women at a Prague prenatal clinic (n ‫؍‬ 134), a Prague dermatovenerealogy clinic (n ‫؍‬ 91), sex workers from northern and central Bohemia (n ‫؍‬ 35), students from a northern Bohemian school (n ‫؍‬ 217), and Gypsies from Jarovnice, Slovakia (n ‫؍‬ 128). These specimens were tested for chlamydia and gonorrhea using a ligase chain reaction pooling algorithm, and for HIV using an enzyme immunoassay confirmed by Western blot. Results: The prevalence of chlamydia was 2.2% (95% CI, 0.4-6.4) in the prenatal clinic, 5.5% (95% CI, 1.8-12.4) in the STD clinic, 22.9% (95% CI, 10.4-40.1) among street sex workers, 8.2% (95% CI, 3.6-15.6) among sexually active female high school students, and 3.9% (95% CI, 1.3-8.9) among Gypsy women. Gonorrhea was found in only two populations: 2.2% (95% CI, 0.3-7.7) in the STD clinic, and 2.9% (95% CI, 0.1-14.9) among sex workers. No HIV-1 infection was detected. Conclusions: Urine screening was an efficient and accurate method for identifying groups at risk for STDs in the Czech Republic and Slovakia because sample collection was fast and noninvasive, and potential participation bias was reduced by high acceptability.

Research paper thumbnail of Eight-Year Clinical Outcomes of Long-Term Enzyme Replacement Therapy for 884 Children With Gaucher Disease Type 1

Pediatrics, 2008

OBJECTIVE. The goal was to analyze the clinical responses to enzyme replacement therapy with algl... more OBJECTIVE. The goal was to analyze the clinical responses to enzyme replacement therapy with alglucerase or imiglucerase in a large international cohort of children with Gaucher disease type 1. METHODS. Anonymized data from 884 children in the International Collaborative Gaucher Group Gaucher Registry were analyzed to determine the effects of long-term enzyme replacement therapy with alglucerase or imiglucerase on hematologic and visceral manifestations, linear growth, and skeletal disease. The parameters measured were hemoglobin levels, platelet counts, spleen and liver volumes, z scores for height and bone mineral density, and reports of bone pain and bone crises. RESULTS. The median height z score for the study population was −1.4 at baseline. After 8 years of treatment, the median height approximated the median value for the normal population. Anemia, although not severe, was present in >50% of patients at baseline and resolved for all patients after 8 years of treatment. Mor...

Research paper thumbnail of Community infection ratio as indicator for tuberculosis control

The Lancet, 1995

The epidemiology of tuberculosis remains poorly understood. We investigated the relative importan... more The epidemiology of tuberculosis remains poorly understood. We investigated the relative importance of within-household and community transmission of infection among children aged 6 months to 14 years living in a Peruvian shanty-town. The prevalence of Mycobacterium tuberculosis exposure among 175 contact children (sharing a household with a person who had confirmed pulmonary tuberculosis) and 382 control children (living in nearby households free of active tuberculosis) was defined as the proportion of children with a positive purified protein derivative (PPD) skin-test. 97 (55%) contact children and 129 (34%) controls were PPD positive. Living in a contact household (odds ratio 1.74, 95% CI 1.11-2.73) and age (1.11, 1.06-1.18) were significant risk factors for PPD positivity. We calculated the community infection ratio (CIR) as the odds ratio of PPD-positive controls to PPD-positive contacts: CIR = [formula: see text] A low CIR therefore suggests mainly household spread of infection, whereas a high value suggests frequent transmission outside the household. The adjusted odds ratio (for age, sex, within-household correlation, and household size) was 0.40 (95% CI 0.26-0.64), compared with values of 0.18-0.37 in studies elsewhere. Currently recommended tuberculosis control strategies are suitable for areas with low CIRs. Different strategies may be needed for areas, such as that we studied, with high values.

