Relationship of urinary polyamines to tumor activity and tumor volume in patients.

Serially obtained urinary polyamine levels were determined for 192 patients during a specified time period. The number of patient urine samples totaled 938. The patients had tumors of either the breast, stomach, prostate, or female genital tract, or metastatic carcinomas of unknown origin. Tumor activity and tumor volume, along with other clinical information, were also recorded during the time period. Possible associations between tumor activity and tumor volume on one hand, and polyamine levels on the other hand, were explored via different statistical analyses. For each tumor type, statistically significant group differences were found in polyamine levels between patients with nonactive tumors and patients with active large tumors. Predictive values of polyamine assays for change in disease activity and stability in disease nonactivity for tumors of the breast, female genital tract, and prostate were also computed. For breast tumors, these predictive values do not support the clinical utility of the use of polyamine levels to monitor disease states. For tumors of the female genital tract and prostate, these predictive values yield an indeterminant conclusion.

Further evidence for the use of polyamines as biochemical markers for malignant tumors.

One hundred ninety patients with a variety of tumor presented within a specified time period and fit a specified protocol. Multiple serial urinary putrescine, spermidine, and spermine levels were obtained in these patients, and their disease activity over time, defined as either active or nonactive, was determined by clinical examination, the results of laboratory tests, and radiological criteria. Twenty-four-hr urine collections were used for analysis of polyamine levels. A linear mixed-effects model and the method of maximum likelihood estimation were used for statistical analysis. Statistically significant differences were found in polyamine levels between patients with active or nonactive disease for tumors of the breast, stomach, prostate, female genital tract, and a variety of metastatic carcinomas of unknown origin. There were 105 patients with these tumors; 319 polyamine determinations were obtained from this subset of patients. Our results suggest that serial determination of polyamine levels in urine may have clinical utility for monitoring the disease states for these tumors.

Study designs for dose-ranging.

Premarketing dose-ranging studies of a drug are done to establish a reasonable initial dose. According to the current procedure sanctioned by the Food and Drug Administration, each patient is given one of several possible doses, including placebo, after an initial placebo run-in period. Data analysis is based on a model in which the mean response at each dose is independent of the magnitude of the dose. The initial dose is the lowest dose tested that has a response that is statistically significantly greater than the response after placebo administration. We suggest that the present conceptual approach to, and standard study design and analysis for, dose-ranging studies be changed. We believe one must begin with a parametric model for patient-specific dose-response curves. Knowledge of the distribution of these curves in a population provides a basis for choice of an initial dose (e.g., the dose that achieves a given response in a given fraction of patients) and, after observation of response to an initial dose, for choice of an incremental dose for a specific patient (by use of Bayes rule). The current parallel-dose design can provide only poor information about the distribution of dose-response curves, biased estimates of the typical curve, and little information on interpatient variability. Crossover studies provide better information. In studies in which a parametric patient-specific dose-response model is used, a dose-escalation design provides no less information than a crossover design, and it has ethical advantages that allow a more representative patient group and clinical setting to be studied.

Blunt diaphragm rupture. A morbid injury.

A review of our past year's trauma experience revealed that we admitted an average of three patients per month with blunt diaphragm rupture, a total of 39 ruptures in 37 patients. Twenty patients (54%) presented to the emergency room in shock. Thirty patients (81%) required urgent airway intervention. All but one patient had associated injuries. Diaphragm rupture is difficult to diagnose; it was not initially recognized in 69% of cases. Chest roentgenogram was often nondiagnostic. Peritoneal lavage gave false-negative results. We ultimately failed to diagnose diaphragm rupture in only three cases. We attributed our low incidence of missed injury to an aggressive approach in the severely injured patient population, where exploratory laparotomy is a routine part of the complete evaluation. One third of the ruptures were on the right side. The complication rate was 82%, excluding a mortality rate of 40.5%. High morbidity and mortality were related primarily to associated injuries.

The risk of splenorrhaphy.

