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OBJECTIVE: Hallux valgus is a common and disabling condition. The objective of this study was to identify factors associated with hallux valgus incidence and progression. METHODS: Participants were from a population-based prospective cohort study, the Clinical Assessment Study of the Foot. All adults aged ≥50 years registered with four general practices in North Staffordshire, UK were invited to take part in a postal survey at baseline and at 7-year follow-up which included health questionnaires and self-assessment of hallux valgus using line drawings. RESULTS: Complete baseline and follow-up data were available for 1,482 participants (739 women and 743 men, mean [standard deviation] age 62.9 [8.1] years), of whom 450 (30.4%) had hallux valgus in at least one foot at baseline. Incident hallux valgus was identified in 207 (20.1%) participants (349 [15.4%] feet) and was associated with baseline age, poorer physical health, foot pain and wearing shoes with a very narrow toe-box shape between the age of 20 and 29 years. Hallux valgus progression was identified in 497 (33.6%) participants (719 [24.3%] feet) but was not associated with any baseline factors. CONCLUSION: Incident hallux valgus develops in one in five adults aged ≥50 years over a 7-year period and is related to age, poorer physical health, foot pain and previous use of constrictive footwear. Progression occurs in one in three adults. These findings suggest that changes in first metatarsophalangeal joint alignment may still occur beyond the age of 50 years.

KEY POINTS Preterm birth occurs when the heart muscle is immature and ill-prepared for the changes in heart and lung function at birth. MRI imaging studies show differences in the growth and function of the heart of young adults born preterm, with the effects more pronounced in the right ventricle. The findings of this study, conducted in sheep, showed that following moderate preterm birth the right ventricular wall was thinner in adulthood, with a reduction in the number and size of the heart muscle cells; in addition, there was impaired blood flow in the main artery leading from the right ventricle to the lungs. The findings indicate that being born only a few weeks early adversely affects the cellular structure of the right ventricle and blood flow to the lungs in adulthood. The reduced number of heart muscle cells has the potential to deleteriously affect right ventricular growth potential and function. ABSTRACT Preterm birth prematurely exposes the immature heart to the haemodynamic transition at birth, which has the potential to induce abnormal cardiac remodelling. Magnetic resonance imaging studies in young adults born preterm have shown abnormalities in the gross structure of the ventricles (particularly the right ventricle; RV), but the cellular basis of these alterations is unknown. The aim of this study, conducted in sheep, was to determine the effect of moderate preterm birth on RV cellular structure and function in early adulthood. Male singleton lambs were delivered moderately preterm (132 ± 1 days; n = 7) or at term (147 ± 1 days; n = 7). At 14.5 months of age, intra-arterial blood pressure and heart rate were measured. Pulmonary artery diameter and peak systolic blood flow were determined using ultrasound imaging, and RV stroke volume and output calculated. Cardiomyocyte number, size, nuclearity and levels of cardiac fibrosis were subsequently assessed in perfusion-fixed hearts using image analysis and stereological methods. Blood pressure (systolic, diastolic and mean), heart rate, levels of myocardial fibrosis and RV stroke volume and output were not different between groups. There was, however, a significant reduction in RV wall thickness in preterm sheep, and this was accompanied by a significant reduction in peak systolic blood flow in the pulmonary artery and in RV cardiomyocyte number. Cellular changes in the RV wall and reduced pulmonary artery blood flow following preterm birth have the potential to adversely affect cardiac and respiratory haemodynamics, especially when the cardiovascular system is physiologically or pathologically challenged.

In patients with chronic kidney disease (CKD), clinical interest often centers on determining treatments and exposures that are causally related to renal progression. Analyses of longitudinal clinical data in this population are often complicated by clinical competing events, such as end-stage renal disease (ESRD) and death, and time-dependent confounding, where patient factors that are predictive of later exposures and outcomes are affected by past exposures. We developed multistate marginal structural models (MS-MSMs) to assess the effect of time-varying systolic blood pressure on disease progression in subjects with CKD. The multistate nature of the model allows us to jointly model disease progression characterized by changes in the estimated glomerular filtration rate (eGFR), the onset of ESRD, and death, and thereby avoid unnatural assumptions of death and ESRD as noninformative censoring events for subsequent changes in eGFR. We model the causal effect of systolic blood pressure on the probability of transitioning into 1 of 6 disease states given the current state. We use inverse probability weights with stabilization to account for potential time-varying confounders, including past eGFR, total protein, serum creatinine, and hemoglobin. We apply the model to data from the Chronic Renal Insufficiency Cohort Study, a multisite observational study of patients with CKD.

