Richard A. Olshen

The Development of Mature Gait

The development of mature gait. D Sutherland;R Olshen;L Cooper;S Woo; The Journal of Bone & Joint Surgery

Intraperitoneal Cisplatin with Systemic Thiosulfate Protection

Seventeen patients with intraperitoneal tumors were treated by 4-hour intraperitoneal dialysis with cisplatin alone, or in combination with an intravenous neutralizing agent, sodium thiosulfate. Cisplatin alone, 90 mg/m2 body surface area intraperitoneally, produced nephrotoxicity. When intraperitoneal cisplatin therapy was combined with intravenous thiosulfate treatment, the dose of cisplatin could be escalated to 270 mg/m2 body surface area without causing an increase in serum creatinine levels or undue myelosuppression. Even at doses up to 270 mg/m2, no local toxicity occurred. The peak peritoneal concentration of free reactive cisplatin averaged 21-fold higher than the plasma level, and the area under the peritoneal cisplatin elimination curve averaged 12-fold more than the area under the plasma curve. Neither of these ratios varied significantly with cisplatin dose. Regression of intraperitoneal tumor masses was observed in patients with far-advanced ovarian carcinoma, mesothelioma, and malignant carcinoid.

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.

Evaluating quality of compressed medical images: SNR, subjective rating, and diagnostic accuracy

Compressing a digital image can facilitate its transmission, storage, and processing. As radiology departments become increasingly digital, the quantities of their imaging data are forcing consideration of compression in picture archiving and communication systems (PACS) and evolving teleradiology systems. Significant compression is achievable only by lossy algorithms, which do not permit the exact recovery of the original image. This loss of information renders compression and other image processing algorithms controversial because of the potential loss of quality and consequent problems regarding liability, but the technology must be considered because the alternative is delay, damage, and loss in the communication and recall of the images. How does one decide if an image is good enough for a specific application, such as diagnosis, recall, archival, or educational use? The authors describe three approaches to the measurement of medical image quality: signal-to-noise ratio (SNR), subjective rating, and diagnostic accuracy. They compare and contrast these measures in a particular application, consider in some depth recently developed methods for determining diagnostic accuracy of lossy compressed medical images and examine how good the easily obtainable distortion measures like SNR are at predicting the more expensive subjective and diagnostic ratings. The examples are of medical images compressed using predictive pruned tree-structured vector quantization, but the methods can be used for any digital image processing that produces images different from the original for evaluation. >

New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients

BackgroundCurrent practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.MethodsWe constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.Results285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.ConclusionWe present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets.

Th17 and Th1 T-cell responses in giant cell arteritis.

Background— In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. Methods and Results— The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-&ggr; and interleukin (IL)-17 and frequencies of interferon-&ggr;-producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1&bgr;, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. Conclusions— Two pathogenic pathways mediated by Th17 and Th1 cells contribute to the systemic and vascular manifestations of GCA. IL-17-producing Th17 cells are sensitive to glucocorticoid-mediated suppression, but interferon-&ggr;-producing Th1 responses persist in treated patients. Targeting steroid-resistant Th1 responses will be necessary to resolve chronic smoldering vasculitis. Monitoring Th17 and Th1 frequencies can aid in assessing disease activity in GCA.

