Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection.

The toxicity and pharmacokinetics of cis-diamminedichloroplatinum (cisplatin) (90 mg/sq m) administered as a single 4-hr peritoneal dialysis, with or without concurrent i.v. infusion of sodium thiosulfate, 0.43 or 2.13 g/sq m/hr for 12 hr, were studied on 20 courses of treatment. When given without thiosulfate, the toxicity of cisplatin was systemic rather than local, and the peritoneal cavity/plasma ratio of the area under the curve was 12. Addition of i.v. thiosulfate significantly reduced the nephrotoxicity. The concentration of cisplatin in the peritoneal cavity was sufficiently greater than that in the plasma to prevent thiosulfate, which equilibrated into the cavity, from interfering with the antitumor activity of cisplatin in the peritoneum. This study demonstrates a pharmacokinetic advantage of i.p. chemotherapy with cisplatin.

Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis.

While diffuse large-cell lymphoma (DLCL) is considered to be highly curable with current therapy, treatment failures are observed even with intensive combination chemotherapy regimens. In order to study the prognostic significance of actual dose intensity of chemotherapy in DLCL, we retrospectively analyzed 115 previously untreated patients treated as Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclosphosphamide, vincristine, prednisone, and bleomycin (MACOP-B). The actual relative dose intensity (RDI), the amount of drug actually administered to each patient during the first 12 weeks of therapy, was calculated as standardized to CHOP and analyzed in addition to clinical factors prognostic for survival by univariate analysis. Multivariate recursive partitioning (tree-structured) survival analysis identified the actual RDI of Adriamycin greater than 75% as the single most important predictor of survival. A model incorporating the actual RDI of Adriamycin and performance status, in combination with serum lactate dehydrogenase (LDH) and extranodal disease, defined three overall prognostic groups of patients with respective 3-year survival rates of 89%, 63%, and 18%. The three prognostic groups remained distinct, even when restricted to complete responders. This model was also predictive of survival when dose intensity was analyzed relative to the optimum dose defined for each of the three regimens and when applied to a subgroup of patients aged 50 years or younger. We conclude that actual RDI is an important prognostic factor for survival in DLCL and that analysis of RDI early in the course of treatment may allow modification of the treatment plan.

Effect of treatment for Hodgkin's disease on pulmonary function: results of a prospective study.

PURPOSE: Because each of very different treatments for Hodgkin's disease (HD) may result in a high rate of cure, attention is currently focused on toxicity. This prospective study was designed to assess the effects of mediastinal irradiation and bleomycin chemotherapy on pulmonary function. PATIENTS AND METHODS: Patients were treated from 1980 to 1990 on randomized controlled trials at Stanford University. Pulmonary function was tested before treatment (baseline), early after treatment (< 15 months), and more than 36 months posttherapy. Treatment options in the 145 patients were grouped as I (mediastinal radiotherapy), II (mediastinal radiotherapy plus bleomycin), and III (bleomycin) for analyses of variance (ANOVAs). A variety of regression models were used to predict early and late effects on pulmonary function. RESULTS: A decrease in forced vital capacity (FVC) and diffusing capacity (DLCO) in the first 15 months after treatment followed by recovery after 36 months was observed for most patients. Patients who received mediastinal radiotherapy (RT) had a more pronounced reduction in pulmonary function and less complete recovery. Overall, 3 or more years after treatment, 32% of group I patients, 37% of group II patients, and 19% of group III patients had FVC values less than 80% of predicted, while only 7% of patients had a DLCO less than 80% of predicted. Linear regression identified baseline measurement as the only significant predictor of change in percent predicted FVC or DLCO; patients with higher baseline values had greater decrements after therapy. Mantle RT was the only significant treatment variable, predictive of FVC and DLCO within 15 months and FVC at 36 or more months. No patient experienced pulmonary toxicity severe enough to require hospitalization. CONCLUSION: This prospective analysis of pulmonary function after treatment for HD showed that mediastinal RT was the only treatment variable that achieved statistical significance. Although there were no significant interactions between mediastinal RT and bleomycin or Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) chemotherapy, the patient numbers were small after correction for mediastinal mass size and drug regimen such that an effect could have been missed. The mild reduction in pulmonary function should be factored into the overall assessment of morbidity risk for each of the potentially curative treatments included in this study. As with all reports of late effects, these data should be interpreted with respect to the population tested, details of the treatment administered, methods of measurement, and length of follow-up.

