Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma.

AIMS: Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC). METHODS AND RESULTS: We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment-naïve high-grade columnar dysplasia (HGD) or EAC, and 23 non-EAC oesophagectomy cases. A gastrointestinal pathologist assessed haematoxylin and eosin-stained ESMG images by using a scoring system that assigns individual ESMG acini to five histological types (mucous, serous, oncocytic, dilated, or ductal metaplastic). In our model, ductal metaplastic acini were more common in patients with HGD/EAC (12.7%) than in controls (3.5%) (P = 0.006). We also identified greater proportions of acini with dilation (21.9%, P < 0.001) and, to a lesser extent, ductal metaplasia (4.3%, P = 0.001) in non-EAC oesophagectomy cases than in controls. Ductal metaplasia tended to occur in areas of mucosal ulceration or tumour. CONCLUSIONS: We found a clear association between ductal metaplastic ESMG acini and HGD/EAC. Non-EAC cases had dilated acini and some ductal dilation. Because ESMGs and ducts harbour putative progenitor cells, these associations could have significance for understanding the pathogenesis of EAC.

Hemorrhagic complications of thoracentesis and small-bore chest tube placement in patients taking clopidogrel.

RATIONALE: Clopidogrel is a commonly used antiplatelet medication. The risk of local hemorrhage associated with use of this drug during routine thoracentesis or small-bore chest tube placement is not well established. OBJECTIVES: We conducted a prospective cohort study to assess the risk of hemothorax in patients taking clopidogrel while undergoing either pleural procedure. METHODS: Twenty-five consecutive adult patients who were taking clopidogrel at the time they were offered thoracentesis or small-bore (14 Fr) chest tube placement consented to continue taking the drug through their procedure. A control group consisted of 50 patients undergoing these pleural procedures who were not taking clopidogrel at the time they consented to undergo either procedure. All of the pleural procedures were performed under ultrasound guidance by an interventional pulmonologist or a fellow under direct faculty supervision. Hospitalized patients were screened for hemothorax by observing for a post-procedure drop in blood hemoglobin content of 2 g/dl or reaccumulation of their pleural effusion within 24 hours of the procedure. Outpatients were called within 2 weeks after their procedure to determine whether they had any symptoms suggestive of hemothorax. MEASUREMENTS AND MAIN RESULTS: There was one case of hemothorax after thoracentesis in the clopidogrel group versus none in the control group. The one patient with hemothorax required transfusion with 2 units of packed red blood cells and small-bore chest tube placement, and clopidogrel was withheld. There were no other clinically apparent complications of either procedure. CONCLUSIONS: Considered in combination with other small previously published studies, this single-center, nonrandomized, controlled prospective cohort study suggests that the rate of clinically consequential hemorrhage after ultrasound-guided thoracentesis or chest tube placement in patients taking clopidogrel is sufficiently low to warrant a large, randomized clinical trial designed to determine the safety of performing these procedures without interrupting clopidogrel therapy.

Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype.

The addition of arsenic trioxide (ATO) to frontline therapy of acute promyelocytic leukemia (APL) has been shown to result in significant improvements in disease-free survival (DFS). FLT3 mutations are frequently observed in APL, but its prognostic significance remains unclear. We analyzed 245 newly diagnosed adult patients with APL treated on intergroup trial C9710 and evaluated previously defined biological and prognostic factors and their relationship to FLT3 mutations and to additional karyotypic abnormalities. FLT3 mutations were found in 48% of patients, including 31% with an internal tandem duplication (FLT3-ITD), 14% with a point mutation (FLT3-D835) and 2% with both mutations. The FLT3-ITD mutant level was uniformly low, < 0.5. Neither FLT3 mutation had an impact on remission rate, induction death rate, DFS or overall survival (OS). The addition of ATO consolidation improved outcomes regardless of FLT3 mutation type or level, initial white blood cell count, PML-RARA isoform type or transcript level. The presence of a complex karyotype was strongly associated with an inferior OS independently of post-remission treatment. In conclusion, the addition of ATO to frontline therapy overcomes the impact of previously described adverse prognostic factors including FLT3 mutations. However, complex karyotype is strongly associated with an inferior OS despite ATO therapy.