Systematic Review: A Century of Inhalational Anthrax Cases from 1900 to 2005

Key Summary Points Initiation of antibiotic or anthrax antiserum therapy during the prodromal phase of inhalational anthrax is associated with an improved short-term survival. Multidrug antibiotic regimens are associated with decreased mortality, especially when they are administered during the prodromal phase. Most surviving patients will probably require drainage of reaccumulating pleural effusions. Despite modern intensive care, fulminant-phase anthrax is rarely survivable. The 2001 anthrax attack demonstrated the vulnerability of the United States to anthrax bioterrorism. The mortality rate observed during the 2001 U.S. attack (45%) was considerably lower than that historically reported for inhalational anthrax (89% to 96%) (1, 2). This reduction generally is attributed to the rapid provision of antibiotics and supportive care in modern intensive care units (3). However, no comprehensive reviews of reports of inhalational anthrax cases (including those from 2001) that evaluate how patient factors and therapeutic interventions affect disease progression and mortality have been published. Before the introduction of antibiotics, anthrax infection was primarily treated with antiserum (4). Anthrax antiserum reportedly decreased mortality by 75% compared with no treatment (5-8), and its efficacy is supported by recent animal data (9). Later, effective antibiotics, such as penicillin and chloramphenicol, were added to anthrax treatment strategies (10, 11). Currently, combination antibiotic therapy with ciprofloxacin (or doxycycline), rifampin, and clindamycin is recommended on the basis of anecdotal evidence from the U.S. 2001 experience (1, 12, 13). Historically, the clinical course of untreated inhalational anthrax has been described as biphasic, with an initial benign prodromal latent phase, characterized by a nonspecific flu-like syndrome, followed by a severe fulminant acute phase, characterized by respiratory distress and shock that usually culminates in death (2, 14). The duration of the prodromal phase has been reported to range from 1 to 6 days (14, 15), whereas that of the fulminant phase has been described as less than 24 hours (14, 16). A 1957 study confirmed these estimates of disease progression but was based on only 6 patients (17). Because a report synthesizing the data from all reported cases of inhalational anthrax (including those from 2001) has not been published, we do not have accurate estimates of the time course associated with disease progression or a clear understanding of the extent to which patient characteristics and treatment factors affect disease progression and mortality. This information is important for developing appropriate treatment and prophylaxis protocols and for accurately simulating anthrax-related illness to inform planning efforts for bioterrorism preparedness. We systematically reviewed published cases of inhalational anthrax between 1900 and 2005 to evaluate the effects of patient factors (for example, age and sex) and therapeutic factors (for example, time to onset of treatment) on disease progression and mortality. Methods Literature Sources and Search Terms We searched MEDLINE to identify case reports of inhalational anthrax (January 1966 to June 2005) by using the Medical Subject Heading (MeSH) terms anthrax and case reports. Because many reports were published before 1966 (the earliest publication date referenced in MEDLINE), we performed additional comprehensive searches of retrieved bibliographies and the indexes of 14 selected journals from 1900 to 1966 (for example, New England Journal of Medicine, The Lancet, La Presse Mdicale, Deutsche Medizinische Wochenschrift, and La Semana Mdica) to obtain additional citations. We considered all case reports of inhalational anthrax to be potentially eligible for inclusion, regardless of language. Study Selection We considered a case report to be eligible for inclusion if its authors established a definitive diagnosis of inhalational anthrax. Appendix Table 1 presents the details of our inclusion criteria. We excluded articles that described cases presenting before 1900 because Bacillus anthracis was not identified as the causative agent of clinical inhalational anthrax until 1877 (18) and because the use of reliable microscopic (19) and culture examination techniques (20) to confirm the diagnosis were not developed until the late 19th century. Appendix Table 1. Inclusion Criteria Data Abstraction One author screened potentially relevant articles to determine whether they met inclusion criteria. Two authors independently abstracted data from each included English-language article and reviewed bibliographies for additional potentially relevant studies. One author abstracted data from nonEnglish-language articles. We resolved abstraction discrepancies by repeated review and discussion. If 2 or more studies presented the same data from 1 patient, we included these data only once in our analyses. We abstracted 4 types of data from each included article: year of disease onset, patient information (that is, age, sex, and nationality), symptom and disease progression information (for example, time of onset of symptoms, fulminant phase, and recovery or death and whether the patient developed meningitis), and treatment information (for example, time and disease stage of the initiation of appropriate treatment and hospitalization). We based our criteria for determining whether a patient had progressed from the prodromal phase to the fulminant phase on distinguishing clinical features of five 2001 (3, 21, 22) and five 1957 (17) cases of fulminant inhalational anthrax. The fulminant phase is described historically as a severe symptomatic disease characterized by abrupt respiratory distress (for example, dyspnea, stridor, and cyanosis) and shock. Meningoencephalitis has been reported to occur in up to 50% of cases of fulminant inhalational anthrax (23). We considered any patient who had marked cyanosis with respiratory failure, who needed mechanical ventilation, who had meningoencephalitis, or who died as having been in the fulminant phase of disease. We used the reported time of an acute change in symptoms or deteriorating clinical picture to estimate when a confirmed fulminant case had progressed from the prodromal phase. We considered therapy for inhalational anthrax to be appropriate if either an antibiotic to which anthrax is susceptible was given (by oral, intramuscular, or intravenous routes) (24-27) or anthrax antiserum therapy was initiated. We classified patients who received antibiotics that are resistant to strains of B. anthracis (<70% susceptibility) as having received no antibiotics. If treatment with antibiotics or antiserum was given, we assumed that the treatment was appropriately dosed and administered. Statistical Analyses We used univariate analyses with SAS software, version 9.1 (SAS Institute Inc., Cary, North Carolina), to summarize the key patient and treatment characteristics. We compared categorical variables with the Fisher exact test and continuous variables with a 2-tailed WilcoxonMannWhitney test. For single comparisons, we considered a P value less than 0.05 to be statistically significant. When comparing U.S. 2001 with pre-2001 cases (or comparing patients who lived with those who died), we applied a Bonferroni correction to account for multiple comparisons (we considered P< 0.025 to be statistically significant: 0.05/2 = 0.025). We computed correlations for pairs of predictors available for each case at the beginning of the course of disease. Adjustments for Censored Data Infectious disease data are subject to incomplete observations of event times (that is, to censoring), particularly in the presence of therapeutic interventions. This can lead to invalid estimation of relevant event time distributions. For example, patients with longer prodromal stage durations are more likely to receive antibiotics than patients with shorter prodromal stage durations, and they may be, therefore, less likely to progress to fulminant stage or death. To account for censoring of our time data, we used maximum likelihood estimates by using both Weibull and log-normal distributions (28). The Appendix provides a detailed description of these analyses. Evaluating Predictors of Disease Progression and Mortality We used a multivariate Cox proportional hazards model to evaluate the prognostic effects of the following features on survival: providing antibiotics or antiserum (a time-dependent covariate in 3 categories: none, single-drug regimen, or multidrug regimen); the stage during which treatment with antibiotics or antiserum was initiated (prodromal stage vs. fulminant stage or no therapy); age (continuous variable); sex; if therapy was given, whether patients received a multidrug regimen (for example, 2 appropriate antibiotics or combination antibioticanthrax antiserum therapy); the use of pleural fluid drainage (a time-dependent covariate); development of anthrax meningoencephalitis (a time-dependent covariate); and whether the case was from the 2001 U.S. attack. We assessed each variable by stepwise backward regression using a P value cutoff of 0.100 or less. We excluded 8 adult patients for whom age was not reported. Although we did not perform extensive goodness-of-fit tests of our models, we did at least fit models in which we entered time not only linearly but also quadratically. Improvement in fit, as judged by conventional Wald and other tests, did not result, nor did including quadratic time variables further explain the data. To estimate mortality as a function of duration from symptom onset to antibiotic initiation, we first calculated a disease progression curve describing the time from symptom onset to fulminant phase among untreated patients by using the Weibull maximum likelihood estimates from the 71 cases for which time estimates were known. We then assigned a mortality rate to patients who had treatmen