Propensity scores are widely used to control for confounding when estimating the effect of a binary treatment in observational studies. They have been generalized to ordinal and continuous treatments in the recent literature. Following the definition of propensity function and its parameterizations (called the propensity parameter in this paper) proposed by Imai and van Dyk, we explore sufficient conditions for selecting propensity parameters to control for confounding for continuous treatments in the context of regression-based adjustment in linear models. Typically, investigators make parametric assumptions about the form of the dose-response function for a continuous treatment. Such assumptions often allow the analyst to use only a subset of the propensity parameters to control confounding. When the treatment is the only predictor in the structural, that is, causal model, it is sufficient to adjust only for the propensity parameters that characterize the expectation of the treatment variable or its functional form. When the structural model includes selected baseline covariates other than the treatment variable, those baseline covariates, in addition to the propensity parameters, must also be adjusted in the model. We demonstrate these points with an example estimating the dose-response relationship for the effect of erythropoietin on hematocrit level in patients with end-stage renal disease.

Objective The race-specific association of inflammation with adiposity and muscle mass in subjects with chronic kidney disease (CKD) was examined. Methods Plasma concentration of interleukin (IL)−1β, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, tumor necrosis factor (TNF)-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin was measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Bioelectric impedance analysis was used to determine body fat mass (BFM) and fat-free mass (FFM). Results Plasma levels of hs-CRP, fibrinogen, IL-1RA, IL-6, and TNF-α increased and serum albumin decreased across the quartiles of body mass index. In multivariable analysis, BFM and FFM were positively associated with hs-CRP, fibrinogen, IL-1β, IL-1RA, and IL-6. One standard deviation (SD) increase in BFM and FFM was associated with 0.36 (95% confidence interval [CI] = 0.33, 0.39) and 0.26 (95% CI = 0.22, 0.30) SD increase in log-transformed hs-CRP, respectively (P

Purpose Erythropoietin (EPO) improves measures of quality of life and reduces transfusions. Clinical trials have reported higher mortality associated with higher hemoglobin targets in varied clinical settings, making difficult the selection of erythropoiesis stimulation strategies in end-stage kidney disease. Observational studies distinguishing an effect of EPO from underlying conditions are challenging, but promise insights relevant to real-world settings. Methods Using data from the United States Renal Data System, we performed a retrospective cohort study of hemodialysis patients treated between 2000 and 2004. 409 364 Medicare insured patients receiving hemodialysis therapy as of January 2000 or who began dialysis after January 2000 and survived >6 months were studied. We examined the association of EPO dose in any given month with death over subsequent follow-up. Results Within each hematocrit group ( 39%), the hazard ratios comparing the 80th percentile to the median EPO dose were 0.88 (95% CI: [0.87–0.90]), 0.94 ([0.93–0.94]), 0.98 ([0.98–0.99]), 1.06 ([1.05–1.06]) and 1.08 ([1.07–1.09]), respectively. Within the highest hematocrit group, the association of a high EPO dose with elevated mortality was attenuated over time. Among patients with malignancy or indications of EPO resistance, the association of higher EPO dose with lower mortality was attenuated when hematocrit was low, while its association with higher mortality was stronger when hematocrit was high. Conclusions These analyses demonstrate a complex relationship between EPO dosing and mortality, suggesting a possible beneficial effect among severely anemic hemodialysis patients, but possible harm when administered to individuals with higher hematocrit levels. Copyright © 2013 John Wiley & Sons, Ltd.

Tom Ten Have made many contributions to causal inference and biostatistics before his untimely death. This paper reviews Tom's contributions and discusses potential related future research directions. We focus on Tom's contributions to longitudinal/repeated measures categorical data analysis and particularly his contributions to causal inference. Tom's work on causal inference was primarily in the areas of estimating the effect of receiving treatment in randomized trials with nonadherence and mediation analysis. A related area to mediation analysis he was working on at the time of his death was posttreatment effect modification with applications to designing adaptive treatment strategies.

We review the concept of time-dependent confounding by using the example in paper “Comparative effectiveness of individual angiotensin receptor blockers on risk of mortality in patients with chronic heart failure” by Desai et al. and illustrate how to adjust for it by using inverse probability of treatment weighting through a simulated example. We discuss a few subtle issues that arise in specification of the model for treatment required to fit marginal structural models (MSMs) and in specification of the structural model for the outcome. We discuss the differences between the effects estimated in MSMs and intention-to-treat effects estimated in randomized trials, followed by an outline of some limitations of MSMs. Copyright © 2012 John Wiley & Sons, Ltd.