Effect of probenecid on cerebrospinal fluid methotrexate kinetics.

The effect of probenecid (PBC) on methotrexate (MTX) kinetics in the cerebrospinal fluid (CSF) and serum was studied in 4 patients on high-dose MTX with leucovorin rescue to determine whether addition of PBC could prolong effective CSF MTX levels. Each patient received 2 courses of MTX, 1 with and 1 without PBC. PBC caused a 2.8 to 4.2-fold increase in CSF MTX concentrations but failed to prolong the CSF half-life (1 1/2). PBC prolonged the initial MTX elimination t 1/2 in the blood from 2.7 to 4.1 hr, but had little effect on subsequent t 1/2s. No effect of MTX on PBC clearance was detected. Our data suggest that in man PBC in concentrations that were high enough to inhibit the renal clearance of MTX failed to alter the clearance of MTX from the CSF when both drugs were administered systemically.

Covariability of V3 loop amino acids.

We reanalyzed for covariability a set of 308 human immunodeficiency virus type 1 (HIV-1) V3 loop amino acid sequences from the B envelope sequence subtype previously analyzed by Korber et al.,1 as well as a new set of 440 sequences that also included substantial numbers of sequences from subtypes A, D, and E. We used the measure employed by Korber et al., essentially the likelihood ratio statistic for independence, plus two additional measures as well as clade information to examine the new set and both data sets simultaneously. We set forth the following conclusions and observations. The eight most highly connected sites identified through these statistical approaches included all of the six residues previously shown to have determining roles in structure, immunologic recognition, virus phenotype, and host range; each of the seven pairs of covariant sites found by Korber were signaled by our additional two measures in the set of 308 sequences, although 2 or 3 dropped out of the examination of the set of 440 when the requirement of stringent significance was applied for some or all of the three tests, respectively; using the same criteria, a total of 20 (including 5 Korber et al. pairs) or a total of 6 (including 4 Korber et al. pairs) were found when the set of 440 was added. Several limitations to statistical analysis of this type of HIV sequence data were also noted. For example, the data sets were, by historical necessity, collected haphazardly. For example, it was not possible to separate substantially sized groups out according to time of or since infection, disease status, antiviral treatment, geography, etc. There was also an enormous "wealth of significance" within the data. For example, for one measure the 440 data set showed 233 of the 465 pairs of sites with a likelihood ratio statistic of < 0.001. Last, most sites had consensus amino acids in 80% or more of the sequences; hence, there was an absence of data on many combinations of amino acids. Given the observed linkage between sites shown to be covariable and those known to have critical biological function, the statistical approaches we and Korber et al. have outlined may find use in predicting critical structural features of HIV proteins as targets for therapeutic intervention.

Clustering and the design of preference-assessment surveys in healthcare.