Research paper thumbnail of Iodofiltic Acid I 123 (BMIPP) Fatty Acid Imaging Improves Initial Diagnosis in Emergency Department Patients With Suspected Acute Coronary Syndromes

Journal of the American College of Cardiology, 2010

The aim of this study was to assess the performance of ␤-methyl-p-[ 123 I]-iodophenyl-pentadecano... more The aim of this study was to assess the performance of ␤-methyl-p-[ 123 I]-iodophenyl-pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) to detect acute coronary syndromes (ACS) in emergency department patients with chest pain. Background Emergency department diagnosis of chest pain is problematic, often requiring prolonged observation and stress testing. BMIPP SPECT detects abnormalities in fatty acid metabolism resulting from myocardial ischemia, even many hours after symptom cessation. Methods Emergency department patients with suspected ACS were enrolled at 50 centers. Patients received 5 mCi BMIPP within 30 h of symptom cessation. BMIPP SPECT images were interpreted semiquantitatively by 3 blinded readers. Initial clinical diagnosis was based on symptoms, initial electrocardiograms, and troponin, whereas the final diagnosis was based on all available data (including angiography and stress SPECT) but not BMIPP SPECT. Final diagnoses were adjudicated by a blinded committee as ACS, intermediate likelihood of ACS, or negative for ACS. Results A total of 507 patients were studied and efficacy was evaluated in 448 patients with sufficient data. The sensitivity of BMIPP by 3 blinded readers for a final diagnosis of ACS and intermediate likelihood of ACS was 71% (95% confidence interval [CI]: 64% to 79%), 74% (95% CI: 68% to 81%), and 69% (95% CI: 62% to 77%); the corresponding specificity of BMIPP was 67% (95% CI: 61% to 73%), 54% (95% CI: 48% to 60%), and 70% (95% CI: 64% to 76%). Compared with the initial diagnosis alone, BMIPP ϩ initial diagnosis increased sensitivity from 43% to 81% (p Ͻ 0.001), negative predictive value from 62% to 83% (p Ͻ 0.001), and positive predictive value from 41% to 58% (p Ͻ 0.001), whereas specificity was unchanged (61% to 62%, p ϭ NS). Conclusions The addition of BMIPP data to the initially available clinical information adds incremental value toward the early diagnosis of an ACS, potentially allowing determination of the presence or absence of ACS to be made earlier in the evaluation process. (Safety and Efficacy Iodofiltic Acid I 123 in the Treatment of Acute Coronary Syndrome [Zeus-ACS]; NCT00514501) (

Research paper thumbnail of Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1

Genetics in Medicine, 2009

Purpose: To determine whether enzyme therapy with imiglucerase/ alglucerase demonstrates dose-res... more Purpose: To determine whether enzyme therapy with imiglucerase/ alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to Ͻ29 U/kg/2 weeks), Group B (29 U to Ͻ48 U/kg/2 weeks), Group C (48 U to Ͻ75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (E max) and half-time to E max (T 50) of enzyme therapy for each parameter were compared across dosing groups. Results: Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to E max and T 50 over 96 months for each disease parameter. Conclusions: Enzyme therapy with imiglucerase/alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries. Genet Med 2009:11(2):92-100.

Research paper thumbnail of Life expectancy in Gaucher disease type 1

American Journal of Hematology, 2008

We estimated life expectancy at birth for Gaucher disease type 1 (GD1) patients by comparing surv... more We estimated life expectancy at birth for Gaucher disease type 1 (GD1) patients by comparing survival data from GD1 patients enrolled in ICGG Gaucher Registry to the U.S. population using standard life table methods. 2,876 GD1 patients had 102 reported deaths in 13,509 person-years of follow-up. Estimated life expectancy at birth was 68 y, compared with 77 y in reference population; splenectomized patients, 64 y; nonsplenectomized, 72 y. Causes of death for 63/102 patients were malignancy (17/63), cardiovascular (11/63), and cerebrovascular (8/63). Estimated life expectancy at birth for GD1 patients was ~9 y less than reference population. Malignancies did not contribute to shortened life expectancy.