BACKGROUND: Sentinel lymph node (SLN) biopsy generally is recommended for patients who have melanoma with a Breslow thickness ≥1 mm. Most patients with melanoma between 1 mm and 2 mm thick have tumor-negative SLNs and an excellent long-term prognosis. The objective of the current study was to evaluate prognostic factors in this subset of patients and determine whether all such patients require SLN biopsy. METHODS: Patients with melanoma between 1 mm and 2 mm in Breslow thickness were evaluated from a prospective multi-institutional study of SLN biopsy for melanoma. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis to compare patients with melanoma that measured from 1.0 mm to 1.59 mm (Group A) versus patients with melanoma that measured from ≥1.6 mm to 2.0 mm thick (Group B). Univariate and multivariate analyses were performed to evaluate factors predictive of tumor-positive SLN status, DFS, and OS. RESULTS: The current analysis included 1110 patients with a median follow-up of 69 months. SLN status was tumor-positive in 133 of 1110 patients (12%) including 66 of 762 patients (8.7%) in Group A and 67 of 348 patients (19.3%) in Group B (P < .0001). On multivariate analysis, age, Breslow thickness, and lymphovascular invasion were independently predictive of a tumor-positive SLN (P < .05). DFS (P < .0001) and OS (P = .0001) were significantly better for Group A than for Group B. When tumor thickness was treated as either a continuous variable (P < 0.0001) or a categorical variable (P < .0001), it was significantly predictive of DFS and OS. On multivariate analysis, Breslow thickness, age, ulceration, histologic subtype, regression, Clark level, and SLN status were significant factors predicting DFS; and Breslow thickness, age, primary tumor location, sex, ulceration, and SLN status were significant factors predicting OS (P < .05). A subgroup of patients who had tumors

We present a linear rank preserving model (RPM) approach for analyzing mediation of a randomized baseline intervention's effect on a univariate follow-up outcome. Unlike standard mediation analyses, our approach does not assume that the mediating factor is also randomly assigned to individuals in addition to the randomized baseline intervention (i.e., sequential ignorability), but does make several structural interaction assumptions that currently are untestable. The G-estimation procedure for the proposed RPM represents an extension of the work on direct effects of randomized intervention effects for survival outcomes by Robins and Greenland (1994, Journal of the American Statistical Association 89, 737-749) and on intervention non-adherence by Ten Have et al. (2004, Journal of the American Statistical Association 99, 8-16). Simulations show good estimation and confidence interval performance by the proposed RPM approach under unmeasured confounding relative to the standard mediation approach, but poor performance under departures from the structural interaction assumptions. The trade-off between these assumptions is evaluated in the context of two suicide/depression intervention studies.

Studies suggest the expression of cyclooxygenase-2 (COX-2) and matrilysin (MMP-7) increase in the early stages of colorectal carcinogenesis, however their interaction with other molecular markers is poorly understood. Results from cell line studies and mouse models suggest polyomavirus enhancer activator 3 (PEA3) may play a role in the activation of COX-2 and MMP-7 promoters. However, the role of E1A-F, the human homolog of murine PEA3, in colorectal cancer (CRC) development has not been elucidated. In this study, we used real-time reverse transcription (RT)-polymerase chain reaction (PCR) to measure the levels of E1A-F, COX-2, and MMP-7 in matched normal mucosa, adenomas, and/or carcinomas from 128 patients. Our results demonstrate significant overexpression of E1A-F and MMP-7 in adenomas and E1A-F, COX-2, and MMP-7 in carcinomas. In carcinomas, E1A-F expression was significantly associated with both COX-2 and MMP-7 overexpression. These results suggest E1A-F is overexpressed in early stages of human CRC development and may be an important factor in the overexpression of COX-2 and MMP-7.

Recent studies have revealed that young infants can form expectations for the spatial location of future visual events. Four experiments examined whether 3-month-old infants also form expectations for content features of events, defined as an invariant color combination. Infants viewed a spatially alternating (left–right) sequence of varying pictures in which pictures on one side (invariant colors) always appeared with the same color combination (e.g., red/green), while on the other side (varied colors) the pictures appeared with any of 4 possible color combinations. Results indicated that infants formed a content expectation for the invariant color combination on the invariant side, such that their anticipatory responding was disrupted by a novel color combination event and by a novel pattern event. A dissociation between reactive and anticipatory eye movements in their sensitivity to the content manipulation suggests that infants' expectations for spatial and content information engage somewhat different processes.

