Colin O'Donnell

The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner.

OBJECTIVE To evaluate levels of biomarkers in preclinical rheumatoid arthritis (RA) and to use elevated biomarkers to develop a model for the prediction of time to future diagnosis of seropositive RA. METHODS Stored samples obtained from 73 military cases with seropositive RA prior to RA diagnosis and from controls (mean 2.9 samples per case; samples collected a mean of 6.6 years prior to diagnosis) were tested for rheumatoid factor (RF) isotypes, anti-cyclic citrullinated peptide (anti-CCP) antibodies, 14 cytokines and chemokines (by bead-based assay), and C-reactive protein (CRP). RESULTS Preclinical positivity for anti-CCP and/or ≥2 RF isotypes was >96% specific for future RA. In preclinical RA, levels of the following were positive in a significantly greater proportion of RA cases versus controls: interleukin-1α (IL-1α), IL-1β, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, fibroblast growth factor 2, flt-3 ligand, tumor necrosis factor α, interferon-γ-inducible 10-kd protein, granulocyte-macrophage colony-stimulating factor, and CRP. Also, increasing numbers of elevated cytokines/chemokines were present in cases nearer to the time of diagnosis. RA patients who were ≥40 years old at diagnosis had a higher proportion of samples positive for cytokines/chemokines 5-10 years prior to diagnosis than did patients who were <40 years old at diagnosis (P < 0.01). In regression modeling using only case samples positive for autoantibodies highly specific for future RA, increasing numbers of cytokines/chemokines were predictive of decreased time to diagnosis, and the predicted time to diagnosis based on cytokines/chemokines was longer in older compared with younger cases. CONCLUSION Levels of autoantibodies, cytokines/chemokines, and CRP are elevated in the preclinical period of RA development. In preclinical autoantibody-positive cases, the number of elevated cytokines/chemokines is predictive of the time of diagnosis of future RA in an age-dependent manner.

Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis†

OBJECTIVE To examine the association between aberrant IgG galactosylation and disease parameters in rheumatoid arthritis (RA). METHODS Analysis of N-glycan in serum samples from multiple cohorts was performed. The IgG N-glycan content and the timing of N-glycan aberrancy relative to disease onset were compared in healthy subjects and in patients with RA. Correlations between aberrant galactosylation and disease activity were assessed in the RA cohorts. The impact of disease activity, sex, age, anti-cyclic citrullinated peptide (anti-CCP) antibody titer, disease duration, and C-reactive protein level on aberrant galactosylation was determined using multivariate analysis. The N-glycan content was also compared between epitope affinity-purified autoantibodies and the remaining IgG repertoire in RA patients. RESULTS Our results confirm the aberrant galactosylation of IgG in RA patients as compared with healthy controls (mean +/- SD 1.36 +/- 0.43 versus 1.01 +/- 0.23; P < 0.0001). We observed a significant correlation between levels of aberrant IgG galactosylation and disease activity (Spearmans rho = 0.37, P < 0.0001). This correlation was higher in women (Spearmans rho = 0.60, P < 0.0001) than in men (Spearmans rho = 0.16, P = 0.10). Further, aberrant IgG galactosylation substantially predated the onset of arthritis and the diagnosis of RA (3.5 years) and resided selectively in the anticitrullinated antigen fraction. CONCLUSION Our findings identify aberrant IgG galactosylation as a dysregulated component of the humoral immune response in RA that begins prior to disease onset, associates with disease activity in a sex-specific manner, and resides preferentially in autoantibodies.

A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with RA

OBJECTIVE To describe a large, multicenter prospective cohort study of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the use of such a study in investigating the natural history of RA development. METHODS A total of 1,058 FDRs, none of whom met the American College of Rheumatology criteria for RA, were enrolled in a prospective study investigating genetic and environmental influences on the development of RA-related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit were described for these FDRs, and the relationship was examined between genetic factors, autoantibodies, inflammation, and joint disease. RESULTS Fifty-five percent of the FDRs had > or =1 copy of the shared epitope, 20% had > or =1 copy of the PTPN22 polymorphism, and approximately 16% were positive for rheumatoid factor (RF; including isotypes) and/or anti-cyclic citrullinated peptide antibody. IgM-RF positivity is associated with > or =1 tender joint on examination (odds ratio [OR] 2.50, 95% confidence interval [95% CI] 1.27-4.89; P < 0.01) and elevated C-reactive protein (CRP) levels (OR 5.31, 95% CI 1.45-19.52; P = 0.01). CONCLUSION FDRs without RA demonstrate high prevalences of genetic risk factors and RA-related autoantibodies. Additionally, an RF association with tender joints and elevated CRP levels suggests that autoantibodies are a valid intermediate marker of RA-related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic and epidemiologic factors and the development of RA-related autoimmunity.