Research paper thumbnail of The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients

American Journal of Hematology, 2009

Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease... more Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross‐sectional study. In addition, the relative risk (RR) of cancer in patients compared with age‐, sex‐, and ethnic‐group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in ...

Research paper thumbnail of 90Y-Edotreotide for Metastatic Carcinoid Refractory to Octreotide

Journal of Clinical Oncology, 2010

Purpose Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flus... more Purpose Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using 90Y-edotreotide to treat symptomatic patients with carcinoid tumors. Patients and Methods Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) 90Y-edotreotide each, once every 6 weeks. Results Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms ...

Research paper thumbnail of Glucosylsphingosine is a key biomarker of Gaucher disease

American journal of hematology, Jan 21, 2016

Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysol... more Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of plasma LGL1 were assessed by Pearson's correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs. Eliglustat Tartrate SRT (ELI-SRT). Plasma Lyso-GL1 levels in healthy controls averaged 1.5 ng/ml (1.3-1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4-216.5) and imiglucerase ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2-129.4) (P < 0.001). Lyso-GL1 correlated with chitotriosidase (r...

Research paper thumbnail of Gaucher disease and cancer incidence: a study from the Gaucher Registry

Blood, 2005

Patients with Gaucher disease (GD) are alleged to be at an increased risk of malignant disorders,... more Patients with Gaucher disease (GD) are alleged to be at an increased risk of malignant disorders, possibly due to potential chronic stimulation of the immune system and lymphoproliferation associated with storage of glucocerebroside in tissue macrophages. Because previous reports of increased risk of malignancy in GD may have been affected by small patient numbers and ascertainment bias, 2742 patients with GD from the International Gaucher Registry were studied. The number of cancers identified among patients in the registry was compared with that expected in the US population of similar attained age and sex. The majority of patients were young or middle-aged adults at the time of last follow-up, with only 14% older than age 60. There were 10 patients with multiple myeloma, yielding an estimated relative risk of 5.9 (95% confidence interval [95% CI]: 2.8, 10.8). The relative risk of cancer overall was 0.79 (95% CI: 0.67, 0.94), and the subgroups for cancers of the breast, prostate, ...

Research paper thumbnail of Initial Analysis of Viral Dynamics and Circulating Viral Variants During the mRNA-1273 Phase 3 COVE Trial

This analysis assessed the impact of mRNA-1273 vaccination on the viral dynamics of severe acute ... more This analysis assessed the impact of mRNA-1273 vaccination on the viral dynamics of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the ongoing Coronavirus Efficacy (COVE) trial. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval [CI]) by 100-fold on the day of diagnosis (4.1 [3.4-4.8] versus placebo (6.2 [6.0-6.4] log10 copies/ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 for placebo. Vaccination also reduced the burden of disease and infection scores. Vaccine efficacies (95% CI) during the trial against SARS-CoV-2 variants circulating in the US were 82.4% (40.4%-94.8%) for Epsilon and Gamma, and 81.2% (36.1%-94.5%) for the Epsilon variants. The detection of other respiratory viruses during the trial was similar between groups. In those who became SARS-CoV-2 infected, the reduction of viral load after mRNA-1273 vaccination is potentially correlated to the risk of transmission, ...