Les etudes cas-temoins comparent souvent les declarations des sujets a propos de leurs antecedents (depistage, exposition,...). Chez les cas, cette information est generalement recueillie apres la survenue de l'evenement d'interet. Cela pose probleme dans les etudes de survie puisque les sujets decedes ne peuvent fournir l'information recherchee. Pour eviter cette difficulte. Weiss et Lazovich (1996, American Journal of Epidemiology)proposent de recueillir l'information sur l'exposition ou le depistage chez des cas potentiels, c'est-a-dire chez des cas diagnostiques, a la date du depistage et chez des sujets de reference. Le protocole peut etre considere comme un nouveau schema d'echantillonnage emboite dans une cohorte. J'utilise titi nouvelle factorisation pour presenter l'estimation des effets d'un depistage ou d'une exposition variant avec le temps. Je montre ensuite sous quelles conditions d'ignorabilite cette factorisation conduit a des estimations valides. Memelorsque la fraction d'echantillonnage des sujets bien portants est inconnue, les risques relatifs causaux sont estimables a condition que le diagnostic reste rare dans la cohorte.

We propose a method for estimating the marginal causal log-odds ratio for binary outcomes under treatment non-compliance in placebo-randomized trials. This estimation method is a marginal alternative to the causal logistic approach by Nagelkerke et al. (2000) that conditions on partially unknown compliance (that is, adherence to treatment) status, and also differs from previous approaches that estimate risk differences or ratios in subgroups defined by compliance status. The marginal causal method proposed in this paper is based on an extension of Robins' G-estimation approach for fitting linear or log-linear structural nested models to a logistic model. Comparing the marginal and conditional causal log-odds ratio estimates provides a way of assessing the magnitude of unmeasured confounding of the treatment effect due to treatment non-adherence. More specifically, we show through simulations that under weak confounding, the conditional and marginal procedures yield similar estimates, whereas under stronger confounding, they behave differently in terms of bias and confidence interval coverage. The parametric structures that represent such confounding are not identifiable. Hence, the proof of consistency of causal estimators and corresponding simulations are based on two different models that fully identify the causal effects being estimated. These models differ in the way that compliance is related to potential outcomes, and thus differ in the way that the causal effect is identified. The simulations also show that the proposed marginal causal estimation approach performs well in terms of bias under the different levels of confounding due to non-adherence and under different causal logistic models. We also provide results from the analyses of two data sets further showing how a comparison of the marginal and conditional estimators can help evaluate the magnitude of confounding due to non-adherence.

Two experiments were conducted with 28-week-old infants using a modification of the Visual Expectation Paradigm. The first sought to determine whether speed of information processing (SIP) could be assessed in infants using a reaction time (RT) measure and approach that is widely used to measure SIP in adults. Infants saw a center fixation cue followed by a peripheral target that could appear in 1, 2, or 4 locations. There was a linear increase in RT of eye movements as the number of locations increased from 1 to 2 and to 4 targets, suggesting that the paradigm does measure SIP. The second experiment asked whether varying the number of cue-target pairings would augment or impair infant's SIP in the trade-off between the benefit of additional information and the liability of additional memory load. The findings showed that the presence of cue information can eliminate the difference in RT between the 1- and 2-location conditions, whereas no benefit of cue was obtained for the 4-location condition.

Purpose To review conceptual issues regarding confounding by indication in the context of studies of calcium channel blockers (CCBs). Methods Review of literature, with special attention to two articles in the current issue. Results Conflicting arguments about the presence of uncontrollable confounding by indication in studies of CCBs are reviewed and criticized. Studies with potential confounding by indication can benefit from appropriate analytic methods, including separating the effects of a drug taken at different times, sensitivity analysis for unmeasured confounders, and instrumental variables and G-estimation. Conclusions Whether confounding by indication accounts for observed associations is often difficult to determine; this is the case in studies of CCBs. When confounding by indication is suspected, a variety of methods to deal with it may be useful. Copyright © 2000 John Wiley & Sons, Ltd.

John Rennie Short’s Liquid City seeks to update Jean Gottmann’sMegalopolis and examine changes in the Northeast United States over the almost five decades that separate the two books. The title, Li...

Photofrin (porfimer sodium) is a porphyrin derivative used in the treatment of a variety of cancers by photodynamic therapy. This oligomer complex and a variety of porphyrin monomers, dimers and trimers were analyzed with five different mass spectral ionization techniques: fast atom bombardment, UV and IR matrix-assisted laser desorption/ionization, electrospray ionization, and laser desorption/jet-cooling photoionization. All five approaches resulted in very similar oligomer distributions with an average oligomer length of 2.7 +/- 0.1 porphyrin units. In addition to the Photofrin analysis, this study provides a side-by-side comparison of the spectra for the five different mass spectrometric techniques.

