Mitotic frequency as a prognostic factor in breast cancer.

Grading of tumor malignancy in breast cancer should contribute essential information both for the prospective outcome of the individual patient as well as for TNM staging. In a series of 104 breast cancer patients we tested the prognostic validity and reproducibility of mitotic figure counting compared with TNM staging, Bloom and Richardson grading, DNA single cell cytometry, and morphometry. Four-micrometer thick hematoxylin-eosin-stained routine slides were investigated. Mitotic figures were counted in representative areas of the tumor in 10 159-microns 2-sized high power fields (HPFs) at a 400X magnification; the median value was seven and the threshold for the 25th percentile was three. This value should replace the common but prognostically invalid threshold of 10. Univariate survival analysis showed that mitotic figure counting allows the identification of three groups of patients (< or = 3, 4 to 20, > 20 mitoses per HPF) with significantly different survival probabilities (P < .0001; P = .0178). Depending on the number of mitotic figures, length of survival was significantly different within the group of T1N0 tumors (P = .0082) and the group of T1N1 or T2N0 tumors (P = .0251). In a Cox stepwise regression model mitotic frequency counting added prognostic information to tumor size and was of higher prognostic significance than lymph node status, DNA ploidy, or mean nuclear area. The 95% confidence limit for interobserver reproducibility, tested in 20 cases, was plus/minus 8 mitoses. After quartilization an agreement of 75% was observed.

Discordance of anti-ischemic and hemodynamic effects of captopril in stable coronary artery disease.

BACKGROUND: The role of angiotensin converting enzyme (ACE) inhibition in patients with coronary artery disease without concomitant disease such as heart failure or hypertension has not been elucidated. In this double-blind, cross-over, randomized trial of the ACE inhibitor captopril, its antianginal and anti-ischemic effects were studied during monotherapy and in the presence of an organic nitrate. METHODS: Thirty-seven patients (34 men, three women) with stable coronary artery disease and exercise-induced ST-segment depression were enrolled. After a washout phase without medication they received placebo, isosorbide dinitrate (ISDN) 20 mg twice daily, captopril 12.5 mg twice daily, and the combination of both for 1 week each, after which exercise tolerance, blood pressure and heart rate (supine, standing and 24 h profile), and peripheral arterial vasodilatation (finger pulse plethysmography) were assessed. RESULTS: Thirty-three patients completed all phases of the study. Exercise-induced anginal symptoms occurred in 17 patients, and asymptomatic ischemia was seen in the other 16 men. In comparison with ISDN, the anti-ischemic effects of captopril were minimal, despite a similar reduction in blood pressure. Compared with baseline, 1 week of placebo reduced the sum of ST-segment depression, the main efficacy parameter, by 10% (NS), captopril by 19% (NS), ISDN by 37% (P < 0.001) and the combination of captopril and ISDN by 42% (P < 0.001; NS versus ISDN). No patient remained completely free of exercise-induced angina during treatment with captopril; however, three patients after ISDN and seven patients after the combination did (P < 0.05). Blood pressure at rest decreased at peak effect by 9-10% systolic (P < 0.001) with monotherapy and by up to 7% diastolic (P < 0.001), and during combined therapy with captopril and ISDN by 18% systolic (P < 0.001) and 12% diastolic (P < 0.001). Significantly enhanced circulatory effects of captopril plus ISDN versus ISDN were found for blood pressure (P < 0.001) and peripheral arterial vasodilation (P < 0.01). The reflex tachycardia induced by ISDN in the upright position (5 beats/min) was not blocked by captopril during combined therapy. CONCLUSIONS: The antianginal and anti-ischemic effects of captopril alone were marginal, despite significant circulatory effects after short-term administration. Although captopril in combination with ISDN resulted in a significant further blood-pressure-lowering effect and increased peripheral arterial vasodilatation, the magnitude of potentiation of the anti-ischemic nitrate effects was, in contrast, small. Only exercise-induced angina was further improved by the use of the combination. No paradoxical worsening of ischemia or angina was seen after captopril. Thus, although captopril has no place as first-line therapy for ischemia, its use in combination with ISDN could be advantageous for long-term prognosis.