OBJECTIVE: To show cluster analysis as a potentially useful tool in defining common outcomes empirically and in facilitating the assessment of preferences for health states. DATA SOURCES: A survey of 224 patients with ventricular arrhythmias treated at Kaiser Permanente of Northern California. STUDY DESIGN/METHODS: Physical functioning was measured using the Duke Activity Status Index (DASI), and mental status and vitality using the Medical Outcomes Study Short Form-36 items (SF-36). A "k-means" clustering algorithm was used to identify prototypical health states, in which patients in the same cluster shared similar responses to items in the survey. PRINCIPAL FINDINGS: The clustering algorithm yielded four prototypical health states. Cluster 1 (21 percent of patients) was characterized by high scores on physical functioning, vitality, and mental health. Cluster 2 (33 percent of patients) had low physical function but high scores on vitality and mental health. Cluster 3 (29 percent of patients) had low physical function and low vitality but preserved mental health. Cluster 4 (17 percent of patients) had low scores on all scales. These clusters served as the basis of written descriptions of the health states. CONCLUSIONS: Employing a clustering algorithm to analyze health status survey data enables researchers to gain a data-driven, concise summary of the experiences of patients.

Empirically defined health states for depression from the SF-12.

OBJECTIVE: To define objectively and describe a set of clinically relevant health states that encompass the typical effects of depression on quality of life in an actual patient population. Our model was designed to facilitate the elicitation of patients' and the public's values (utilities) for outcomes of depression. DATA SOURCES: From the depression panel of the Medical Outcomes Study. Data include scores on the 12-Item Short Form Health Survey (SF-12) as well as independently obtained diagnoses of depression for 716 patients. Follow-up information, one year after baseline, was available for 166 of these patients. METHODOLOGY: We use k-means cluster analysis to group the patients according to appropriate dimensions of health derived from the SF-12 scores. Chi-squared and exact permutation tests are used to validate the health states thus obtained, by checking for baseline and longitudinal correlation of cluster membership and clinical diagnosis. PRINCIPAL FINDINGS: We find, on the basis of a combination of statistical and clinical criteria, that six states are optimal for summarizing the range of health experienced by depressed patients. Each state is described in terms of a subject who is typical in a sense that is articulated with our cluster-analytic approach. In all of our models, the relationship between health state membership and clinical diagnosis is highly statistically significant. The models are also sensitive to changes in patients' clinical status over time. CONCLUSIONS: Cluster analysis is demonstrably a powerful methodology for forming clinically valid health states from health status data. The states produced are suitable for the experimental elicitation of preference and analyses of costs and utilities.

Tree-structured vector quantization of CT chest scans: image quality and diagnostic accuracy.

The authors apply a lossy compression algorithm to medical images, and quantify the quality of the images by the diagnostic performance of radiologists, as well as by traditional signal-to-noise ratios and subjective ratings. The authors' study is unlike previous studies of the effects of lossy compression in that they consider nonbinary detection tasks, simulate actual diagnostic practice instead of using paired tests or confidence rankings, use statistical methods that are more appropriate for nonbinary clinical data than are the popular receiver operating characteristic curves, and use low-complexity predictive tree-structured vector quantization for compression rather than DCT-based transform codes combined with entropy coding. The authors' diagnostic tasks are the identification of nodules (tumors) in the lungs and lymphadenopathy in the mediastinum from computerized tomography (CT) chest scans. Radiologists read both uncompressed and lossy compressed versions of images. For the image modality, compression algorithm, and diagnostic tasks the authors consider, the original 12 bit per pixel (bpp) CT image can be compressed to between 1 bpp and 2 bpp with no significant changes in diagnostic accuracy. The techniques presented here for evaluating image quality do not depend on the specific compression algorithm and are useful new methods for evaluating the benefits of any lossy image processing technique.

Pruned tree-structured vector quantization of medical images with segmentation and improved prediction.

The authors use predictive pruned tree-structured vector quantization for the compression of medical images. Their goal is to obtain a high compression ratio without impairing the image quality, at least so far as diagnostic purposes are concerned. The authors use a priori knowledge of the class of images to be encoded to help them segment the images and thereby to reserve bits for diagnostically relevant areas. Moreover, the authors improve the quality of prediction and encoding in two additional ways: by increasing the memory of the predictor itself and by using ridge regression for prediction. The improved encoding scheme was tested via computer simulations on a set of mediastinal CT scans; results are compared with those obtained using a more conventional scheme proposed recently in the literature. There were remarkable improvements in both the prediction accuracy and the encoding quality, above and beyond what comes from the segmentation. Test images were encoded at 0.5 bit per pixel and less without any visible degradation for the diagnostically relevant region.