Background The management of micrometastatic disease from squamous cell carcinoma (SCC) of the oral tongue remains controversial. This study describes prognostic factors in the disease and reviews the role of elective neck dissection (END). Methods A retrospective analysis of all patients undergoing definitive surgical treatment of T1 and T2 SCC of the oral tongue between 1956 and 1994 at the University of Alabama at Birmingham was performed. Results Patient, disease, and treatment variables were compiled for 169 patients. Multivariate analysis showed age (p = .02), sex (p = .02), disease differentiation (p = .0003), and palpable lymphadenopathy (p = .02) to be significant prognostic variables. Fifteen patients underwent END and 6 were shown to have micrometastatic disease (40.0%). There were no neck recurrences in these patients, but END was not shown to improve survival. Conclusions The presence of poorly differentiated disease gave the worst prognosis in this population of patients with T1 and T2 SCC of the oral tongue. A high incidence of nodal micrometastatic disease and the absence of recurrent disease after END suggest that END is appropriate therapy for these patients. © 1999 John Wiley & Sons, Inc. Head Neck 21: 124–130, 1999.

The direct effect of a treatment on some outcome is that part of the treatment's effect not referred through a specified covariate intermediate on the pathway between treatment and outcome. Such direct effects are often of primary interest in a data analysis. Unfortunately, standard methods of analysis (for example, stratification or modelling) do not, in general, produce consistent estimates of direct effects whether or not the covariate is 'controlled'. Robins and co-authors have proposed two methods for estimation of direct effects applicable when reliable information is available on the covariate. We propose a third approach for reducing bias: data restriction. By restricting the analysis to strata of the data in which the effect of treatment on the covariate is small, we can (under certain assumptions) reduce bias in estimating treatment's direct effect. We discuss these points with reference to difference and ratio measures of treatment effect. The approach will sometimes be applicable even with an unmeasured or poorly measured covariate. We illustrate these points with data from an observational study of the effect of hormone replacement therapy on breast cancer.

Researchers commonly express scepticism about using observational data to estimate the effect of a treatment on an outcome the treatment is intended to affect. In this paper, we consider using data from the Multicenter AIDS Cohort Study (MACS) to determine whether zidovudine prevents the development of Kaposi's sarcoma among HIV-positive gay men. Several methodologic issues common to observational data characterized the study: information on potentially important confounders was missing at some study visits; investigators did not always know the time of changes in treatment level, nor the value of confounders at that time, and the censoring process depended strongly on time-varying covariates related to outcome. We describe application to our data of Robins' paradigm for defining, modelling and estimating the effect of a time-varying treatment and show how to modify his approach to deal with the methodologic issues we have mentioned. Further, we demonstrate that relative risk regression is less well equipped to deal with these issues. We compare our results to the findings from randomized trials, and conclude that observational studies may sometimes be useful in evaluating the effect of treatment on an intended outcome.

Background and Objectives: Approximately one third of all melanoma patients will experience disease recurrence. Factors that affect patient survival following local, regional, or distant first recurrences of localized melanoma are the subject of this investigation. Methods: Survival times for a total of 1,085 first recurrences from 4,568 localized melanoma patients were examined in relationship to patient and disease factors by Cox regression. Nearly half (48.8%) of all first recurrences were regional, 21.8% were local, and 29.4% were distant recurrences. Results: Survival following recurrence differed significantly by site of recurrence (local, regional, or distant; P < 0.0001). Within each site, the median survival time did not differ by time of recurrence following diagnosis. Significant tumor factors for survival following local recurrence included tumor thickness (P = 0.0263) and lesion location (P < 0.0001). For regional recurrences, survival was significantly related to ulceration (P = 0.0105) and whether the recurrence was combined with a local recurrence (P = 0.0429). Survival following distant metastasis was related to number of distant sites (P < 0.0001) and whether a visceral site was involved (P < 0.0001). Conclusions: Patient and tumor characteristics predict survival following recurrence. Regardless of disease-free interval, long-term follow-up of melanoma patients is necessary. Patients experiencing distant metastasis have the shortest median survival time compared to patients experiencing local or regional recurrences.