The Role of 3-Dimensional Mapping Biopsy in Decision Making for Treatment of Apparent Early Stage Prostate Cancer

PURPOSE We determined the impact of a grid based, transperineal 3-dimensional mapping biopsy on decision making for primary management of early stage prostate cancer. MATERIALS AND METHODS We prospectively performed 3-dimensional mapping biopsy on 180 consecutive men who presented to our clinic between 2006 and 2009 with early stage, organ confined prostate cancer based on transrectal ultrasound guided 10 to 12-core biopsy, and on 35 with prior negative transrectal ultrasound biopsies. RESULTS At presentation median patient age was 60.5 years (range 43 to 77), median prostate specific antigen was 4.8 ng/ml (range 0.5 to 72.4) and median prostate volume was 35 cc (range 9 to 95). The median number of cores acquired by transrectal ultrasound and 3-dimensional mapping biopsy was 12 and 56, and the median number of positive cores was 1 and 2, respectively. We documented Gleason score upgrade in 49 of 180 cases (27.2%) and up-stage in 82 (45.6%). The incidence of urinary retention catheter requirement of greater than 48 hours was 3.2% and the incidence of transient orthostatic hypotension was 5%. No urinary tract infections were documented. A total of 38 men received radical extirpative therapy, 11 radiation and 45 cryotherapy while 60 enrolled in a targeted focal therapy study, 44 entered active surveillance and 5 underwent other focal investigational treatments. Post-mapping data on 12 men were not available for analysis. CONCLUSIONS Three-dimensional mapping biopsy revealed that a significant portion of men initially diagnosed with apparently low risk disease harbored clinically significant cancers requiring more aggressive therapy. The technique also enabled a number of men with low risk disease to elect surveillance or another less morbid option.

Autoimmunity to Peptidyl Arginine Deiminase Type 4 Precedes Clinical Onset of Rheumatoid Arthritis

OBJECTIVE To determine whether antibodies against peptidyl arginine deiminase type 4 (PAD-4) are present in the preclinical phase of rheumatoid arthritis (RA) and to compare the timing and extent of their appearance with those of other preclinical autoantibodies. METHODS Prediagnosis serum samples from 83 patients with RA were evaluated for the presence of anti-PAD-4 antibody, anti-cyclic citrullinated peptide (anti-CCP) antibody, and rheumatoid factor. In addition, a control cohort (n = 83) matched by age, sex, race, number of serum samples, and duration of serum storage was tested for the presence of anti-PAD-4 antibody to determine its sensitivity and specificity for the subsequent development of RA. RESULTS Fifteen of 83 patients with RA (18.1%) had at least 1 prediagnosis sample positive for anti-PAD-4. One of 83 control subjects (1.2%) had at least 1 positive sample, resulting in a sensitivity and specificity of 18.1% and 98.8%, respectively, of anti-PAD-4 for the future development of RA. The mean duration of anti-PAD-4 positivity prior to clinical diagnosis was 4.67 years. Anti-PAD-4 positivity was associated with anti-CCP positivity (odds ratio 5.13 [95% confidence interval 1.07-24.5]). In subjects with prediagnosis samples that were positive for both antibodies, anti-CCP positivity predated anti-PAD-4 positivity in 9 of 13 cases (69%). CONCLUSION Autoantibodies to PAD-4 are present during the preclinical phase of RA in a subset of patients and are associated with anti-CCP positivity. Further exploration is needed regarding the timing of appearance and disease-related effects of PAD-4 autoimmunity.

Long-term results of a smoking reduction program.

Introduction:There have been few comprehensive evaluations of smoking reduction, especially in health care delivery systems, and little is known about its cost, maintenance of reduced smoking, or robustness across patient subgroups. Methods:A generally representative sample of 320 adult smokers from an HMO scheduled for outpatient surgery or a diagnostic procedure was randomized to enhanced usual care or a theory-based smoking reduction intervention that combined telephone counseling and tailored newsletters. Outcomes included cigarettes smoked, carbon monoxide levels, and costs. Results:Both intervention and control conditions continued to improve from 3- to 12-month assessments. Between-condition differences using intent-to-treat analyses on both self-report and carbon monoxide measures were nonsignificant by the 12-month follow-up (25% vs. 19% achieved 50% or greater reductions in cigarettes smoked). The intervention was implemented consistently despite logistical constraints and was generally robust across patient characteristics (eg, education, ethnicity, health literacy, dependence). Conclusions:In the absence of nicotine replacement therapy, the long-term effects of this smoking reduction intervention seem modest and nonsignificant. Future research is indicated to enhance intervention effects and conduct more comprehensive economic analyses of program variations.

Artificial neural network model to predict biochemical failure after radical prostatectomy.