Diversity and clonal selection in the human T-cell repertoire

Significance A decline in the diversity of the T-cell receptor repertoire owing to thymic involution has been implicated as causing defective immune responses in the elderly. By applying next-generation sequencing of replicate TCRB libraries from highly purified T-cell subsets, and using nonparametric statistical analysis, we obtain estimates of repertoire richness in the young adult that are higher than previously reported. Although contracting with age, the repertoire remains highly diverse. These data challenge the paradigm that thymic rejuvenation is needed to maintain diversity and prevent immune incompetence in the elderly. However, we observe an increasing inequality of clonal sizes with age even among naïve T cells. This clonal selection could result in biased and possibly autoreactive immune responses. T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini–Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.

A Polymorphism in the β1 Adrenergic Receptor Is Associated with Resting Heart Rate

Resting heart rate is significantly associated with cardiovascular morbidity and mortality. However, the extent to which resting heart rate is genetically determined is poorly understood, and no genes have been found that contribute to variation in resting heart rate. Because signaling through the beta1 adrenergic receptor is a key determinant of cardiac function, we tested whether polymorphisms in this receptor are associated with resting heart rate. A cohort of >1,000 individuals of Chinese and Japanese descent, from nuclear families, was genotyped for two polymorphisms, resulting in a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly), in the beta1 adrenergic receptor. For comparison, polymorphisms in the beta2 and beta3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated (P=.0004) with resting heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data support an additive model in which individuals heterozygous for the Ser49Gly polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the Arg389Gly polymorphism in the beta1 adrenergic receptor nor polymorphisms in the beta2 and beta3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% +/- 7.1% (P<10-7).

Multiresolution image classification by hierarchical modeling with two-dimensional hidden Markov models

This paper treats a multiresolution hidden Markov model for classifying images. Each image is represented by feature vectors at several resolutions, which are statistically dependent as modeled by the underlying state process, a multiscale Markov mesh. Unknowns in the model are estimated by maximum likelihood, in particular by employing the expectation-maximization algorithm. An image is classified by finding the optimal set of states with maximum a posteriori probability. States are then mapped into classes. The multiresolution model enables multiscale information about context to be incorporated into classification. Suboptimal algorithms based on the model provide progressive classification that is much faster than the algorithm based on single-resolution hidden Markov models.