Despite the prognostic importance of mitotic count as one of the components of the Bloom – Richardson grade [3], several studies ([2, 9, 10]) have found that pathologists’ agreement on the mitotic grade is fairly modest. Collecting a set of more than 4,200 candidate mitotic figures, we evaluate pathologists' agreement on individual figures, and train a computerized system for mitosis detection, comparing its performance to the classifications of three pathologists. The system’s and the pathologists’ classifications are based on evaluation of digital micrographs of hematoxylin and eosin stained breast tissue. On figures where the majority of pathologists agree on a classification, we compare the performance of the trained system to that of the individual pathologists. We find that the level of agreement of the pathologists ranges from slight to moderate, with strong biases, and that the system performs competitively in rating the ground truth set. This study is a step towards automatic mitosis count to accelerate a pathologist's work and improve reproducibility.

The hypothesis was tested among 83 patients with multiple lacunar infarctions that cerebral hypoperfusion will correlate with cognitive impairments. Patients were subdivided according to Cognitive Capacity Screening Examination (CCSE) scores into a cognitively impaired group (Group D, n = 40; mean age, 68.2 years) with CCSE scores between 6 and 25 (mean, 19.9) and a cognitively intact group (Group I, n = 43; mean age, 66.0) with normal scores (mean, 29.4). Gray and white matter tissue densities were measured by plain computed tomography (CT), and their compartmental perfusions were estimated during stable xenon inhalation. Eighty infarcts in basal ganglia and white matter were detected in Group D and 62 in Group I. Cognitive impairments correlated with (a) multiplicity and bilaterality of lacunes; (b) hypertension, diabetes mellitus, and multiplicity of risk factors for stroke; (c) hypoperfusion of white and gray matter, but particularly of frontal white matter; (d) leuko-araiosis; (e) aging; and (f) lower education. The conclusion was that hypertension and diabetes mellitus are potent risk factors for cerebral small vessel disease or arteriolosclerosis ultimately resulting in lacunar infarcts, leuko-araiosis, white matter hypoperfusion, and impaired cognitive test performance.

This article discusses whether diaschisis is an epiphenomenon or whether it truly has any clinical relevance. Because of my interest in diaschisis for the past 30 years, and because this laboratory has studied the phenomenon both clinically and experimentally, I will once again review the subject (1,2). Von Monakow (3), a Russian neurologist who was active at the turn of the 19th and 20th centuries, was the first to describe his clinical observations of depressed brain function that occurred at distances remote from localized injuries to the central nervous system (CNS). He was the first to propose the term diasch isis, by which he described a splitting apart of the brain to describe the phenomenon. Von Monakow postulated that diaschisis was caused by severance of afferent CNS connections via white matter fiber tracts. Since then, technical advances in neuroimaging including regional measurements of cerebral blood flow and metabolism have proven Von Monakow's concept to be correct, so that the term diaschisis is now used to cover all remote effects of localized CNS injury, including not only depressed function but the associated decreases in perfusion and metabolism. It has long been clinically obvious to neurologists, physiatrists, and neurophysiologists caring for patients with acute trauma to the cord that spinal shock results. This is characterized by widespread areflexia, hypotonia, and flaccid paralysis of the limbs extending beyond the level of the lesion and including loss of control of bowel and bladder with eventual partial or complete recovery within weeks or months, depending on the severity of the cord lesion. Controlled collaborative clinical trials have recently established that functional recovery following acute traumatic cord paralysis is hastened and im-

Journal of Surgical OncologyVolume 102, Issue 7 p. 717-718 Guest Editorial Competing roles of phenotype and genotype in prognosis of breast carcinoma: Enter the RNA expression profile John S. Meyer MD, Corresponding Author John S. Meyer MD john.meyer@stlukes-stl.com St. Luke's Hospital, Chesterfield, MissouriSt. Luke's Hospital, 232 S. Woods Mill Road, Chesterfield, MO 63017. Fax: 314 205-6870.Search for more papers by this author John S. Meyer MD, Corresponding Author John S. Meyer MD john.meyer@stlukes-stl.com St. Luke's Hospital, Chesterfield, MissouriSt. Luke's Hospital, 232 S. Woods Mill Road, Chesterfield, MO 63017. Fax: 314 205-6870.Search for more papers by this author First published: 03 September 2010 https://doi.org/10.1002/jso.21670Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume102, Issue71 December 2010Pages 717-718 RelatedInformation