Research paper thumbnail of Phase 1a/b open-label study of IK-175, an oral AHR inhibitor, alone and in combination with nivolumab in patients with locally advanced or metastatic solid tumors and urothelial carcinoma

Journal of Clinical Oncology

TPS3169 Background: Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor th... more TPS3169 Background: Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activity of multiple innate and adaptive immune cells. Kynurenine, generated from tryptophan by IDO1 and TDO2, is a ligand that binds AHR and leads to a net immunosuppressive tumor microenvironment, making AHR an attractive therapeutic target in multiple cancer types. IK-175 is a selective, small molecule inhibitor of AHR being developed as an oral agent. In preclinical mouse tumor models, IK-175 demonstrates antitumor activity as a single agent or in combination with checkpoint inhibitors. AHR immunohistochemistry (IHC) tumor microarray analysis across 15 different tumor types revealed that bladder cancer has the highest level of AHR protein expression and nuclear localization indicative of ligand-bound and active AHR signaling. Therefore, nuclear AHR in urothelial carcinoma tumors is being investigated for potential predictive clinical benefit with IK-175. Methods: Thi...

Research paper thumbnail of Machine-learning, MRI bone shape and important clinical outcomes in osteoarthritis: data from the Osteoarthritis Initiative

Annals of the Rheumatic Diseases, 2020

ObjectivesOsteoarthritis (OA) structural status is imperfectly classified using radiographic asse... more ObjectivesOsteoarthritis (OA) structural status is imperfectly classified using radiographic assessment. Statistical shape modelling (SSM), a form of machine-learning, provides precise quantification of a characteristic 3D OA bone shape. We aimed to determine the benefits of this novel measure of OA status for assessing risks of clinically important outcomes.MethodsThe study used 4796 individuals from the Osteoarthritis Initiative cohort. SSM-derived femur bone shape (B-score) was measured from all 9433 baseline knee MRIs. We examined the relationship between B-score, radiographic Kellgren-Lawrence grade (KLG) and current and future pain and function as well as total knee replacement (TKR) up to 8 years.ResultsB-score repeatability supported 40 discrete grades. KLG and B-score were both associated with risk of current and future pain, functional limitation and TKR; logistic regression curves were similar. However, each KLG included a wide range of B-scores. For example, for KLG3, ri...

Research paper thumbnail of A novel structural status assessment of oa is strongly associated with all patient important outcomes - an mri study of 9,433 knees from the osteoarthritis initiative

Osteoarthritis and Cartilage, 2020

Research paper thumbnail of Effect of Enzyme Replacement Therapy on Bone Mineral Density in Type 1 Gaucher Disease

Blood, 2005

Objective: To determine the effect of enzyme replacement therapy (ERT; Cerezyme®, imiglucerase fo... more Objective: To determine the effect of enzyme replacement therapy (ERT; Cerezyme®, imiglucerase for injection) on bone mineral density (BMD) in patients with type 1 Gaucher disease (GD). Methods: The GD population included all adults (males 18–70y, females 18–50y) with type 1 GD enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry for whom serial spine BMD measurements were submitted. BMD data with up to 12 years of follow-up were analyzed for 111 patients not on ERT, 218 patients on ERT only and 34 patients on ERT plus bisphosphonates. BMD was measured by dual energy X-ray absorptiometry (DXA) Z-scores (age and sex-adjusted) in the lumbar spine of each patient. All measurements were compared to a reference population (Hologic reference standard). Results: DXA Z-scores for GD patients not on ERT were significantly lower than the reference population and remained approximately one standard deviation below the reference population over time (y intercept = −...

Research paper thumbnail of Pooling of Urine Samples for Screening for Neisseria gonorrhoeae by Ligase Chain Reaction: Accuracy and Application

Journal of Clinical Microbiology, 1998

The accuracy of detection of genital Neisseria gonorrhoeae infection in pooled urine samples by l... more The accuracy of detection of genital Neisseria gonorrhoeae infection in pooled urine samples by ligase chain reaction (LCR) was examined in three populations. Firstly, urine specimens from 300 female military recruits (FMR) were tested by LCR individually and in pools of four and six. Secondly, 300 urine specimens from middle-school students (MSS) were tested individually by LCR, and then the processed specimens were stored frozen for subsequent testing in pools of 4 and 10. Thirdly, 600 frozen urine specimens from high-school students (HSS) were tested by using the LCR pooling algorithm, i.e., testing processed specimens in pools of four in one test unit dose, and retesting individual specimens from positive pools. Finally, the pooling algorithm results were compared to culture results for a subset of 344 students from the original 600 HSS from whom cervical or urethral samples were taken at the discretion of the school nurse practitioners. Compared to individual testing of specime...

