Biweekly cisplatin and gemcitabine in patients with advanced biliary tract cancer.

Treatment with cisplatin and gemcitabine demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1,000 mg/m2 /min) and cisplatin 20 mg/m2 on days 1 and 15 of every 28-day cycle. Patients received treatment until time of progression, death, or discontinuation due to intolerance. Collected data included demographics, clinico-pathologic features, toxicities, and survival. Kaplan-Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%), and bile duct (74.8%). Median number of cycles was 6 (1-27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade ≥3 adverse events included neutropenia (11%), fatigue (10%), and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies.

Next-generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance.

BACKGROUND: Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum-based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. METHODS: Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). RESULTS: When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. CONCLUSIONS: In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66. © 2016 American Cancer Society.

Predicting short-term mortality and long-term survival for hospitalized US patients with alcoholic hepatitis.

BACKGROUND: No study has evaluated current scoring systems for their accuracy in predicting short and long-term outcome of alcoholic hepatitis in a US population. METHODS: We reviewed electronic records for patients with alcoholic liver disease (ALD) admitted to Parkland Memorial Hospital between January 2002 and August 2005. Data and outcomes for 148 of 1,761 admissions meeting pre-defined criteria were collected. The discriminant function (DF) was revised (INRdf) to account for changes in prothrombin time reagents that could potentially affect identification of risk using the previous DF threshold of >32. Admission and theoretical peak scores were calculated by use of the Model for End-stage Liver Disease (MELD). Analysis models compared five different scoring systems. RESULTS: INRdf was closely correlated with the old DF (r (2) = 0.95). Multivariate analysis of the data showed that survival for 28 days was significantly associated with a scoring system using a combination of age, bilirubin, coagulation status, and creatinine (p < 0.001), and an elevated ammonia result within two days of admission (p = 0.012). When peak values for MELD were included, they were the most significant predictor of short-term mortality (p < 0.001), followed by INRdf (p = 0.006). CONCLUSION: On admission, two scoring systems that identify a subset of patients with severe alcoholic liver disease are able to predict >50 % mortality at four weeks and >80 % mortality at six months without specific treatment.

Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls.

OBJECTIVE: To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case-control association study. PATIENTS AND METHODS: 1300 SSc cases (961 white, 178 black and 161 Hispanic subjects) characterised for clinical skin forms (limited vs diffuse), SSc-specific autoantibodies (anticentromere (ACA), anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 ribonucleoprotein (fibrillarin)) and others were studied using molecular genotyping. Statistical analyses in SSc itself by ethnicity, gender, skin type and autoantibodies were performed using exact logistic regression modelling for dominant, additive and recessive effects from HLA. RESULTS: The strongest positive class II associations with SSc in white and Hispanic subjects were the DRB1*1104, DQA1*0501, DQB1*0301 haplotype and DQB1 alleles encoding a non-leucine residue at position 26 (DQB1 26 epi), while the DRB1*0701, DQA1*0201, DQB1*0202 haplotype and DRB1*1501 haplotype were negatively correlated and possibly protective in dominant and recessive models, respectively. These associations did not discriminate between limited and diffuse SSc. SSc in black subjects was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles. DPB1*1301 showed the highest odds ratio for ATA (OR = 14). Moreover, it showed no linkage disequilibrium or gene interaction with DR/DQ. ACA was best explained by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and DQB1*03 alleles in white and Hispanic subjects but DRB1*08 in black subjects. CONCLUSION: These data indicate unique and multiple HLA-class II effects in SSc, especially on autoantibody markers of different subphenotypes.

Diffusion-tensor MR imaging of cortical lesions in multiple sclerosis: initial findings.

PURPOSE: To prospectively perform a direct measurement of fractional anisotropy (FA) and mean diffusivity (MD) in cortical lesions of patients with multiple sclerosis (MS). MATERIALS AND METHODS: The study was approved by the institutional review board and was HIPAA compliant; informed consent was obtained. Magnetic resonance (MR) images, including double inversion-recovery (DIR), phase-sensitive inversion-recovery (PSIR), and diffusion-tensor images, were acquired from nine MS patients with cortical lesions (five women, four men; median age, 47 years) and nine age- and sex-matched volunteer control subjects. Following nonlinear elastically constrained image registration for aligning diffusion-weighted images to DIR images, maps of FA and MD were computed for each subject. Cortical lesions were identified on DIR images and validated by using PSIR images. The diffusion-tensor imaging maps were then overlaid on the coregistered DIR images, and mean FA and MD values were measured in regions of interest drawn on the cortical lesions. Differences between normal gray matter (GM) and cortical lesions were evaluated by using the generalized estimating equation. FA and MD histograms of whole brain and GM (global analysis) in healthy control subjects and MS patients were also computed for comparison with those in previously published studies. RESULTS: FA and MD values were significantly higher in cortical lesions compared with similar regions in healthy control subjects. Histogram peak FA was significantly decreased and peak MD was significantly increased in patients relative to control subjects. CONCLUSION: DIR and PSIR combined with nonlinear image registration allowed direct focal measurement of FA and MD in cortical lesions.