The main reason for splenorrhaphy is to prevent the occurrence of overwhelming postsplenectomy sepsis. This fear of postsplenectomy sepsis has led to an enthusiasm for splenic salvage to the extent that it may be felt that the injured spleen must be saved at all costs. However, if that is valid, the complications that result from splenic salvage must not exceed the risk incurred by loss of this organ. To assess this, 119 splenic injuries treated by splenorrhaphy were reviewed. These were major splenic injuries that were actively hemorrhaging at laparotomy and, therefore, required specific operative intervention for hemostasis. There were 14 complications in 11 patients (11.8%) directly attributed to the splenorrhaphy. In one patient, the repaired spleen rebled 17 days postoperatively, necessitating splenectomy. Ten patients had persistent or recurrent bleeding, requiring blood transfusions. Three of these underwent reexploration for additional hemostasis. Blood transfusion in association with splenorrhaphy has not previously been considered a complication. However, the literature clearly documents that the risk of blood transfusion heavily outweighs the risk of postsplenectomy sepsis. Therefore, if blood transfusion becomes a necessary adjunct for successful splenorrhaphy, then splenectomy without transfusion is the safer treatment.

Estimating population kinetics.

This paper will review the methods that have been advanced for the estimation of parameters of models quantifying the population characteristics of the kinetic behavior of endogenous and exogenous substances in individuals of the population. Such methods are used frequently, for example, in pharmacokinetic studies. In certain populations, especially biological ones, considerable kinetic variability between population members is present. The models with which we are concerned describe this variability. Some interindividual kinetic variability may be explainable on the basis of measureable concomitant variables, but much of it may remain unexplainable on such a basis. We give this matter particular attention. The assumptions underlying the models are critically discussed.

Successful atrial caval shunting in the management of retrohepatic venous injuries.

Over a 3-year period, 519 patients underwent laparotomy for liver injuries. Nine (2 percent) required insertion of an atrial caval catheter to control hemorrhage from perihepatic venous injuries. In three cases, the shunt arrested the hemorrhage, allowing successful surgical repair of the venous injuries. From a careful analysis of our experience, we have identified common errors made in shunt placement, developed a modified atrial caval catheter, and have simplified the surgical technique for insertion.

Long-term disability associated with flail chest injury.

Twenty-two trauma victims who had sustained flail chest as their only significant injury were evaluated to determine the final outcome. Fourteen patients (63.9 percent) were found to have long-term sequelae. The most common long-term problems after flail chest injury were persistent chest wall pain, chest wall deformity, and dyspnea on exertion. Five patients (22 percent) remained disabled in varying degrees.

Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods.

One may attempt to individualize drug dosage by estimating an individual's pharmacokinetic parameters. Information useful for this purpose consists of certain population pharmacokinetic parameters (notably those describing the typical relationship between dosage and drug concentrations) and also measured drug concentrations from the individual of concern. Both types of information should be used. A (Bayesian) method that does so has been described in the pharmacokinetic literature. In this report an implementation of the Bayesian method that is readily adapted to a microcomputer is presented. Using simulated data it is compared with two other methods proposed by others, for estimating individual theophylline clearances. Both previously suggested methods are shown to be less precise than the Bayesian method: their typical error magnitudes are 20-70% larger.

Some clarifications regarding moments of residence times with pharmacokinetic models.

The stochastic formulation of linear kinetic models is elaborated in order to introduce some new concepts and help clarify the meaning and role of residence time moments. Certain conditional moments are introduced. Multicompartment and steady-state dosing within the stochastic context are considered. A general model-independent formula for steady state volume of distribution and a new concept of steady-state moments are presented. A technique for constructing a model of a given topology from its moments is also given.

Asymptotic confidence intervals for the difference between two binomial parameters for use with small samples.

Some asymptotically-based confidence intervals for the difference between the binomial parameters from two binomial populations are described. Five of these, including the usual simple interval, are extensively evaluated in terms of actual confidence level and interval length. A new simple interval behaves much better than the usual interval, as do some recently proposed iteratively computed intervals.

Computation of the explicit solution to the Michaelis-Menten equation.

An explicit solution to the Michaelis-Menten differential equation with bolus and zero-order input is presented. This solution involves certain simple functions whose values are not readily available. Efficient algorithms for computing values of these functions to any desired degree of accuracy and FORTRAN codes for implementing them are also given.

On the solution to the Michaelis-Menten equation.

An "explicit" solution to the Michaelis-Menten differential equation is presented. Instead of involving the exponential function, the solution involves another simple function. A table for this function is presented.

Fatal hepatic hemorrhage: an unresolved problem in the management of complex liver injuries.