Post-transplantation B cell function in different molecular types of SCID.

PURPOSE: Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B and sometimes NK cell function. Non-ablative HLA-identical or rigorously T cell-depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T cell development in the recipients, leading to a high rate of long-term survival. However, the development of B cell function has been more problematic. We report here results of analyses of B cell function in 125 SCID recipients prior to and long-term after non-ablative BMT, according to their molecular type. METHODS: Studies included blood immunoglobulin measurements; antibody titers to standard vaccines, blood group antigens and bacteriophage Φ X 174; flow cytometry to examine for markers of immaturity, memory, switched memory B cells and BAFF receptor expression; B cell chimerism; B cell spectratyping; and B cell proliferation. RESULTS: The results showed that B cell chimerism was not required for normal B cell function in IL7Rα-Def, ADA-Def and CD3-Def SCIDs. In X-linked-SCID, Jak3-Def SCID and those with V-D-J recombination defects, donor B cell chimerism was necessary for B cell function to develop. CONCLUSION: The most important factor determining whether B cell function develops in SCID T cell chimeras is the underlying molecular defect. In some types, host B cells function normally. In those molecular types where host B cell function did not develop, donor B cell chimerism was necessary to achieve B cell function. 236 words.

Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia.

Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRα/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PRα/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD+ were also associated with reduced postrelapse survival.

FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group.

BACKGROUND: FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL). PROCEDURE: Diagnostic specimens from 104 pediatric APL patients were screened for FLT3/Mut (FLT3/ITD or FLT3/ALM). FLT3/Mut status was correlated with disease characteristics and clinical outcome for patients treated on CALGB C9710 (n = 50). RESULTS: Forty-two of the 104 patients (40%) had either FLT3/ITD (n = 28, 27%) or FLT3/ALM (n = 15, 14%). Median diagnostic WBC count was 23,400 cells/µl vs. 3,600 cells/µl for those with and without FLT3/Mut (P < 0.001), and similar results for the cohort of 50 patients treated on C9710 (P < 0.001). In patients treated on C9710, presence of a FLT3 mutation was highly correlated with diagnostic WBC count >10,000 (P = 0.004), microgranular variant histology (P = 0.035), and a lower remission rate (P = 0.009). In patients who received ATRA (C9710 or CCG-2911, n = 8), those with FLT3/Mut had an induction death rate of 30% (7/23) compared to 3% (1/35) in FLT3/WT patients (P = 0.005). In patients with high WBC counts (>10,000), those with FLT3/Mut had a significantly higher risk of induction death versus FLT3/WT patients (47% vs. 0%, P = 0.05). FLT3/Mut was not associated with adverse outcome in those who survived induction therapy. CONCLUSIONS: FLT3/Mut are prevalent in pediatric APL and are associated with high WBC count and increased induction death. This study provides further evidence for testing APL patients for FLT3/Mut and the potential role for FLT3 inhibitors in this disease.

Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras.

Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen-identical or rigorously T cell-depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term.

Reformulating the hazard ratio to enhance communication with clinical investigators.

BACKGROUND: Clinical trials with time to event outcomes are often designed utilizing the Cox [1] proportional hazard model with a hazard ratio parameter Delta. PURPOSE: The purpose of this article is to demonstrate that a Cox proportional hazard model with a hazard ratio parameter is equivalent to a Cox proportional hazard model with a parameter equal to the probability that a patient given one treatment will have an event earlier than if the same patient were given a different treatment. This probability will subsequently be referred to as theta. Clinically interesting differences between the treatment arms are easier for researchers to quantify in terms of in situations where they have a difficult time with the hazard ratio, allowing better communication between the statistician and the researcher. METHODS: The problem and its solution are demonstrated mathematically. The utility of the Cox proportional hazard model in terms of theta is illustrated through a Lymphoma clinical trial example. RESULTS: The Cox proportional hazard model with parameter theta is shown to be equivalent to the Cox proportional hazard model with a hazard ratio parameter Delta. A table of typical hazard ratios Delta is presented with their equivalent theta values. In the appendix the mathematical derivations are developed and an unbiased estimate of theta is provided using Gehan's [2] generalization of the Wilcoxon statistic. LIMITATIONS: The equivalence of the Cox proportional hazard model in terms of the probability theta and the hazard ratio Delta is established only for continuous failure times with a single binary covariate. Conditions under which approximate equivalence holds with multiple covariates are discussed in the Appendix. CONCLUSIONS: The probability theta provides a natural parameterization for the Cox proportional hazard model, affords a tool to conceptualize treatment differences, and provides a method to improve communication between statisticians and researchers.