Research paper thumbnail of Pooling Urine Samples for Ligase Chain Reaction Screening for Genital Chlamydia trachomatis Infection in Asymptomatic Women

Journal of Clinical Microbiology, 1998

The accuracy of pooling urine samples for the detection of genital Chlamydia trachomatis infectio... more The accuracy of pooling urine samples for the detection of genital Chlamydia trachomatis infection by ligase chain reaction (LCR) was examined. A model was also developed to determine the number of samples to be pooled for optimal cost savings at various population prevalences. Estimated costs included technician time, laboratory consumables, and assay costs of testing pooled samples and retesting individual specimens from presumptive positive pools. Estimation of population prevalence based on the pooled LCR results was also applied. After individual urine specimens were processed, 568 specimens were pooled by 4 into 142 pools and another 520 specimens were pooled by 10 into 52 pools. For comparison, all 1,088 urine specimens were tested individually. The sample-to-cut-off ratio was lowered from 1.0 to 0.2 for pooled samples, after a pilot study which tested 148 samples pooled by 4 was conducted. The pooling algorithm was 100% (48 of 48) sensitive when samples were pooled by 4 and ...

Research paper thumbnail of Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, asc...

Neuromuscular Disorders, 2018

Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel e... more Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatmentnaïve and alglucosidase alfa-treated patients with late-onset Pompe disease A phase 1, open-label, multicenter, multinational, ascending dose study NEO1 Investigator Group

Research paper thumbnail of Long-term efficacy of alglucosidase alfa in late-onset Pompe disease

Molecular Genetics and Metabolism, 2017

enriched for genes that were deregulated in four different phenotypes-Gba1 mutant mouse model (Gb... more enriched for genes that were deregulated in four different phenotypes-Gba1 mutant mouse model (Gba1 m), Gba1 m treated with Velaglucerase-alfa or with Imiglucerase and patient fibroblast (N370S/L444P mutations). Microarray datasets were acquired from the Gene Expression Omnibus database: GSE14520, GSE45436, GSE44647, GSE44569 and GSE21899. We hypothesized that up-and downstream deregulated genes/pathways depend on tissue differential expression (DEG), which makes patient's fibroblast phenotype not comparable to any output obtained from master regulator (MR) and gene set enrichment analysis (GSEA) using liver tissue datasets. MR found in patient's fibroblast were HOXC8, DUX1, CDX1, FEV, NKX3-1, CREBL2, ZNF444, ATF1, CNOT8; whereas Gba1 m showed common MR/DEG, including E2F2, PSMD10, RNF4, SMAD4, TRIM22, TSC22D1 between phenotype Gba1 m and the one treated either with Velaglucerase alfa and with Imiglucerase using and stringency threshold of p-value = 0.05. In conclusion, these results do not only provide new insights into the pathogenetic relationship between sphingolipidosis and cancer, but also propose a novel methodology to analyze differential molecular impact of the GBA1 mutation in mice and human, the effect of two similar biopharmaceuticals for GD treatment and the most promising candidates for future experimental validation for targeted metabolic pathways using signature drug-profiling.