Fever-range whole-body thermal therapy combined with cisplatin, gemcitabine, and daily interferon-alpha: a description of a phase I-II protocol.

PURPOSE: The purpose of the Phase I component of this study was to find the maximally tolerated dose (MTD) of cisplatin administered within a regimen of fever-range whole body thermal therapy (FR-WB-TT), cisplatin, gemcitabine, and low-dose interferon-alpha (IFN-alpha). The Phase II component aimed to assess which cancer diagnoses responded to the regimen, the response rate, and response duration. MATERIALS AND METHODS: The protocol design derived from a schedule-optimized preclinical regimen. Drugs were administered together, and also with thermal therapy in a schedule that optimized the therapeutic index. Eligible patients were those with therapy-resistant, metastatic or advanced solid malignancies. Beginning at 40 mg/m(2), the cisplatin dose was escalated by 10 mg/m(2) to the maximally tolerated dose (MTD) in successive cohorts of 3 patients. A treatment cycle consisted of cisplatin on day one, followed by thermal therapy and simultaneous gemcitabine 36 hours later; then a second dose of gemcitabine one week later; and daily IFN- alpha. RESULTS: Thirty-seven patients were treated on protocol. The MTD of cisplatin in the thermochemotherapy regimen was established to be 60 mg/m(2). The dose limiting toxicities (DLT) were peripheral neuropathy and ototoxicity. Complete and partial responses combined were 43%. The therapy improved the quality of life of responding patients. CONCLUSION: The protocol was well tolerated and was associated with antitumor activity in patients with a variety of advanced metastatic solid tumors. Tumor response occurred with the thermochemotherapy treatment despite treating malignancies that had progressed on the same chemotherapy drugs administered as standard treatment. Notably, good responses were observed in patients with high-grade neuroendocrine and pancreas cancers. This regimen will be tested in a phase II study.

Second-order interactions with the treatment groups in controlled clinical trials.

The occurrence of significant second-order interactions for group characteristics was examined using real data in a randomized controlled trial (RCT). The interactions exist in all RCTs; they could be easily overlooked when using the simple randomization or stratification methods, but could become more obvious when minimization methods are used. Using real data from an RCT, the minimization method enabled balancing the distributions of the four selected stratified factors. Analyses for three-way second-order interactions including six additional potential confounding variables (for a total of 10 variables) presented 8 significant second-order interactions with the treatment groups. Interaction effects need to be evaluated when treatment effects are examined to maximize the power of the treatment effects in any RCTs. A stepwise regression method with piecewise linear functions would be useful to select the significant variables with interaction effects affecting the treatment outcomes in RCTs. Additional ways to handle interaction effects in RCTs are presented in this paper.

Clonidine reduces diarrhea and sodium loss in patients with proximal jejunostomy: a controlled study.