CONTEXT:Mitotic figure counts are related to breast cancer behavior but have not been sufficiently reproducible to be accepted for clinical decision-making.OBJECTIVE:To improve reproducibility and accuracy of the mitotic count.DESIGN:Mitotic index (MI) was defined as the mitotic cell count per 10 high-power fields (HPFs), an area 0.183 mm(2). Two to 6 replicate sets of 10 HPFs were counted from 328 invasive breast carcinomas. Standard errors and coefficients of variation for mean MI were compared with expected results predicted by the binomial distribution.RESULTS:The boundaries for MI that separated the data into equal thirds (tertials) were 1.14 and 5.33. Standard errors and coefficients of variation for MI followed distributions predicted by binomial probability. Mean coefficient of variation was 147% for the low tertial, 72% for the midtertial, and 34.6% for the upper tertial.CONCLUSIONS:Standard errors for MI based on a single count of 10 HPFs are too broad and coefficients of variation too large to be acceptable for clinical use. This is explained as a binomial probability effect, possibly with a contribution from tumor heterogeneity. Errors can be reduced in proportion to the square root of the number of sets of 10 HPFs counted. Tertial cutoffs of MI of the Nottingham system currently used in breast carcinoma grading are too high to be applicable to the population we studied. We recommend validation of cutoffs before they are applied to a particular population of breast carcinomas. Counting 5 sets of 10 HPFs is necessary to accurately rank carcinomas with low MIs.

A mainstay in cancer diagnostics is the classification or grading of cell nuclei based on their appearance. While the analysis of cytological samples has been automated successfully for a long time, the complexity of histological tissue samples has prevented a reliable classification with machine vision techniques. We approach this complex problem in multiple stages, analyzing first image quality, staining quality, and tissue appearance, before segmenting nuclei and finally classifying or grading areas of tissue. The key step is the training of a classifier to judge the nuclei segmentation quality. Using active learning techniques, we train this classifier to identify problems in the image as well as weaknesses of the image analysis tools. This way we obtain robust nuclear segmentation allowing precise measurements of features that can be used safely for classification. We validate our findings on several hundred cases of breast cancer, demonstrating that automatic pleomorphism grading is possible with high accuracy. This technique can provide a stable and objective basis for what has been a subjective process that suffers from low reproducibility.

OBJECTIVE:Neuropsychological outcomes after carotid endarterectomy (CEA) have been investigated extensively. However, cognitive impacts of carotid angioplasty and stenting (CAS), an emerging alternative to CEA, have not been studied. This study is aimed at investigating pattern and degree of cognitive changes after CAS among patients with high-grade carotid stenosis.PATIENTS AND METHODS:Fifty-four patients with high-grade carotid artery stenosis and received elective CAS were followed. Sixty-six patients with similar medical conditions requiring carotid angiography (CAG) were enrolled as controls. Cognitive functions among patients in both groups were evaluated at baseline and follow-ups utilizing a battery of neuropsychometric tests. Results were analysed by inter-group and within-group comparisons.RESULTS:There were no statistically significant differences between CAS and CAG patients regarding demographic characteristics, risk factors for stroke and baseline cognitive performance (p>0.05). CAS patients performed significantly better than CAG patients in Rey auditory verbal learning tests (RAVLT) at week 1 (41.2 +/- 5.2 versus 37.4 +/- 4.0, p<0.001) and week 12 follow-ups (43.3 +/- 7.7 versus 37.3 +/- 4.5, p<0.001). Comparison of z score also indicated CAS patients improved significantly more than CAG patients in RAVLT at both weeks 1 (1.08 +/- 1.29 versus 0.25 +/- 0.99, p<0.001) and 12 follow-ups (1.62 +/- 1.95 versus 0.05 +/- 1.02, p<0.001).CONCLUSION:CAS patients demonstrated improvement in verbal memory after procedures. Correction of cerebral hypoperfusion and reduction of artery-to-artery embolization after CAS are postulated responsible for the cognitive improvement.