Research paper thumbnail of 36. Dose–response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type I

Molecular Genetics and Metabolism, 2008

Introduction: Gaucher disease (GD)-related bone disease puts children at risk for developing irre... more Introduction: Gaucher disease (GD)-related bone disease puts children at risk for developing irreversible complications and interferes with the achievement of optimal bone mass. Appropriate disease management includes an initial assessment and ongoing monitoring of the bone marrow and mineral components, and guidelines addressing the clinical and technical challenges of these evaluations are needed. Methods: A working group met in October 2006 to develop evidenceand consensus-based guidelines to facilitate the assessment and monitoring of bone disease in children with GD. Results: Magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) are recommended for the evaluation of bone marrow infiltration and bone mineral density, respectively. Assessments should be performed at centers with expertise in children. MRI measurements (T1-weighted and STIR sequences) of the femur, pelvis and spine should be made at baseline and at least every 2 years thereafter, preferably annually. DXA measurements of the lumbar spine, proximal femur, and entire body should be made at baseline and annually thereafter, with serial scans performed on the same DXA machine. DXA measurements must be analyzed with the appropriate pediatric software option and reported as Zscores with respect to the best available databases of age-matched controls. Conclusions: These guidelines will facilitate the assessment of GDrelated bone disease needed to tailor clinical management in order to achieve the therapeutic goals of eliminating bone marrow infiltration and achieving optimal bone density in children with GD.

Research paper thumbnail of Chlamydia, Gonorrhea, and HIV-1 Prevalence Among Five Populations of Women in the Czech and Slovak Republics

Sex Transm Dis, 2001

Background: Five populations at risk for sexually transmitted diseases (STDs) in the Czech and Sl... more Background: Five populations at risk for sexually transmitted diseases (STDs) in the Czech and Slovak Republics were sampled. Goal: To estimate prevalence of Chlamydia trachomatis, Neisseria gonorrhoeae, and HIV-1 infections. Study Design: Urine specimens were collected serially from women at a Prague prenatal clinic (n ‫؍‬ 134), a Prague dermatovenerealogy clinic (n ‫؍‬ 91), sex workers from northern and central Bohemia (n ‫؍‬ 35), students from a northern Bohemian school (n ‫؍‬ 217), and Gypsies from Jarovnice, Slovakia (n ‫؍‬ 128). These specimens were tested for chlamydia and gonorrhea using a ligase chain reaction pooling algorithm, and for HIV using an enzyme immunoassay confirmed by Western blot. Results: The prevalence of chlamydia was 2.2% (95% CI, 0.4-6.4) in the prenatal clinic, 5.5% (95% CI, 1.8-12.4) in the STD clinic, 22.9% (95% CI, 10.4-40.1) among street sex workers, 8.2% (95% CI, 3.6-15.6) among sexually active female high school students, and 3.9% (95% CI, 1.3-8.9) among Gypsy women. Gonorrhea was found in only two populations: 2.2% (95% CI, 0.3-7.7) in the STD clinic, and 2.9% (95% CI, 0.1-14.9) among sex workers. No HIV-1 infection was detected. Conclusions: Urine screening was an efficient and accurate method for identifying groups at risk for STDs in the Czech Republic and Slovakia because sample collection was fast and noninvasive, and potential participation bias was reduced by high acceptability.

Research paper thumbnail of Eight-Year Clinical Outcomes of Long-Term Enzyme Replacement Therapy for 884 Children With Gaucher Disease Type 1

Pediatrics, 2008

OBJECTIVE. The goal was to analyze the clinical responses to enzyme replacement therapy with algl... more OBJECTIVE. The goal was to analyze the clinical responses to enzyme replacement therapy with alglucerase or imiglucerase in a large international cohort of children with Gaucher disease type 1. METHODS. Anonymized data from 884 children in the International Collaborative Gaucher Group Gaucher Registry were analyzed to determine the effects of long-term enzyme replacement therapy with alglucerase or imiglucerase on hematologic and visceral manifestations, linear growth, and skeletal disease. The parameters measured were hemoglobin levels, platelet counts, spleen and liver volumes, z scores for height and bone mineral density, and reports of bone pain and bone crises. RESULTS. The median height z score for the study population was −1.4 at baseline. After 8 years of treatment, the median height approximated the median value for the normal population. Anemia, although not severe, was present in >50% of patients at baseline and resolved for all patients after 8 years of treatment. Mor...