Impact of the Cancer Risk Intake System on patient-clinician discussions of tamoxifen, genetic counseling, and colonoscopy.

The Cancer Risk Intake System (CRIS), a computerized program that "matches" objective cancer risks to appropriate risk management recommendations, was designed to facilitate patient-clinician discussion. We evaluated CRIS in primary care settings via a single-group, self-report, pretest-posttest design. Participants completed baseline telephone surveys, used CRIS during clinic visits, and completed follow-up surveys 1 to 2 months postvisit. Compared with proportions reporting having had discussions at baseline, significantly greater proportions of participants reported having discussed tamoxifen, genetic counseling, and colonoscopy, as appropriate, after using CRIS. Most (79%) reported CRIS had "caused" their discussion. CRIS is an easily used, disseminable program that showed promising results in primary care settings.

Patients' interest in discussing cancer risk and risk management with primary care physicians.

Little is known about patients' preferences for discussing cancer risks and risk management with primary care physicians. We sought to determine whether patients want to discuss such topics and what factors are associated with this interest. Participants (375 patients ages 40-85, of diverse race and education level) completed a telephone survey prior to scheduled physician visits. Survey included items on perceived health, perceived cancer risk, education level, and whether participants would like to discuss with a physician their breast, ovarian or colon cancer risk, tamoxifen, cancer genetic counseling, and colon cancer screening. Greater proportions were interested in discussing risks for each cancer, compared with those who were not (P < 0.0001). More participants were interested in discussing mammograms (80%) and cancer genetic counseling (60%) than tamoxifen (49%) or colon cancer screening modalities (43-53%). For many topics, poorer perceived health was associated with greater interest in future discussion; higher education level was associated with less interest.

Improving the accuracy of syndromic diagnosis of genital ulcer disease in Malawi.

OBJECTIVES/GOAL: Most resource-poor settings rely on syndromic criteria to diagnose genital ulcer disease (GUD). However, the etiologic pathogens of GUD vary temporally and geographically, and current criteria may not reflect changes in the prevalence of specific pathogens. STUDY: In 1999, we estimated the prevalence of Treponema pallidum (Tp), herpes simplex virus (HSV), and Haemophilus ducreyi (Hd) in Malawi. We then used regression coefficients of independent correlates of HSV and Hd to develop weighted diagnostic algorithms, in which weights were beta-coefficients corresponding to each factor. RESULTS: Overall, a decrease in the proportion of sexually transmitted disease attributable to GUD was noted in 7 years. Thirty-five percent were attributable to HSV, 30% to H. ducreyi, and 4% to T. pallidum. Areas under the receiver operating characteristic curves for weighted and unweighted HSV diagnostic algorithms were 67.6% and 66.5%, respectively. There was no significant difference in the explanatory performance of the weighted and unweighted algorithms. CONCLUSIONS: Unweighted algorithms can therefore be used to improve diagnostic accuracy of GUD.

A general formulation for a one-sided group sequential design.