Questions of reproducibility and efficacy of histologic malignancy grading relative to alternative proliferation index measurements for outcome prediction remain unanswered. Microsections of specimens from the Cooperative Breast Cancer Tissue Resource (CBCTR) were evaluated by seven pathologists for reproducibility of grade and classification. Nuclear figure classification was assessed using photographs. Grade was assigned by the Bloom–Richardson method, Nottingham modification. Proliferation index was evaluated prospectively by deoxyribose nucleic acid precursor uptake with thymidine (autoradiographic) or bromodeoxyuridine (immunohistochemical) labeling index using fresh tissue from 631 node-negative breast cancer patients accessioned at St Luke's Hospital. A modified Nottingham–Bloom–Richardson grade was derived from histopathologic data. Median post-treatment observation was 6.4 years. Agreement on classification of nuclear figures ( N =43) was less than good by kappa statistic ( κ =0.38). Grade was moderately reproducible in four trials ( N =10,10,19, 10) with CBCTR specimens ( κ =0.50–0.59). Of components of Bloom–Richardson grade, agreement was least for nuclear pleomorphism ( κ =0.37–0.50), best for tubularity ( κ =0.57–0.83), and intermediate for mitotic count ( κ =0.45–0.64). Bloom–Richardson grade was a univariate predictor of prognosis in node-negative St Luke's patients, and was improved when mitotic count was replaced by labeling index (low, mid, or high). When labeling index was added to a multivariate model containing tumor size and vessel invasion, grade was no longer a significant predictor of tumor-specific relapse-free or overall survival. Mitotic index predicted best when intervals were lowered to 0–2, 3–10, and >10 mitotic figures per ten 0.18 mm 2 high-power fields. We conclude that Nottingham–Bloom–Richardson grades remain only modestly reproducible. Prognostically useful components of grade are mitotic index and tubularity. The Nottingham–Bloom–Richardson system can be improved by lowering cutoffs for mitotic index and by counting 20–30 rather than 10 high-power fields. Measurement of proliferation index by immunohistochemically detectable markers will probably give superior prognostic results in comparison to grade.

A prospective study of mean hemispheric cerebral blood flow (CBF) correlated with clinical status has now been completed for the past 54 months. Thirty-eight patients underwent superficial temporal to middle cerebral artery (STA-MCA) by-pass. They were compared with 22 patients with similar arteriographic lesions and clinical symptoms, treated medically throughout the same interval of time. Assignment to either treatment group was not randomized but depended solely on choice of patient or treating physician. Both groups were matched for age, clinical symptoms, angiographic abnormalities, and CBF values. All patients had proximal occlusion of one internal carotid artery or intracranial occlusive disease of the internal carotid or middle cerebral arteries. CBF measurements and clinical evaluations were repeated at regular intervals up to 54 months following surgery or institution of medical treatment. Mean follow up interval after STA-MCA by-pass was 28.7 months and for medical treatment was 29.7 months. Mean hemispheric CBF values for STA-MCA patients became significantly increased 2 weeks after operation. After that, CBF flow values decreased. At 24 months after surgery, flow values for surgically treated patients were significantly higher than among those treated medically, although there were no differences in flow values between the two groups at 3, 6,12, 36 and 48 months. Prospective clinical evaluations after STAMCA by-pass were as follows: 12 (32%) improved with cessation of TIAs and/or neurological improvement, 16 (42%) remained unchanged, 7 (18%) deteriorated (due to new or recurrent strokes) and 3 (8%) expired. Clinical results were the same for medical treatment: 6 (27%) improved, 10 (46%) unchanged, 4 (18%) deteriorated due to new or recurrent stroke, and 2 (9%) expired.