Bayes risk weighted vector quantization with posterior estimation for image compression and classification.

Classification and compression play important roles in communicating digital information. Their combination is useful in many applications, including the detection of abnormalities in compressed medical images. In view of the similarities of compression and low-level classification, it is not surprising that there are many similar methods for their design. Because some of these methods are useful for designing vector quantizers, it seems natural that vector quantization (VQ) is explored for the combined goal. We investigate several VQ-based algorithms that seek to minimize both the distortion of compressed images and errors in classifying their pixel blocks. These algorithms are investigated with both full search and tree-structured codes. We emphasize a nonparametric technique that minimizes both error measures simultaneously by incorporating a Bayes risk component into the distortion measure used for the design and encoding. We introduce a tree-structured posterior estimator to produce the class posterior probabilities required for the Bayes risk computation in this design. For two different image sources, we demonstrate that this system provides superior classification while maintaining compression close or superior to that of several other VQ-based designs, including Kohonen's (1992) "learning vector quantizer" and a sequential quantizer/classifier design.

Tree-structured survival analysis.

In this note, tree-structured recursive partitioning schemes for classification, probability class estimation, and regression are adapted to cover censored survival analysis. The only assumptions required are those which guarantee identifiability of conditional distributions of lifetime given covariates. Thus, the techniques are applicable to more general situations than are those of the famous semi-parametric model of Cox.

Probability estimation for biomedical classification problems.

Suppose that we wish to know the probability that an object belongs to a class. For example, we may wish to estimate the probability that a patient has a particular disease, given a set of symptoms, or we may wish to know the probability that a novel peptide binds to a receptor, given the peptide's amino-acid composition. The conventional approach is to first use a classification algorithm to find partitions in feature space and to assign each partition to a class, and then to estimate the conditional probabilities as the proportion of patients or peptides that are correctly and incorrectly classified in each partition. Unfortunately, this estimation method often gives probability estimates that are in error by 20% or more, and thus can cause incorrect decisions. We have implemented and compared alternative methods. In Monte Carlo simulations the alternative methods are substantially more accurate than is the current method.

Angiotensin-converting enzyme inhibitor for slowing progression of diabetic and nondiabetic kidney disease.

A growing body of evidence suggests that agents that inhibit the angiotensin-converting enzyme are renoprotective. In experimental animal models of chronic renal injury, such renoprotection can virtually eliminate progression of the renal injury, provided that therapy is started at the time of injury. In humans with chronic renal injury, renoprotection has been successfully demonstrated only late in the course of the renal disease. The rate of progression to end-stage renal failure can be delayed, but progression continues at a slower pace. Further study is required to determine whether earlier intervention can better preserve nephron structure and function. A strategy for future trials is recommended. It emphasizes more sensitive outcome measures so as to achieve greater statistical power.

Statistical analysis of gait patterns of persons with cerebral palsy.

Patients at Boston's Children's Hospital diagnosed as having cerebral palsy were filmed walking. These films were digitized and translated into measurements associated with leg motion. In this paper we use the gait measurements of 128 such patients to illustrate the the kth nearest neighbour clustering procedure results in a gait typology for patients with cerebral palsy. The procedure identifies four subpopulations from the sample data; the membership of a patient within this typology is mostly determined by the patient's motor control. The developed typology differs from the present diagnostic system which classifies a cerebral palsy patient as either quadriplegic, diaplegic or hemiplegic.

Intraperitoneal chemotherapy with melphalan.