Detection of high risk patients in chronic myelogenous leukemia by DNA-image cytometry.

Peripheral blood smears from the time of diagnosis of 64 patients with chronic myelogenous leukemia (CML) in chronic phase were restained according to Feulgen. Nuclear DNA content of at least 100 myeloblasts and promyelocytes was measured by interactive DNA-cytometry using a TV-image analysis system, combined with an automated microscope. From the resulting DNA values the DNA parameters stemline ploidy, stemline shoulder fraction and "proliferative" fraction, which reflect cytogenetic and cell kinetic characteristics of CML, were derived. Each of these DNA parameters identified subgroups with a significantly different survival time and duration of chronic phase. Indicators for a good prognosis were a near-diploid stemline ploidy (median survival time 49 v. 26 months), a low percentage of nuclei in the stemline shoulder fraction (45 v. 28 months) and a high "proliferative" fraction (45 v. 23 months). Independently of clinical and hematological features, the DNA-cytometric parameters yielded additional prognostic information both in the univariate and multivariate analysis.

[The effect of carbon dioxide baths on blood pressure of borderline hypertensive patients]. / Wirkung von Kohlensäurebädern auf den Blutdruck von Grenzwerthypertonikern.

In 423 patients with borderline hypertension (at rest and/or during exercise) the potential blood pressure reducing effect of CO2-baths was studied. Using standardized blood pressure measurements at rest and during exercise, it was investigated to what extent a fourweek course of CO2-baths could induce a reduction of blood pressure in these patients. They were randomly assigned to a course of baths with either high or low CO2-concentration. A significant fall in blood pressure, both at rest and during exercise was observed in both groups during the course of treatment. Multiple regression analysis identified the loss in body weight during treatment as the main influence factor on reduction in blood pressure. By contrast, no (additional) specific therapeutic effect of CO2-baths on blood pressure reduction could be observed.

DNA grading of malignancy in breast cancer. Prognostic validity, reproducibility and comparison with other classifications.

The prognostic significance of the "DNA malignancy grade" (DNA-MG) was tested in a series of 104 breast cancer patients in comparison with TNM staging, histomorphologic grading according to Bloom and Richardson, mean nuclear area (MNA) and DNA-histogram classification according to Auer. The reproducibility and representativity of the grading systems were investigated, and their results in primary tumors and lymph node metastases were compared. The scalar DNA-MG was assessed on monolayer smears prepared from paraffin-embedded tissues; the smears were automatically Feulgen stained and used for rapid interactive DNA cytometric evaluation by an automated microscope and a TV image-analysis system. TNM staging showed the highest correlation with survival, followed by histomorphologic grading and DNA-MG; MNA and the DNA-histogram classification failed to give statistically significant prognostic information. Both histomorphologic grading and DNA-MG were identified as parameters adding independent prognostic information to the TNM staging. However, only DNA-MG demonstrated an acceptable reliability, with small 95% ranges between repeated measurements within the primary tumor (+/- 0.3 DNA-MG) and a strong correlation between the results in the primary tumor and its lymph node metastases. These findings show that the DNA-MG is a valid and reliable prognostic index that adds significant prognostic information to TNM staging.

Representativity and reproducibility of DNA malignancy grading in different carcinomas.

The reproducibility of the determination of the "DNA malignancy grade" (DNA-MG) was tested in 56 carcinomas of the colon, breast and lung while its representativity was tested on 195 slides from 65 tumors of the colon, breast and lung. DNA measurements were performed on Feulgen-stained smears with the TAS Plus TV-based image analysis system combined with an automated microscope. The variance of the DNA values of tumor cells around the 2c peak, the "2c deviation index" (2cDI), was taken as a basis for the computation of the DNA-MG, which ranges on a continuous scale from 0.01 to 3.00. The representativity, analyzed by comparison of the DNA-MGs measured in three different areas of the same tumor greater than or equal to 1.5 cm apart from each other, yielded an 81% agreement. No significant differences between DNA-MGs of these areas were found. The intraobserver and interobserver reproducibilities of the DNA grading system, investigated by repeated DNA measurements, were 83.9% and 82.2%, respectively. In comparison, histopathologic grading of the 27 breast cancers studied yielded 65% intraobserver and 57% interobserver reproducibilities and 66% representativity.