BACKGROUND: Patients with short bowel syndrome have significant fluid losses. This represents a significant management problem, especially in patients with minimal residual intestine. We determined whether clonidine, an alpha2-adrenergic agonist, is effective in decreasing fecal water and sodium (Na) losses in patients with proximal jejunostomy. Eight parenteral nutrition (PN)-dependent subjects (3 men, 5 women), aged 49.9+/-10.2 years, with a residual small bowel length of 71.8+/-152.0 cm that ended in a jejunostomy, were studied. METHODS: Subjects were admitted to the North-western General Clinical Research Center (GCRC) for a 2-day equilibrium period while receiving a self-selected 100 g fat diet with protein 1.5 g/kg/d and 30 kcal/kg/d and 1 L/d of oral rehydration solution. A D-xylose test was performed after an overnight fast. On days 3-5, all stool and urine were collected for volume, weight, fat, nitrogen, energy, sodium, magnesium, potassium, and calcium. Meals were provided in duplicate and the equivalent portions consumed by each patient were analyzed for fluid volume, fat, nitrogen, energy, sodium, magnesium, calcium, and potassium in order to calculate nutrient balances. At the conclusion of the stool and urine collections (day 6), a clonidine (0.3 mg) patch was applied to the shoulder. Subjects were restudied after 1 week. RESULTS: Daily fecal volume and weight were 4.514+/-1.769 L/d and 4394+/-1727 g/d, respectively, at baseline. Five subjects were net "secretors" in that excreted fecal volume exceeded oral intake. Fecal volume decreased by 427+/-562 mL/d (8.9%, p=.07). Fecal weight decreased by 438+/-527 g/d (9.4%, p=.05). Urine volume correspondingly increased by 747+/-1934 mL (18.9%, p=not significant [NS]). The increase in urine output was weakly and negatively correlated with the decrease in fecal volume and weight (r=-0.37 and -0.41, respectively, p=NS). Oral fluid intake decreased slightly from 3.328+/-1.246 L/d baseline to 3.203+/-1.119 L/d with clonidine therapy (-3.8%, p=NS). Fecal Na loss was significantly decreased from baseline (887+/-996 mg/d, 11.2+/-12.3%; p=.036). This was not related to decreased oral Na intake, which actually increased from baseline (3.799+/-2.271 g/d) to 3.933+/-1.314 g/d after clonidine therapy (p=NS). No patient developed hypotension. CONCLUSIONS: Our results show the transdermal administration of clonidine is associated with a modest but clinically significant decrease in fecal output in patients with short bowel syndrome and high-output proximal jejunostomy that require chronic parenteral fluid infusion. This is accompanied by decreased fecal Na loss.

Urinary vascular cell adhesion molecule, but not neutrophil gelatinase-associated lipocalin, is associated with lupus nephritis.

OBJECTIVE: Vascular cell adhesion molecule-1 (VCAM-1), an adhesion molecule, is involved in the progression of glomerular and tubulointerstitial injury. Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin superfamily, has been shown to rise in both acute and chronic kidney damage. Both VCAM-1 and NGAL have been found at high levels in the urine of patients with active lupus nephritis. We investigated both as potential biomarkers for lupus nephritis. METHODS: VCAM-1 and NGAL were measured by ELISA during 1 to 8 clinic visits in 107 patients with systemic lupus erythematosus (SLE; 91% women, 51% black, 36% white, 4% Asian, 4% Hispanic, and 5% others) for a total of 190 visits. Patients' mean age was 41 years. We analyzed the relationship between these potential urine biomarkers and the urine protein/creatinine ratio (urine Pr/Cr), the Systemic Lupus International Collaborating Clinics (SLICC) renal activity score, SLE Disease Activity Index renal descriptors, and other clinical variables. RESULTS: VCAM-1 levels were strongly associated with the physician's global estimate of disease activity (p = 0.0002), the renal visual analog scale (p < 0.0001), the urine Pr/Cr (p < 0.0001), and SLICC renal activity score (p < 0.0001). VCAM-1 levels were also associated with a urine Pr/Cr ≥ 0.5 (p < 0.0001). NGAL was not associated with any measure of disease activity or with lupus serologies. CONCLUSION: Urine VCAM-1 had a strong association with measures of disease activity, including multiple renal activity descriptors. In contrast to previous SLE studies, NGAL failed to show any association with lupus nephritis.

Macronutrient absorption characteristics in humans with short bowel syndrome and jejunocolonic anastomosis: starch is the most important carbohydrate substrate, although pectin supplementation may modestly enhance short chain fatty acid production and fluid absorption.

BACKGROUND: Diet may play an important role in the management of patients with short bowel syndrome who have colon in continuity. However, macronutrient absorption has not been well characterized, and the most appropriate dietary constituents have not been well defined. OBJECTIVE: To define carbohydrate absorption characteristics in patients with short bowel syndrome and determine the potential role of pectin as a dietary substrate. METHODS: The authors studied the effect of a custom pectin-based supplement in 6 subjects (3 male/3 female) aged 29-67 years with jejunocolonic anastomosis, 4 of whom required long-term parental nutrition. Small intestinal absorption capacity, macronutrient and fluid balance, gastrointestinal transit time, and energy consumption were measured. RESULTS: Data showed that 53% nitrogen, 50% fat, and 32% total energy were malabsorbed. In contrast, the majority (92%) of total carbohydrate was utilized. Fecal short-chain fatty acids (SCFAs) were increased, an indication of increased fermentation. Although only 4% of starch was recovered in stool, it is indicative of considerable starch malabsorption, thus providing the main carbohydrate substrate, for colonic bacterial fermentation. In contrast, nonstarch polysaccharide was a relatively minor fermentation substrate with only 49% utilized. Eighty percent of the pectin was fermented. Supplementation was associated with increased total SCFAs, acetate, and propionate excretion. There was a trend observed toward greater fluid absorption (-5.9% ± 54.4% to 26.9% ± 25.2%) following pectin supplementation. Nonsignificant increases in gastric emptying time and orocolonic transit time were observed. CONCLUSION: Despite malabsorption, starch is the primary carbohydrate substrate for colonic bacterial fermentation in patients with short bowel syndrome, although soluble fiber intake also enhances colonic SCFA production.