We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to dwell in the peritoneal cavity for 4 hours. No local toxicity was detected by clinical examination, laboratory tests, or histologic examination. The intraperitoneal route allowed the dose to be increased to approximately three times the maximum dose tolerated intravenously before drug leaking into the systemic circulation produced dose-limiting myelosuppression. The peak peritoneal concentration averaged 93-fold greater than the plasma concentration, and total drug exposure for the peritoneal cavity averaged 63-fold greater than that for plasma. Tumor regressions were observed in patients with ovarian carcinoma and gastrointestinal adenocarcinomas. This study shows that from the pharmacologic point of view, if any portion of the tumor can be reached by intraperitoneal instillation, then there is a very strong rationale for the administration of melphalan by the intraperitoneal route, rather than the oral or intravenous route, for the treatment of tumors confined to the peritoneal cavity.

PAH extraction and estimation of plasma flow in diseased human kidneys.

We have analyzed the efficiency with which p-amino-hippuric acid (PAH) is extracted (EPAH) by patients with healthy kidneys (n = 13) or kidneys damaged by chronic cyclosporin nephropathy (n = 21) or primary glomerulopathy (n = 12); respective values (mean +/- SE) for EPAH were 0.87 +/- 0.03, 0.77 +/- 0.03, and 0.69 +/- 0.04. Judged by a 131I-hippuran-to-PAH clearance ratio of 0.75 +/- 0.05, extraction ratio of hippuran was less efficient than EPAH in three glomerulopathic patients. A direct relationship was defined between EPAH and glomerular filtration rate (GFR) (r = 0.54) or calculated efferent oncotic pressure (IIE; r = 0.41, P less than 0.01). Curve fitting by means of quadratic spline functions revealed GFR and IIE to be additive in predicting EPAH (R2 = 0.45). Linear model prediction methods and a sample reuse technique failed to predict EPAH reliably from GFR and preglomerular oncotic pressure (IIA); however, 95% prediction intervals exceed 0.30 EPAH units in width. We conclude that oncotic pressure (presumably reflecting albumin concentration) along with GFR is predictive of EPAH depression in humans with chronic renal disease. However, even sophisticated curve-fitting techniques are too imprecise for accurate prediction of EPAH in a given individual. We submit that renal venous sampling to determine EPAH continues to be necessary for the accurate determination of the rate of plasma flow in the injured human kidney.

Modeling of progressive glomerular injury in humans with lupus nephritis.

We studied glomerular function longitudinally for 36-120 mo in 21 patients undergoing treatment for diffuse, proliferative lupus nephritis. We determined glomerular filtration rate (GFR) and glomerular oncotic pressure (IIGC) and computed the two-kidney ultrafiltration coefficient (Kf) at 6- to 12-mo intervals. The relationships and cross talk among the three variables over time were then analyzed by eigenfunction regression and canonical correlations. We also performed a morphometric analysis of serial biopsies and computed single-nephron Kf in patent glomeruli at baseline and after 36-94 mo of follow-up. Patients were divisible into progressors (n = 12) or nonprogressors (n = 9) according to the presence or absence, respectively, of an irrevocable decline in GFR over time. Examination of longitudinal variables revealed GFR to be strongly related to Kf in all patients and inversely related to IIGC in progressors. By serial morphometric analysis we observed a threefold increase in the prevalence of global sclerosis in progressors but unchanged prevalence in nonprogressors. Whereas single-nephron Kf of remnant glomeruli increased to supernormal levels in nonprogressors, the absence of this compensatory phenomenon in progressors permitted GFR and Kf to decline in parallel with the declining number of functional glomeruli.

Predicting chemically induced duodenal ulcer and adrenal necrosis with classification trees.