Objectives This prospectively designed longitudinal study assesses prevalence, incidence and prognosis of depressive symptoms among cognitively normal elderly volunteers compared with patients with mild cognitive impairment (MCI), dementia of Alzheimer type (DAT), and vascular dementia (VAD). Possible relationships between depressive symptoms, cognitive performance, disease types, and effects of antidepressant treatment were analyzed.Methods Two hundred and ninety four subjects exhibiting different levels of cognitive performance were admitted to this study. Demographics, cardiovascular and neurodegenerative risk factors, together with measures of neuropsychological test performance, were obtained at sequential visits. Depressive symptoms were selectively treated with antidepressant medications.Results One hundred and forty six subjects with normal cognition, 19 subjects with MCI, 42 patients with DAT. and 32 patients with VAD were followed for a mean of 3.5 years. With the passage of time, there were trends showing prevalence of depressive symptoms to decrease among DAT and to increase among VAD patients. VAD patients exhibited the highest incidences of new-onset depressive symptoms, followed in incidence by DAT and MCI groups. Depressive symptoms among VAD and MCI patients were more persistent and refractory to antidepressant medications than for DAT patients, Trends suggested that antidepressant treatment might benefit MCI and VAD subjects more than DAT patients. Motivationally related depressive symptoms accounted for major components of elevated Hamilton depression rating scale scores.Conclusions Depressive symptoms among DAT patients have higher rates of spontaneous resolution, without requiring intensive drug treatment, than among VAD patients in whom depressive symptoms are more persistent and refractory to drug treatment. Early depressive symptoms among subjects with MCI may represent a preclinical sign and should be considered as a risk factor for impending DAT or VAD among the elderly. Copyright (C) 2001 John Wiley & Sons, Ltd.

BACKGROUND AND PURPOSE:Vascular dementia (VAD) and dementia of the Alzheimer type (DAT) are malignant conditions of the elderly. More information is required to clarify expected lengths of survival, which condition is more lethal, and which risk factors may influence survival duration.METHODS:Cross-sectional and longitudinal designs were used. Survival interval was the period after study admission to death. From a population of 392 patients (of the 150 patients with VAD, mean age at entry was 68.3 years, of the 242 patients with DAT, mean age at entry was 73.0 years), there were 52 deaths, 26 patients with VAD and 26 patients with DAT. Pre-entry dementia symptoms were present for a mean of 3.1 years, with median follow-up of 3.6 years. Among 236 control subjects, there were 19 deaths. Entry age was 69.5 years, with median follow-up of 8.8 years. Influences of risk factors for stroke and body mass index on symptom duration, survival intervals, and cause of death were evaluated.RESULTS:Family history of neurodegenerative disorders, principally DAT, negatively influenced DAT survival. Body mass index declined with age and duration of pre-entry symptoms among men and women in all three groups. Before entry, for men, dementia symptoms were present for shorter periods compared with women. After entry, VAD and DAT patients had similar survival intervals. Causes of death were similarly distributed (78% of patients with VAD died from vascular causes, 56% of patients with DAT and 67% of the controls).CONCLUSION:VAD and DAT are malignant conditions negatively influencing survival times. Being a woman seems to play a protective role in symptom duration before diagnosis, but after diagnosis survival times of men and women were similar. We attribute equivalence of survival intervals among dementia groups to control of risk factors for cerebrovascular disease.

Stage and histologic type have a significant impact on the long term clinical course of breast carcinoma. Clinical course is governed by two components: likelihood of cure and median tumor‐related survival time among uncured patients. Estimates of these components can be derived only by using survival models that incorporate cured fraction as a specific parameter.

Part I of this study [Spratt JS, Meyer JS, Spratt JA: J Surg Oncol 60:137-146, 1995] reviewed the early reports of investigators, predominantly mathematical biologists and statisticians considering the mathematical laws that would describe the growth of a neoplasm. Included were cytokinetic measurements of the mitotic index, thymidine labeling index, bromodeoxy-uridine labeling index, and the relation of these indices to the potential tumor volume doubling time. The actual doubling time of benign and malignant colonic neoplasms were reported. This second part provides the cumulative observations on the actual doubling times of pulmonary metastases, primary pulmonary cancers, skeletal sarcomas, melanomas, a chemodectoma, tumors of maxillary antrum, testicular cancers, prostate cancer, and the relation between the accumulation of multiple primary cancers and growth rates. The most complete data set is for breast cancer concluding that the cancer growth curve is a decelerating curve with great natural variance. Understanding of the rates of growth of human cancers is essential for understanding the spectrum of cancer behavior observed clinically.