Research paper thumbnail of Community infection ratio as indicator for tuberculosis control

The Lancet, 1995

The epidemiology of tuberculosis remains poorly understood. We investigated the relative importan... more The epidemiology of tuberculosis remains poorly understood. We investigated the relative importance of within-household and community transmission of infection among children aged 6 months to 14 years living in a Peruvian shanty-town. The prevalence of Mycobacterium tuberculosis exposure among 175 contact children (sharing a household with a person who had confirmed pulmonary tuberculosis) and 382 control children (living in nearby households free of active tuberculosis) was defined as the proportion of children with a positive purified protein derivative (PPD) skin-test. 97 (55%) contact children and 129 (34%) controls were PPD positive. Living in a contact household (odds ratio 1.74, 95% CI 1.11-2.73) and age (1.11, 1.06-1.18) were significant risk factors for PPD positivity. We calculated the community infection ratio (CIR) as the odds ratio of PPD-positive controls to PPD-positive contacts: CIR = [formula: see text] A low CIR therefore suggests mainly household spread of infection, whereas a high value suggests frequent transmission outside the household. The adjusted odds ratio (for age, sex, within-household correlation, and household size) was 0.40 (95% CI 0.26-0.64), compared with values of 0.18-0.37 in studies elsewhere. Currently recommended tuberculosis control strategies are suitable for areas with low CIRs. Different strategies may be needed for areas, such as that we studied, with high values.

Research paper thumbnail of Iodofiltic Acid I 123 (BMIPP) Fatty Acid Imaging Improves Initial Diagnosis in Emergency Department Patients With Suspected Acute Coronary Syndromes

Journal of the American College of Cardiology, 2010

The aim of this study was to assess the performance of ␤-methyl-p-[ 123 I]-iodophenyl-pentadecano... more The aim of this study was to assess the performance of ␤-methyl-p-[ 123 I]-iodophenyl-pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) to detect acute coronary syndromes (ACS) in emergency department patients with chest pain. Background Emergency department diagnosis of chest pain is problematic, often requiring prolonged observation and stress testing. BMIPP SPECT detects abnormalities in fatty acid metabolism resulting from myocardial ischemia, even many hours after symptom cessation. Methods Emergency department patients with suspected ACS were enrolled at 50 centers. Patients received 5 mCi BMIPP within 30 h of symptom cessation. BMIPP SPECT images were interpreted semiquantitatively by 3 blinded readers. Initial clinical diagnosis was based on symptoms, initial electrocardiograms, and troponin, whereas the final diagnosis was based on all available data (including angiography and stress SPECT) but not BMIPP SPECT. Final diagnoses were adjudicated by a blinded committee as ACS, intermediate likelihood of ACS, or negative for ACS. Results A total of 507 patients were studied and efficacy was evaluated in 448 patients with sufficient data. The sensitivity of BMIPP by 3 blinded readers for a final diagnosis of ACS and intermediate likelihood of ACS was 71% (95% confidence interval [CI]: 64% to 79%), 74% (95% CI: 68% to 81%), and 69% (95% CI: 62% to 77%); the corresponding specificity of BMIPP was 67% (95% CI: 61% to 73%), 54% (95% CI: 48% to 60%), and 70% (95% CI: 64% to 76%). Compared with the initial diagnosis alone, BMIPP ϩ initial diagnosis increased sensitivity from 43% to 81% (p Ͻ 0.001), negative predictive value from 62% to 83% (p Ͻ 0.001), and positive predictive value from 41% to 58% (p Ͻ 0.001), whereas specificity was unchanged (61% to 62%, p ϭ NS). Conclusions The addition of BMIPP data to the initially available clinical information adds incremental value toward the early diagnosis of an ACS, potentially allowing determination of the presence or absence of ACS to be made earlier in the evaluation process. (Safety and Efficacy Iodofiltic Acid I 123 in the Treatment of Acute Coronary Syndrome [Zeus-ACS]; NCT00514501) (