BACKGROUND: A major contribution to the statistical literature on group sequential designs was provided by Pampallona and Tsiatis who developed closed form functions that can be used to iteratively calculate the boundary points of a family of popular group sequential designs. A related area of interest is the use of conditional probability calculations to make interim decisions in stochastic curtailment procedures. PURPOSE: The purpose of the paper is to develop group sequential designs based on conditional probabilities, to compare our results to the general closed form family of designs developed by Pampallona and Tsiatis, and to relate these to commonly used stochastic curtailment procedures. METHODS: The problem and its solution are formulated and derived mathematically. A graphical interpretation of the results provides the reader with an alternative mechanism to understand the results and their significance. RESULTS: One-sided group sequential design boundary points, as closed form functions, are derived from conditional probability statements. These conditional probability statements can be interpreted as the probability, at the final analysis, of reversing the conclusion reached at an interim state. Under mild constraints, these boundary points are identical to the Pampallona and Tsiatis boundary points. At any interim stage when a boundary point is attained or surpassed we suggest a graphical approach to examine the conditional probability of reversing the interim decision at the final stage versus a range of possible parameter values. For stochastic curtailment procedures, we recommend relaxing (increasing) the conditional probability levels to at least 0.50 so that early stopping is at least as likely as for the O'Brien-Fleming procedure. LIMITATIONS: The results are limited to one-sided group sequential designs. CONCLUSIONS: Conditional probabilities of reversing interim decisions provides a useful concept to develop group sequential designs and to evaluate stochastic curtailment procedures.

Racial differences in analgesic/anti-inflammatory medication use and perceptions of efficacy.

BACKGROUND AND OBJECTIVE: Pharmacotherapy is a key component to osteoarthritis (OA) treatment. Research has shown important racial differences in pain thresholds and perceptions, but little is known about racial variations in responses to pain medications. The purpose of this study was to compare perceptions of efficacy of pain medications among African-American and Caucasian veterans with OA. METHODS: Participants (N = 202; 70% Caucasian, 30% African-American) were under care for OA within the VA healthcare system. Participants rated the helpfulness of current analgesic/anti-inflammatory medications (scale of 1--not at all helpful to 10--very helpful). RESULTS: The mean rating of medication helpfulness was 6.1. African-American participants reported significantly greater ratings of medication helpfulness than Caucasians (6.6 vs. 5.9), controlling for demographics, disease severity, total number of analgesic/anti-inflammatory medications being taken, and the class of the medication. CONCLUSION: African Americans had somewhat more favorable perceptions of medication helpfulness than Caucasians. However, overall ratings of medication helpfulness were relatively low. Further research is needed to examine whether modifiable factors (such as low dosing or patient nonadherence to prescription instructions) contribute to perceptions of poor efficacy.

Number of children associated with obesity in middle-aged women and men: results from the health and retirement study.

OBJECTIVE: To study associations between number of children and obesity in middle-aged women and men. METHODS: In the Health and Retirement Study, a national survey of households, we tested the association between increasing number of children and obesity (body mass index [BMI] >or= 30) in 9046 middle-aged women and men (4523 couples). RESULTS: Women (n = 4523) who were obese were more frequently nonwhite, reported lower household income, were more frequently employed outside the home, were less frequently covered by health insurance, and were more frequently less educated compared with nonobese women. Men (n = 4523) who were obese were younger, were more frequently African American, and were more frequently less educated and poorer compared with nonobese men. Among women, a 7% increase in risk of obesity was noted for each additional child, adjusting for age, race, household income, work status, physical activity, tobacco use, and alcohol use. Among men, a 4% increase in risk of obesity was noted for each additional child, adjusting for the same covariates. These sex differences were not significantly different. CONCLUSIONS: Previous research has demonstrated an association between number of children and obesity among women. These results suggest a similar association among men. Public health interventions focused on obesity prevention should target both parents, especially those parents with several children.

Sample Size Requirements for Accurate Estimation of Squared Semi-Partial Correlation Coefficients.

The increase in the squared multiple correlation coefficient associated with a variable in a regression equation is a commonly used measure of importance in regression analysis. An alternative measure of importance is the difference in the adjusted squared multiple correlation coefficients. Both estimate the difference in the population squared multiple correlation coefficients (Δρ(2)), a quantity also called a squared semi-partial correlation coefficient. In planning a study that will use regression analysis, it is important to select a sample size that will allow Δρ(2) to be estimated with adequate accuracy. Results showed that the sample size necessary for adequate accuracy depend strongly on three factors: (a) the population squared multiple correlation coefficient (ρ(2)), (b) the population increase in ρ(2), and (c) the desired degree of accuracy. The number of predictors had a small effect on the required sample size. Tables to facilitate sample size selection were presented.