A prospective case-control study was carried out to clarify associations of cerebr transient ischemic attacks (TIAs) and other stroke risk factors with progression and exa erbation of cardiovascular and cerebrovascular disorders; 243 neurologically norm controls and 123 TIA patients without prior history of stroke were followed up for mean interval of 4.4 years. Of TIA patients, 26 (21%) developed other events (excludi recurrent TIAs); 10 died of vascular causes (8.1%). Of controls, 44 (18%) develope events; 13 died of vascular causes (5.4%) and 3 from cancer. TIA patients were at 2 times greater risk than normal controls for stroke or death from vascular causes. The were predominantly male with significantly higher associations of risk factors for strok including hypertension, heart disease, diabetes mellitus, smoking, hyperlipidemia, alcoh consumption, and limited education. Controls developing vascular events compared wi controls who did not were older, more frequently male, and with greater incidences heart disease. TIA patients had lower rates of cerebral perfusion compared with contro that persisted throughout the study, with similar rates of decline related to aging amor both groups. Among TIA patients, stroke risk factors were more prevalent than amor controls. The longer their duration, the greater the incidence and the more rapid the rate of severe often fatal cardiovascular complications

The purpose of this article is to consolidate data collected from a variety of sources that have permitted calculations of the rates of growth of human neoplasms. These sources include Fischel State Cancer Hospital (Columbia, MO); Mallinckrodt Institute of Radiology, (St. Louis, MO); Roentgen Diagnostic Institute, Allmanna Sjukhuset (Malmo, Sweden); University of Louisville (Louisville, Kentucky); University of Heidelberg (Heidelberg, Germany); and St. Luke's Hospital (St. Louis, MO). Included in the data are laboratory measurements of cell replication rates. All gross measurements were made either on imaging studies or with a centimeter scale for surface or palpable neoplasms. Data have been reported for breast and pulmonary cancers and metastases of many types, melanomas, skeletal sarcomas, benign and malignant colonic neoplasms, and isolated cases of less frequent neoplasms. Related cytokinetic measurements by tritriated thymidine labelling, bromodeoxyuridine labelling, S‐phase fraction from DNA flow cytometric analysis, and mitotic indices are discussed. The various mathematical formulae applicable to the analysis of the collected data and the determination of rates and patterns of growth are included. Also considered are the clinical implications of these data and the importance of ever better knowledge on the cytokinetics of human cancer. Prior studies on the evolution of insight into this field are cited and discussed. The authors conclude that a more accurate quantification of the growth rates of human cancer is essential for understanding the biological variance of human cancers seen clinically. © 1995 Wiley‐Liss, Inc.

Cerebral atrophy, tissue densities, and local perfusions were measured prospectively utilizing computed tomography among 19 cognitively intact stroke patients and 24 age-matched cognitively and neurologically normal controls. Mean follow-up intervals were 27.0 months for stroke patients and 31.0 months for controls. Stroke patients were treated by controlling risk factors and antiplatelet drugs. Cognitive testing remained normal among patients and controls. Among stroke patients, annual rates for cerebral atrophic indices were +3.4%, for ventricular enlargement +6.9%, for subarachnoid space enlargement +0.1%, and for cortical atrophy -2.5%. Annual reductions in cerebral perfusion, per 100 g brain/min, for cortex were total, -2.3 ml; frontal -3.8 ml; temporal, -2.4 ml; occipital, 2.0 ml; basal ganglia, -2.3 ml; and thalamus -3.8 ml. Annual decreases in local Hounsfield unit (LHU) densities for cortex were total, -0.6 HU; frontal, -0.8 HU; and temporal, -0.4 HU. Among controls, annual rates for cortical atrophy were -1.0% and for declines in cerebral perfusion were -0.7 ml for total cortex, and -1.4 ml for temporal cortex. Annual decreases in HU densities were total cortex, -0.6 HU; frontal, -0.9 HU; and temporal -0.4 HU. Among cognitively intact stroke patients, annual rates for cerebral atrophy and reductions in cerebral cortical perfusion were accelerated by more than three times those seen among agematched controls but were significantly less than similar measures among stroke patients with dementia.

Education and occupation as sociodemographic risk factors for dementias of the Alzheimer (DAT) and ischemic vascular types (IVD) were evaluated by two case series studies. Cases were compared to well-evaluated individuals identified as healthy normals acting as controls. There were 150 patients with probable DAT, 102 patients with probable IVD, and 188 neurologically and cognitively normal subjects. Logistic regression indicated that for DAT, education with occupation was the best predictor (OR, 1.51; 95% CI, 1.23-1.87). For IVD, the two predictors were: education with occupation (OR, 1.84; 95% CI 1.38-4.50) and education with gender (OR, 3.40; 95% CI, 1.29-8.92). We conclude that risk of dementia is increased in those with limited educational background and occupational achievement.