General and rapid methods were developed for determining the extent of non-covalent binding between small molecules and proteins, using the model system of human cytomegalovirus protease and several drug candidates which inhibit the protease by non-covalently binding to it. The assay was performed by off-line coupling of size-exclusion methods with mass spectrometry in the following manner. The protease and inhibitor were incubated together under native conditions and then subjected to separation based on size, by use of a spin column (gel permeation chromatography) and/or a microconcentrator (ultrafiltration). The spin column selectively passed the high molecular mass (M(r)) protease and trapped low M(r) molecules. Alternatively, the microconcentrator passed low M(r) molecules and retained the protease. If the inhibitor bound non-covalently to the protease, both the inhibitor and protease passed through the spin column (or were retained by the microconcentrator). Electrospray ionization mass spectrometry was used to assay the spin column eluate (or the microconcentrator retentate) and to characterize the amounts of protease and inhibitor based on known standards. An advantage of these techniques is that a mixture containing inhibitors can be analyzed in the presence of the protease, and inhibitors with the greatest binding affinity can be identified. Non-covalent binding specificity was demonstrated using spin columns by comparing the binding affinity of inhibitors using several mutants of cytomegalovirus protease. The techniques described are applicable to the rapid screening of compound libraries for selecting substances which bind non-covalently to a known protein.

Electrospray ionization mass spectrometry was used in the negative ion mode to analyze complexes of sucrose octasulfate, sucrose heptasulfate and sulfated alpha-, beta- and gamma-cyclodextrins with synthetically prepared basic peptides, the basic protein ubiquitin and polyamines. The spectra presented demonstrate that complexes with these basic molecules facilitate the analysis of these polysulfated oligosaccharides. Stable (1:1) complexes result from the ion pairing between the protonated basic arginine and lysine residues of the peptide and the anionic sulfate groups of the polysulfated oligosaccharides. Fragmentation of the polysulfated oligosaccharides resulting in the loss of SO3 could be suppressed by controlling the experimental conditions, such as the nozzle-skimmer voltage, used to obtain the spectra. In the absence of fragmentation, it was possible to obtain data on the purity of sucrose octasulfate and sucrose heptasulfate as well as the distribution of the sulfated cyclodextrins. The confounding presence of sodium counter-ions is also eliminated using this method. Complete chemical sulfation of oligosaccharides is difficult to achieve. Thus, data on sample purity are essential for the characterization of sulfated oligosaccharides used as pharmaceutical agents.

BACKGROUND Over the past 2 decades, remarkable progress has been made in the identification of clinical and pathologic factors that affect the survival of patients with melanoma. Through the use of multivariate regression methods, key prognostic factors, such as tumor thickness, tumor ulceration, invasion level, and lesion location, have been identified. Clinical investigators are often interested in developing criteria to classify melanoma patients into different risk groups based on the key prognostic factors identified. However, classical multivariate regression models are generally less efficient in accomplishing this task than newly developed tree-based methods. METHODS In this study, the authors applied the exponential survival trees method to analyze a combined data set (n = 4568) from the University of Alabama at Birmingham and the Sydney Melanoma Unit in Camperdown, Australia. A survival tree was created according to prognostic factors that classified patients into homogeneous subgroups by survival. Six clinical and pathologic factors were included in the analysis. This tree-based method provided a superior means of prognostic classification and was shown to have greater ability to detect interactions among the variables than regression models. RESULTS Tumor thickness was found to be the most important prognostic factor, followed by tumor ulceration and primary lesion site. Some important interactions among these prognostic factors were identified. Five distinct risk groups, defined by tumor thickness, ulceration, and primary lesion site, were created. Patients who had tumor thickness less than or equal to 0.75 mm and lesions on their arms or legs had the best prognosis. Patients who had ulcerated tumors with thickness greater than 4.50 mm had the poorest prognosis. CONCLUSIONS The authors' analysis, based on exponential survival trees, provides a comprehensive, easy-to-use risk grouping system for classifying patients with localized melanoma. This grouping system would be useful in the clinical management of melanoma patients and in designing and analyzing clinical trials. Cancer 1997; 79:1122-8. © 1997 American Cancer Society.