BACKGROUND Biochemical failure, defined here as a rise in the serum prostate specific antigen (PSA) concentration to >0.3 ng/mL or the initiation of adjuvant therapy, is thought to be an adverse prognostic factor for men who undergo radical prostatectomy (RP) as definitive treatment for clinically localized cancer of the prostate (CAP). We have developed an artificial neural network (ANN) to predict biochemical failure that may benefit clinicians and patients choosing among the definitive treatment options for CAP. MATERIALS AND METHODS Clinical and pathologic data from 196 patients who had undergone RP at one institution between 1988 and 1999 were utilized. Twenty-one records were deleted because of missing outcome, Gleason sum, PSA, or clinical stage data. The variables from the 175 remaining records were analyzed for input variable selection using principal component analysis, decision tree analysis, and stepped logistic regression. The selected variables were age, PSA, primary and secondary Gleason grade, and Gleason sum. The records were randomized and split into three bootstrap training and validation sets of 140 records (80%) and 35 records (20%), respectively. RESULTS Forty-four percent of the patients suffered biochemical failure. The average duration of follow up was 2.5 years (range 0-11.5 years). Forty-two percent of the patients had pathologic evidence of non-organ-confined disease. The average area under the receiver operator characteristic (ROC) curve for the validation sets was 0.75 +/- 0.07. The ANN with the highest area under the ROC curve (0.80) was used for prediction and had a sensitivity of 0.74, a specificity of 0.78, a positive predictive value of 0.71, and a negative predictive value of 0.81. CONCLUSION These results suggest that ANN models can predict PSA failure using readily available preoperative variables. Such predictive models may offer assistance to patients and physicians deciding on definitive therapy for CaP.

Breast cancer risk assessment in 64,659 women at a single high-volume mammography clinic.

RATIONALE AND OBJECTIVES In 2007, the American Cancer Society (ACS) recommended that women at elevated risk of breast cancer be screened with breast magnetic resonance imaging (MRI) as an adjunct to mammography. This study estimates the proportion of women presenting for screening mammography who are at elevated lifetime risk of breast cancer as determined by the Gail model. This study provides preliminary information for a proposed follow-up study, including the proportion of women who completed the recommended MRI at the same clinic that had conducted the risk assessment. MATERIALS AND METHODS This study is an observational prospective cohort of 64,659 women presenting for mammographic screening at a single high-volume clinic. If a woman reported a first-degree maternal relative with breast cancer and had at least 20% lifetime risk on the Gail model, the radiologists report included a recommendation that the primary care physician refer the woman for breast MRI screening. Records were examined to determine if women completed the recommended MRI at the clinic within one year of the initial risk assessment. RESULTS Of 64,659 women, 1,246 (1.9%) had a lifetime risk of breast cancer of 20% or greater, and 436 (0.7 %) had a lifetime risk of breast cancer 25% or greater. Of the women at elevated risk, 173 (13.9%) completed the recommended breast MRI screening at the clinic within a year. CONCLUSION The effectiveness of matching screening intensity to risk on cancer detection, biopsy rate, and cost should be evaluated by studying multiple clinics and multiple risk assessment tools.

Ventriculoperitoneal Shunt Infections After Bladder Surgery: is Mechanical Bowel Preparation Necessary?

PURPOSE We investigated whether children with a ventriculoperitoneal shunt who undergo mechanical bowel preparation before bladder reconstruction with bowel have a lower rate of infection than children who do not undergo preoperative bowel preparation. MATERIALS AND METHODS We performed an institutional review board approved, retrospective chart review of the incidence of ventriculoperitoneal shunt infections after bladder reconstruction using bowel and compared infection rates using Fishers exact test. Mean ± SD followup was 2.9 ± 2.3 years. RESULTS Between 2003 and 2009, 31 patients with a ventriculoperitoneal shunt underwent bladder reconstruction using bowel, of whom 19 (61%) and 12 (39%) did and did not undergo mechanical bowel preparation, respectively. There was no significant difference in gender or age at surgery between the 2 groups. Infection developed in 3 children (9.6%) within 2 months postoperatively, including 2 (10.5%) with and 1 (8.3%) without bowel preparation (2-tailed p = 1.0). CONCLUSIONS There was no significant difference in the shunt infection rate between patients with a ventriculoperitoneal shunt who did and did not undergo preoperative bowel preparation. Our results add to the current literature suggesting that bowel preparation is unnecessary even in patients with a ventriculoperitoneal shunt.

Use Of Artificial Neural Networks In Prostate Cancer

Artificial neural networks (ANNs) are a type of artificial intelligence software inspired by biological neuronal systems that can be used for nonlinear statistical modeling. In recent years, these applications have played an increasing role in predictive and classification modeling in medical research. We review the basic concepts behind ANNs and examine the role of this technology in selected applications in prostate cancer research.