Binary tree-structured statistical classification algorithms and properties of 56 model alkyl nucleophiles were brought to bear on two problems of experimental pharmacology and toxicology. Each rat of a learning sample of 745 was administered one compound and autopsied to determine the presence of duodenal ulcer or adrenal hemorrhagic necrosis. The cited statistical classification schemes were then applied to these outcomes and 67 features of the compounds to ascertain those characteristics that are associated with biologic activity. For predicting duodenal ulceration, dipole moment, melting point, and solubility in octanol are particularly important, while for predicting adrenal necrosis, important features include the number of sulfhydryl groups and double bonds. These methods may constitute inexpensive but powerful ways to screen untested compounds for possible organ-specific toxicity. Mechanisms for the etiology and pathogenesis of the duodenal and adrenal lesions are suggested, as are additional avenues for drug design.

Intracellular reduction of selenite into glutathione peroxidase. Evidence for involvement of NADPH and not glutathione as the reductant.

Selenium (Se) in selenite is present in an oxidized state, and must be reduced for it to be incorporated as selenocysteine into selenoenzymes such as glutathione peroxidase (GPx). In vitro, Se, as in selenite, can be reduced utilizing glutathione (GSH) and glutathione reductase (GRed). We determined the effects of decreasing GSH levels, inhibiting GRed activity, and decreasing cellular NADPH on the selenite-dependent rate of GPx synthesis in cultured cells: PC3, CHO, and the E89 glucose-6-phosphate dehydrogenase (G-6-PD)-deficient cell line. A novel statistical analysis method was developed (using Box Cox transformed regression and a bootstrap method) in order to assess the effects of these manipulations singly and in combinations. Buthionine sulfoximine (BSO) was used to decrease GSH levels, 1,3 bis-(2 chloroethyl)-1 -nitrosourea (BCNU) was used to inhibit GRed activity and methylene blue (MB) was used to decrease cellular NADPH levels. This statistical method evaluates the effects of BSO, BCNU, MB and selenite alone and in combinations on GPx activity. Decreasing the GSH level (< 5% of control) did not have an effect on the selenite-dependent rate of GPx synthesis in PC3 or CHO cells, but did have a small inhibitory effect on the rate of GPx synthesis in E89 cells. Inhibiting GRed activity was also associated with either no effect (CHO, E89) or a small effect (PC3) on GPx activity. In contrast, decreasing NADPH levels in cells treated with MB was associated with a large decrease in the selenite-dependent rate of GPx synthesis to 36, 34 and 25% of control in PC3, CHO, and E89 cells, respectively. The effects of BSO plus BCNU were not synergistic in any of the cell lines. The effects of BSO plus MB were synergistic in G-6-PD-deficient E89 cells, but not in PC3 or CHO cells. We therefore conclude that under normal culture conditions, NADPH, and not glutathione, is the primary reductant of Se in selenite to forms that are eventually incorporated into GPx. For cells with abnormal ability to generate NADPH, lowering the GSH levels had a small effect on selenite-dependent GPx synthesis. GRed activity is not required for the selenite-dependent synthesis of GPx.

Relationships among protein and albumin concentrations and oncotic pressure in nephrotic plasma.

We determined oncotic pressure (pi) by membrane osmometry and assayed total protein (TP) and albumin (Alb) concentrations in plasma of 102 nephrotic subjects and 27 healthy controls. All three quantities were markedly depressed in the nephrotic group. When plasma was serially diluted and concentrated, nephrotic but not control plasma also exhibited a highly variable change point in the nonlinear relationship between TP or Alb and pi. Absent a unique change point, we developed quadratic models which incorporated TP, Alb, and (TP x Alb) to prospectively predict pi in unperturbed plasma. The ability of the most successful quadratic model to predict pi in afferent or efferent arteriolar plasma was limited; the prediction errors reached 10 mmHg in nephrotic and 6 mmHg in control subjects. The nephrotic model coefficients also differed significantly from control and pointed to an important influence of nonalbumin proteins on pi in nephrotic plasma. Investigation of the intrinsic membrane properties of diseased glomerular capillary walls requires precise knowledge of pi. For this purpose we recommend that pi be directly determined by membrane osmometry rather than calculated from protein concentration(s).