The cases reported in this paper were treated at 7 different clinical centers and present clinical and histologic observations from 15 patients and 21 human biopsies. The biopsies were taken from extraction sockets or dental implant sites which were grafted with either autologous intra-oral bone (6 sites), demineralized freeze-dried bone (DFDBA) (7 sites), or mineralized freeze-dried bone (MFDBA) (7 sites), or a combination of autologous bone, DFDBA and a barrier membrane (1 site). Six sites were grafted with DFDBA and augmented with expanded polytetrafluoroethylene (ePTFE) barrier membranes. Biopsies for histological evaluation were taken 4 to 13 months after implantation. A bone scoring system of 0 to 4 was used to evaluate the sections for dead implanted particles or the presence of vital bone. A bone score of 3 indicated the presence of dead implant material, blood vessels, islands of cartilage, osteoblasts, and new bone formation. A score of 4 indicated total replacement of the implanted material by the host bone. The average bone score for sites which received autologous bone was 2.33; for DFDBA sites, 0.98; and MFDBA was 0.18. The over-riding histologic characteristic of sites implanted with DFDBA or MFDBA was retention of non-vital graft particles within fibrous connective tissue. Biopsies taken adjacent to the host bed demonstrated incorporation of the allografts (osteoconduction). Sites grafted with autologous bone chips also demonstrated non-vital bone chips surrounded by vital host bone (osteoconduction). Sites which received barrier membranes did not appear to improve or impair bone healing of the augmented sites. Autologous bone chips harvested from within the oral cavity as well as allografts may serve as biologic fillers, but do not apparently contribute to osteoinduction. Autologous bone will eventually be resorbed and replaced by the host. DFDBA and MFDBA are resorbed very slowly and apparently do not contribute to osteoinduction. Allografts apparently are not resorbed by osteoclasts and therefore their continued use around dental implants is questioned.

We consider the problem of interpreting categorical regression models, such as the polytomous logistic model, the continuation-ratio model, the stereotype model, and the cumulative-odds model. We present a method to convert categorical regression coefficients into estimates of standardized fitted probabilities, probability differences and probability ratios. We use a delta-method approach to estimate standard errors. We then present a small simulation study to compare different transforms for setting confidence limits, and provide an illustration of our approach in an observational study of drug therapy of polymyositis.

Background. In a Phase II trial, surgical adjuvant active specific immunotherapy using a live vaccinia virus-augmented allogeneic polyvalent melanoma cell lysate, vaccinia melanoma oncolysate (VMO), produced a significant disease free interval (DFI) in patients with International Union Against Cancer Stage II melanoma with positive lymph nodes. Therefore, a Phase III randomized prospective, double-blind, multiinstitutional, surgical adjuvant VMO trial was performed to determine the efficacy of VMO to increase the DFI and the overall survival in this group of patients with Stage II disease. Methods. Two hundred and fifty patients with Stage II melanoma were divided into two postsurgical groups. One group received VMO (total protein equals 2 mg/ml) and the other received the placebo of live vaccinia vaccine virus (V) (105.4 TCID50/ml), an adjuvant component of the VMO. Patients initially received these biologies once a week for 13 weeks and then once every 2 weeks for an additional 39 weeks or until recurrence. All surviving patients have been followed for at least 30 months. Results. Statistical analysis of survival data (n = 217) for this first interim analysis shows that there is no statistically significant (P = 0.99) increase in DFI of patients treated with VMO (n = 104) when compared with V (n = 113). The median DFI is 38.0 months for patients treated with VMO and 37.0 months for patients treated with V. At 2- and 4-year intervals, 70 and 38%, respectively, of patients treated with VMO vs. 66 and 36%, respectively, of patients treated with V were free of melanoma. The median overall survival is not available because the pa-tients treated with VMO have not yet reached the 50% mark and the median overall survival is 45.0 months for patients treated with V. At 2- and 4-year intervals, 70 and 38%, respectively, of VMO-treated patients survived when compared with 66 and 36%, respectively, of pa-tients treated with V. Although the overall survival of pa-tients treated with VMO is not statistically significant (P = 0.88) at this point, there is an increasing trend in the overall survival of patients treated with VMO; a 10% increase at the 4-year time point. Moreover, in the subset analysis, VMO-treated male patients (n = 63) showed a 17% improvement in survival at 4-year time point when compared with male patients treated with V (n = 67) (P = 0.19) at the same time point and male patients (n = 20) between the ages of 44 and 57 having 1-5 positive lymph nodes showed a 37% difference in overall survival at the 4-year time point when compared with those patients treated with V (n = 18) (P = 0.13) at the same time point. Conclusion. In this first interim analysis, active specific immunotherapy with VMO vs. V showed no difference in the disease free interval or overall survival. Subset analyses likewise showed no significant differences in outcome but the data suggest a potential difference in immunoreactivity between male and female patients with melanoma that awaits further follow up and may merit further investigation.