The operative records of 683 patients who required an exploratory laparotomy for trauma with the findings of a liver injury were reviewed. Of the 683 patients 18% (121) sustained severe liver injuries with difficult to control hemorrhage, and 82% of the deaths, in this group of severe liver injuries, were due to exsanguination. A critical analysis of the specific surgical techniques used for hemostasis was undertaken. Hepatotomy with subsequent direct vascular and/or biliary duct repair or ligation was used in 44% of the cases and was successful 87% of the time. Hepatic resection was employed in 10% of the cases with a 50% mortality. Liver packs were used in 29% of the cases which included 14 hepatic vein and six retrohepatic vena caval injuries and five extensive bilobar parenchymal disruptions. The survival rate for this group of patients was 86%. Vascular isolation of the liver was used 8.3% of the cases and was successful 40% of the time. An algorithm for the successful surgical control of hemorrhage from severe liver injuries including indications and contra-indications of specific surgical techniques is presented.

Sample size determination for confidence intervals on the population mean and on the difference between two population means.

Sample size determination is usually based on the premise that a hypothesis test is to be used. A confidence interval can sometimes serve better than a hypothesis test. In this paper a method is presented for sample size determination based on the premise that a confidence interval for a simple mean, or for the difference between two means, with normally distributed data is to be used. For this purpose, a concept of power relevant to confidence intervals is given. Some useful tables giving required sample size using this method are also presented.

Ways to fit a PK model with some data below the quantification limit.

Pharmacokinetic data consist of drug concentration measurements, as well as reports of some measured concentrations being below the quantification limit of the assay (BQL). A pharmacokinetic model may befit to these data, and for this purpose, the BQL observations must be either discarded or handled in a special way. In this paper, seven methods for dealing with BQL observations are evaluated. Both single-subject and population data are simulated from a one-compartment model. A moderate amount of data is simulated for each individual. The actual cv of concentration measurements at the quantification limit is assumed to be no greater than 20%, in accord with the FDA Guidance. The results of this paper should be interpreted in this context. The methods include handling BQL observations as fixed-point censored observations, i.e., by using the likelihoods that these observations are in fact BQL. This method is shown to have some overall statistical advantage. However, the gain in using this method over that of simply discarding the BQL observations is not always much, and this is especially so when the frequency of BQL observations is small. Some simple methods entailing (i) replacing one or more BQL observations with the value 0, or (ii) replacing them with the value QL/2, where QL is the quantification limit, are also included. The first of these two approaches should not be used With population data, use of the second approach can result in some noticeably improved estimation of the typical value of a parameter, but then there is also marked degradation in the estimation of the population variance of the parameter.

Population pharmacokinetic data and parameter estimation based on their first two statistical moments.

A statistical model is set forth that can be taken as a very general description of most data sets that arise from population pharmacokinetic studies. A (nontraditional) method for estimating the parameters of the model--called the NONMEM method in previously published papers--is described. This method involves a linearization of the model. An investigation of the effect of this linearization is reported. This investigation is an empirical one, based on the simulation of data from special cases of the model and the application of a few different estimation methods to these data. From the limited evidence in this investigation it appears that the linearization per se does not significantly adversely affect the estimates.

Maxillofacial trauma: a potentially fatal injury.

Trauma remains one of the fastest growing causes of death in the United States, especially within the young adult population. Injuries to both the soft tissue and bony skeleton of the face constitute a high percentage of all traumatic admissions that pass through many emergency rooms. Because maxillofacial injuries are often dramatic, they can easily divert attention away from other medical priorities. In spite of numerous significant advances, the management of maxillofacial trauma remains a challenging problem for all reconstructive surgeons. From reading the literature, it can be assumed that maxillofacial trauma is rarely life threatening or an immediate cause of death, unless associated with airway compromise. We present our experience with 6 illustrative patients who either succumbed to complications or had life-threatening exsanguination secondary to isolated facial trauma.

A note on confidence intervals with extended least squares parameter estimates.

It has previously been shown that the extended least squares (ELS) method for fitting pharmacokinetic models behaves better than other methods when there is possible heteroscedasticity (unequal error variance) in the data. Confidence intervals for pharmacokinetic parameters, at the target confidence level of 95%, computed in simulations with several pharmacokinetic and error variance models, using a theoretically reasonable approximation to the asymptotic covariance matrix of the ELS parameter estimator, are found to include the true parameter values considerably less than 95% of the time. Intervals with the ordinary least squares method perform better. Two adjustments to the ELS confidence intervals, taken together, result in better performance. These are: (i) apply a bias correction to the ELS estimate of variance, which results in wider confidence intervals, and (ii) use confidence intervals with a target level of 99% to obtain confidence intervals with actual level closer to 95%. Kineticists wishing to use the ELS method may wish to use these adjustments.