Research paper thumbnail of Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1

Genetics in Medicine, 2009

Purpose: To determine whether enzyme therapy with imiglucerase/ alglucerase demonstrates dose-res... more Purpose: To determine whether enzyme therapy with imiglucerase/ alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to Ͻ29 U/kg/2 weeks), Group B (29 U to Ͻ48 U/kg/2 weeks), Group C (48 U to Ͻ75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (E max) and half-time to E max (T 50) of enzyme therapy for each parameter were compared across dosing groups. Results: Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to E max and T 50 over 96 months for each disease parameter. Conclusions: Enzyme therapy with imiglucerase/alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries. Genet Med 2009:11(2):92-100.

Research paper thumbnail of Life expectancy in Gaucher disease type 1

American Journal of Hematology, 2008

We estimated life expectancy at birth for Gaucher disease type 1 (GD1) patients by comparing surv... more We estimated life expectancy at birth for Gaucher disease type 1 (GD1) patients by comparing survival data from GD1 patients enrolled in ICGG Gaucher Registry to the U.S. population using standard life table methods. 2,876 GD1 patients had 102 reported deaths in 13,509 person-years of follow-up. Estimated life expectancy at birth was 68 y, compared with 77 y in reference population; splenectomized patients, 64 y; nonsplenectomized, 72 y. Causes of death for 63/102 patients were malignancy (17/63), cardiovascular (11/63), and cerebrovascular (8/63). Estimated life expectancy at birth for GD1 patients was ~9 y less than reference population. Malignancies did not contribute to shortened life expectancy.

Research paper thumbnail of The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients

American Journal of Hematology, 2009

Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease... more Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross‐sectional study. In addition, the relative risk (RR) of cancer in patients compared with age‐, sex‐, and ethnic‐group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in ...

Research paper thumbnail of 90Y-Edotreotide for Metastatic Carcinoid Refractory to Octreotide

Journal of Clinical Oncology, 2010

Purpose Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flus... more Purpose Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using 90Y-edotreotide to treat symptomatic patients with carcinoid tumors. Patients and Methods Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) 90Y-edotreotide each, once every 6 weeks. Results Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms ...

Research paper thumbnail of Glucosylsphingosine is a key biomarker of Gaucher disease

American journal of hematology, Jan 21, 2016

Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysol... more Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of plasma LGL1 were assessed by Pearson's correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs. Eliglustat Tartrate SRT (ELI-SRT). Plasma Lyso-GL1 levels in healthy controls averaged 1.5 ng/ml (1.3-1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4-216.5) and imiglucerase ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2-129.4) (P < 0.001). Lyso-GL1 correlated with chitotriosidase (r...

Research paper thumbnail of Gaucher disease and cancer incidence: a study from the Gaucher Registry

Blood, 2005

Patients with Gaucher disease (GD) are alleged to be at an increased risk of malignant disorders,... more Patients with Gaucher disease (GD) are alleged to be at an increased risk of malignant disorders, possibly due to potential chronic stimulation of the immune system and lymphoproliferation associated with storage of glucocerebroside in tissue macrophages. Because previous reports of increased risk of malignancy in GD may have been affected by small patient numbers and ascertainment bias, 2742 patients with GD from the International Gaucher Registry were studied. The number of cancers identified among patients in the registry was compared with that expected in the US population of similar attained age and sex. The majority of patients were young or middle-aged adults at the time of last follow-up, with only 14% older than age 60. There were 10 patients with multiple myeloma, yielding an estimated relative risk of 5.9 (95% confidence interval [95% CI]: 2.8, 10.8). The relative risk of cancer overall was 0.79 (95% CI: 0.67, 0.94), and the subgroups for cancers of the breast, prostate, ...