Bone healing in critical-size defects treated with new bioactive glass/calcium sulfate: a histologic and histometric study in rat calvaria.

This study analyzed histologically the influence of new spherical bioactive glass (NBG) particles with or without a calcium sulfate (CS) barrier on bone healing in surgically created critical-size defects (CSD) in rat calvaria. A CSD was made in each calvarium of 60 rats, which were divided into three groups: C (control): the defect was filled with blood clot only; NBG: the defect was filled with NBG only; and NBG/CS: the defect was filled with NBG covered by CS barrier. Subgroups were euthanized at 4 or 12 weeks. Amounts of new bone and remnants of implanted materials were calculated as percentages of total area of the original defect. Data were statistically analyzed. In contrast to Group C, thickness throughout defects in Groups NBG and NBG/CS was similar to the original calvarium. At 4 weeks, Group C had significantly more bone formation than Group NBG/CS. No significant differences were found between Group NBG and either Group C or Group NBG/CS. At 12 weeks, Group C had significantly more bone formation than Group NBG or NBG/CS. NBG particles, used with or without a CS barrier, maintained volume and contour of area grafted in CSD. Presence of remaining NBG particles might have accounted for smaller amount of new bone in Groups NBG and NBG/CS at 12 weeks post-operative.

Perceived functioning has ethnic-specific associations in systemic sclerosis: another dimension of personalized medicine.

OBJECTIVE: To measure self-reported physical and mental functioning and associated clinical features at study entry in 3 ethnic groups with systemic sclerosis (SSc). METHODS: Sixty Hispanic, 39 African American, and 104 Caucasian patients with recent-onset SSc (< 5 yrs) were assessed for perceived physical and mental functioning, using the Medical Outcomes Study Short Form-36 (SF-36) and Scleroderma-Health Assessment Questionnaire (Scleroderma-HAQ). Socioeconomic, demographic, clinical, immunologic, immunogenetic, behavioral, and psychological variables (Interpersonal Support Evaluation List, ISEL; Illness Behavior Questionnaire, IBQ; and Arthritis Helplessness Index, AHI) were analyzed by linear regression models for associations with SF-36 and mHAQ scores as dependent variables. RESULTS: Perceived physical functioning scores had ethnic-specific associations with AHI > fatigue scores > IBQ > clinical variables (hypertension, skin score, and percentage predicted DLCO). Scleroderma-HAQ scores had ethnic-specific associations with IBQ > AHI scores > most clinical and laboratory variables. Decreased mental component summary (MCS) scores associated with AHI > ISEL. Ethnic-specific immunogenetic variables HLA-DQB1*0202 (Caucasian) and HLA-DRB 1*11 (African American), and HLA-DQA1*0501 (Hispanic) also associated with MCS. Antinuclear autoantibodies, anti-topoisomerase I, and RNA polymerases I and III also demonstrated associations with functioning in African American and Hispanic groups. CONCLUSION: Clinical, psychosocial, and immunogenetic variables had ethnic-specific associations with perceived physical and mental functioning. Consideration of ethnic-specific psychological and behavioral support in designing more personalized, relevant therapeutic interventions for the patient may improve therapeutic efficacy in SSc.

Tests for the homogeneity of two binomial proportions in extremely unbalanced 2 x 2 contingency tables.

Asymptotic tests such as the Pearson chi-square test are unreliable for testing the homogeneity of two binomial probabilities in extremely unbalanced cases. Two exact tests (conditional and unconditional) are available as alternatives and can be implemented easily in StatXact 6.0. In equal sample cases it is well known that the unconditional exact test is more powerful than the conditional exact test. However, in this paper, we show that the opposite result holds in extremely unbalanced cases. The reason is that the peaks of the type I error occur at the extremes of the nuisance parameter when the imbalance among the sample sizes becomes severe. After we show that the conditional exact test is more powerful than the unconditional exact test in extremely unbalanced cases whose sample ratio is greater than 20, we compare the conditional exact test with the Berger and Boos approach (J. Amer. Stat. Assoc. 1994; 89:1012-1016) in which the supremum is taken over a confidence interval for the nuisance parameter. The Berger and Boos approach turns out to be slightly more powerful than the conditional exact test in extremely unbalanced data. A real example is provided.