A series of substituted bisaryl phosphate compounds, (R1CH2)+ ArOP = O(O−)(OArR2R3), was analyzed and characterized by fast atom bombardment mass spectrometry. Abundant fragment ions were observed and correlated with the proposed structures. From fragmentation pattersn, ‘ortho effect’ reactions were demonstrated to have occurred when the phosphoryl oxygen reacted with the (CH2R1)+ and CO(OCH3) substituents in the ortho position, relative to the phosphate group, and displaced the R1 and OCH3 groups, respectively, to produce phosphorus containing six-membered rings fused to the aryl moiety. When the (CH2R1)+ substituents were in the meta position relative to the phosphate group, the ‘ortho effect’ reactions were not observed. However, when the CO(OCH3) substituent was in the meta position relative to the phosphate group, an abundant fragment ion containing a five-membered phosphate ring fused to the aryl ring was detected with the original phosphoryl oxygen ortho to both the phosphate oxygen and a formyl group, formed from the original CO(OCH3) substituent. All other fragmentations not involving the ‘ortho effect’ reactions were nearly identical for the different structural isomers of the substituted bisaryl phosphate compounds.

The loading values of high levels of anti-cancer drugs and sugars conjugated to human serum albumin were determined by matrix-assisted ultraviolet (UV) laser desorption/ionization mass spectrometry. The values were compared with those obtained by UV spectrometry, radioactivity labeling or by chemical analysis, and were found to be consistent. The matrix-assisted UV laser desorption/ionization method has been demonstrated to be a routine and reliable method for obtaining high loading values and therefore was applied to the determination of the loading of two experimental drugs, for treating AIDS and septic shock, respectively, when conjugated to bovine serum albumin, which could not be routinely determined by UV spectrometry since the chromophores of the drugs and protein overlap.

Fourteen antimitochrodrial antibody-positive patients (13 women, 1 man) with biopsy-proven primary biliary cirrhosis, aged 40 to 71 years (mean, 57 years) weighing 43 to 102 kg (mean, 63 kg), along with 14 age- and sex-matched healthy controls, received a single 1.0- to 1.2-g dose of intravenous antipyrine. Plasma antipyrine levels were determined during a 12- to 24-hour period. Patients' mean serum chemistry values were: albumin, 3.9 g/dL (range, 3.1-4.4) and total bilirubin, 1.9 mg/dL (range, 0.3-10.9). Seven of the fourteen patients had cirrhosis. Mean kinetic variables for antipyrine in controls and primary biliary cirrhosis patients were: Vd, .54 versus .49 L/kg; half-life, 12.0 versus 15.1 hours (P < .07); clearance, .55 versus .41 mL/min/kg (P < .04). Within the primary biliary cirrhosis group, there was no correlation between total bilirubin and clearance (r = .09), nor did clearance vary significantly among histologic categories. Clearance of antipyrine in primary biliary cirrhosis patients is reduced by an average of 25%, but the clinical prognosticators of serum bilirubin levels and histologic grade do not correlate with or predict the degree of clearance impairment.

Bioxalomycins α1, α2 β1, and β2 are novel compounds with potent antimicrobial and antitumor activity isolated from fermentation broths of Streptomyces viridostaticus. These structures are closely related to that of naphthyridinomycin and call into question the published structure of the naturally occurring form of that antitumor antibiotic

Two novel heptadecaglycoside antibiotics, saccharomicins A (1) and B (2), were isolated from a new species of Saccharothrix. Their structures were determined by a combination of chemical degradation and spectroscopic methods. Saccharomicin B (2) was identified as N-(m,p-dihydroxycinnamoyl) taurine p-O-[α-4-epi-vancosaminopyranosyl(1→4)-α-4-epi-vancosaminopyranosyl(1→4)-α-digitoxopyranosyl(1→4)-α- 4-epi-vancosaminopyranosyl(1→4)-α-digitoxopyranosyl(1→3)-β-fucopyranosyl(1→4)-β-saccharosaminopyranosyl(1→4)-α-digitoxopyranosyl(1→3)]-[α-4-epi-vancosaminopyranosyl(1→4)]-β-fucopyranosyl(1→4)-β- saccharosaminopyranosyl(1→4)-α-rhamnopyranosyl(1→3)-β-fucopyranosyl(1→4)-β-saccharosaminopyranosyl(1→4)-β-fucopyranosyl(1→4)-β-saccharosaminopyranosyl(1→4)-β-2-sulfate-fucopyranoside. Saccharomicin A (1) differs from saccharomicin B (2) only in the 10th sugar residue, where α-digitoxopyranosyl(1→3) is replaced with α-rhamnopyranosyl(1→3). The novel amino sugar residue, designated saccharosamine, was identified by NMR spec...