Age- and sex-related differences in the tissue Doppler imaging parameters of left ventricular diastolic dysfunction.

BACKGROUND: The effect of age and gender on tissue Doppler imaging measurements comparing the septal and mitral annulus needs to be investigated. METHODS: We investigated in 276 outpatients in a university cardiology practice the relationship of age and gender to left atrial (LA) size, LA volume, mitral pulse-wave Doppler E/A ratio, E/Ea ratios by tissue Doppler image of mitral annular velocity (TDI), and left ventricular diastolic dysfunction (LVDD) by TDI. RESULTS: Mitral E/A inflow was statistically decreased with age. E/Ea ratios of the lateral and mean of both lateral and septal annulus showed a statistical increase with age, while the E/Ea ratio of the septal annulus did not correlate with age. When comparing men and women of all ages, the mean LA volume for men was 59.2 cm3 +/- 24.36 cm3 versus 48.54 cm3 +/- 16.14 cm3 (P-value < 0.0001) and the mean LA size was 4.0 + 0.51 cm for men and 3.65 + 0.47 for women (P-value < 0.0001). There was no statistical difference between men and women when looking at mitral E/A inflow ratio, deceleration time, E/Ea ratio of the septal annulus, E/Ea ratio of the lateral annulus, E/Ea ratio of the mean of both septal and lateral annulus, and grades of LVDD. CONCLUSION: In patients 70 years of age or older, the mean diastolic grade was mild-to-moderate LVDD when using lateral or mean of septal and lateral annular measurements. When only the septal annular measurements were used to determine diastolic grade, all four age groups showed a mean of mildly to moderately impaired LVDD and showed no correlation with age. There were no differences in tissue Doppler imaging measurements between men and women.

Changing spectrum of the diffuse infiltrative lymphocytosis syndrome.

OBJECTIVE: To describe the changing clinical spectrum of patients with diffuse infiltrative lymphocytosis syndrome (DILS) after the introduction of highly active antiretroviral treatment (HAART), and to carry out HLA class II oligotyping in these patients. METHODS: A retrospective chart review of patients with DILS who were referred to an outpatient facility for human immunodeficiency virus (HIV)-positive individuals between 1994 and 2003 was performed. DILS was diagnosed as suggested by previous criteria. Demographic features and relevant clinical, laboratory, and radiologic data were recorded and results analyzed. RESULTS: A total of 129 patients with DILS were identified. Of them, 56 (43%) were African American, 41 (32%) were white, and 32 (25%) were Hispanic. Parotid gland swelling appeared to be the sine qua non of DILS. Twenty-seven percent of patients had opportunistic infections. The status of 103 patients was available as of December 2003: 26 (25%) had died, of which only 6 (6%) succumbed to opportunistic infections. The prevalence of DILS had significantly decreased in the post-HAART era (1998 onwards) compared with that of the pre-HAART period (P < 0.000001). The prevalence of lymphocytic interstitial pneumonitis had also dropped significantly following introduction of HAART therapy (P = 0.015). A higher frequency of certain HLA class II alleles (DRB1) was found in African Americans with DILS compared with those with HIV without DILS (P = 0.006). CONCLUSION: The epidemiology, clinical presentation, and certain extraglandular manifestations of DILS have changed, concomitant with the introduction of HAART, further suggesting that DILS is an antigen (viral)-driven response and the primary treatment for it is anti-HIV therapy.

Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis.

OBJECTIVE: To determine any associations of the PTPN22 R620W single-nucleotide polymorphism (SNP) with systemic sclerosis (SSc) or with anticentromere antibody (ACA)-positive or anti-topoisomerase I (anti-topo I) antibody-positive SSc, in a case-control study of US white, black, Hispanic, and Choctaw Indian individuals. METHODS: A total of 850 white, 130 black, 120 Hispanic, and 20 Choctaw Indian patients with SSc were compared with 430 white, 164 black, 146 Hispanic, and 76 Choctaw Indian control subjects, respectively. All subjects were living in the US. PTPN22 SNP (rs2476601) genotyping was performed by TaqMan 5' allelic discrimination assay and pyrosequencing. RESULTS: The PTPN22 CT/TT genotype showed significant association with anti-topo I antibody-positive SSc in white patients (odds ratio [OR] 2.21, 95% confidence interval [95% CI] 1.3-3.7) and with ACA-positive white patients with SSc (OR 1.70, 95% CI 1.1-2.7). Frequency of the PTPN22*T allele also showed significant association with anti-topo I antibody-positive SSc in white patients (OR 2.03, 95% CI 1.3-3.2). When data for patients in the 3 ethnic groups (black, white, and Hispanic) were combined, a significant association with both genotype and allele frequencies was observed, suggesting a trend toward association in ACA-positive and anti-topo I antibody-positive SSc. Stepwise logistic regression analysis (controlled for the confounding effects of sex and race) showed that the PTPN22 CT/TT genotype was associated with a significantly higher risk of SSc compared with the CC genotype (for patients with SSc, OR 1.64, 95% CI 1.2-2.2; for ACA-positive patients with SSc, OR 1.63, 95% CI 1.0-2.6; for anti-topo I antibody-positive SSc, OR 2.33, 95% CI 1.5-3.7). CONCLUSION: Our results indicate that the PTPN22 R620W polymorphism is associated with ACA-positive and anti-topo I antibody-positive subsets of SSc and represents a risk factor in both white patients and black patients. The association of subsets of SSc with the PTPN22 R620W polymorphism further strengthens the classification of SSc within the spectrum of autoimmune diseases and strongly suggests the involvement of common susceptibility genes and similarly disordered immunoregulatory pathways.

Sample size for a two-group comparison of repeated binary measurements using GEE.

Controlled clinical trials often randomize subjects to two treatment groups and repeatedly evaluate them at baseline and intervals across a treatment period of fixed duration. A popular primary objective in these trials is to compare the change rates in the repeated measurements between treatment groups. Repeated measurements usually involve missing data and a serial correlation within each subject. The generalized estimating equation (GEE) method has been widely used to fit the time trend in repeated measurements because of its robustness to random missing and mispecification of the true correlation structure. In this paper, we propose a closed form sample size formula for comparing the change rates of binary repeated measurements using GEE for a two-group comparison. The sample size formula is derived incorporating missing patterns, such as independent missing and monotone missing, and correlation structures, such as AR(1) model. We also propose an algorithm to generate correlated binary data with arbitrary marginal means and a Markov dependency and use it in simulation studies.

Exact tests for one sample correlated binary data.

In this paper we developed exact tests for one sample correlated binary data whose cluster sizes are at most two. Although significant progress has been made in the development and implementation of the exact tests for uncorrelated data, exact tests for correlated data are rare. Lack of a tractable likelihood function has made it difficult to develop exact tests for correlated binary data. However, when cluster sizes of binary data are at most two, only three parameters are needed to characterize the problem. One parameter is fixed under the null hypothesis, while the other two parameters can be removed by both conditional and unconditional approaches, respectively, to construct exact tests. We compared the exact and asymptotic p-values in several cases. The proposed method is applied to real-life data.

Plasma uric acid levels in women with cervical intraepithelial neoplasia.

The objective of this study was to determine the association of plasma levels of uric acid, an endogenous antioxidant, in women with cervical intraepithelial neoplasia (CIN), while controlling for the confounding effects of human papillomavirus (HPV) infection, age, smoking, and use of oral contraception. Plasma-reduced and oxidized uric acid levels were determined in 650 women by high-performance liquid chromatography, employing electrochemical technique. The findings demonstrated that 1) plasma-reduced uric acid (PRUA) levels in women with CIN (n = 311) were significantly lower (P < 0.05) compared with women in a control group (n = 339); 2) according to multiple logistic regression analysis, PRUA levels were negatively (P = 0.0113) and HPV infection were positively associated (P < 0.0001) with CIN, after controlling for the confounding effects of the studied factors; 3) according to multiple regression analysis, there was a 31% decrease in CIN risk for each incremental increase of 1mg/dl of PRUA; and 4) according to polychotomous logistic regression analysis, independent of HPV infection, PRUA level was inversely associated with the histopathological graded severity of CIN. We have previously reported decreased plasma levels of exogenous antioxidants, for example, vitamins C and E, in women with CIN independent of HPV infection. The data suggest that plasma deficiencies of several antioxidants in HPV-infected uterine cervical tissue may create an oxidative environment that renders the tissue susceptible to free radical damage. It may be speculated that chronic free radical-induced tissue damage in the context of persistent HPV infection may be involved in the pathogenesis of CIN.