Tissue reaction following endobronchial application of iopamidol and ioxithalamate in rats.

Lung tissue reaction to endobronchial application of iopamidol and ioxithalamate were compared by chest radiograph and histological examination in the rat. Radiographs cleared within hours in both groups. Tissue reaction after ioxithalamate application was significantly more pronounced than with iopamidol and included macrophage response, partial atelectasis, and intra-alveolar and interstitial oedema. Different from iopamidol, ioxithalamate induced a significantly stronger reaction than tracheotomy alone. Because no important significant side effects were observed on chest radiographs or in lung histology, iopamidol is recommended for the radiological examination of the gastrointestinal tract in patients with an increased risk of aspiration.

DNA-grading of prostatic carcinoma: prognostic validity and reproducibility.

The prognostic significance of the DNA-Malignancy-Grade (DNA-MG) was tested in 52 prostatic carcinoma patients in comparison with a cytomorphological grading system and the clinical staging. Papanicolaou- or MGG stained smears from transrectal aspiration biopsies were automatically restained according to Feulgen in a modified Shandon staining machine. The DNA-MG, based on the variation of the nuclear DNA content of tumor cells around the normal DNA peak, ranges on a continuous scale from 0.01 to 3.0. It was determined with a TV-image analysis system (Leitz, TAS plus), combined with an automatic microscope. The DNA-MG revealed a high prognostic validity, the clinical stage showed only a minor influence on the survival time and the cytopathologic grading system was of insufficient prognostic information. Significant differences in survival time could be demonstrated between patients with DNA-MGs of 0.01-1.5 and 1.5-3.0, as well as with DNA-MGs 1.0-2.0 and 2.0-3.0. The intra- and interobserver variations of the DNA grading system were found to be sigma = 0.014 and sigma = 0.036 respectively. The reproducibilities were 86.7% for intra- and interobserver measurements, when the continuous DNA-MG scale was divided in three groups.

HLA-DR4 and Gm(1,3;5,21) are associated with U1-nRNP antibody positive connective tissue disease.

Patients with U1-nRNP antibodies (n = 35, 31 female, four male) were typed for HLA-A, -B, -C, and -DR antigens and IgG heavy chain allotypes G1m(1), -(2), -(3), G3m(5), and -(21). The patient group was clinically heterogeneous. Four met the American Rheumatism Association criteria for systemic lupus erythematosus, six for progressive scleroderma, and 14 for rheumatoid arthritis. Sicca syndrome was present in seven cases. Twenty three had overlapping features compatible with mixed connective tissue disease (MCTD). Healthy blood donors served as controls for HLA typing (n = 64), Gm typing (n = 228), or both (n = 56). Sixty six per cent of the patients with U1-nRNP antibodies were DR4 positive compared with 28% of the controls (relative risk = 4.9, p = 0.00053). The Gm(1,3;5,21) phenotype was found in 46% of the patients and 25% of the controls (relative risk = 2.47, p = 0.0247). Within the patient group Gm(1,3;5,21) was found only in DR4 positive individuals. The coincidence of HLA-DR4 and Gm(1,3;5,21) increases the relative risk values to 8.0 (compared with the group with neither risk factor). DR4 and Gm(1,3;5,21) primarily seem to be related to U1-nRNP antibody formation and not to disease expression. Patients with or without MCTD did not differ with respect to DR4 or Gm(1,3;5,21) frequency. Disease onset was earlier in patients with HLA-DR4/Gm(1,3;5,21) than in patients without both markers (mean 27.9 v 40.1 years; p less than 0.05).

[Heart valve replacement in patients over 60]. / Herzklappenersatz bei über Sechzigjährigen.

UNLABELLED: Between 1976 and 1984, 182 patients over 60 years with valvular defects were examined invasively and valve replacement was performed. 34 patients (19%) were older than 70 years. Hospital mortality was 2% in aortic valve replacement, 4% in mitral valve and 8% in double valve replacement. Overall early mortality in patients between 60 and 70 years of age was 3.4% and 6% in patients over 70 years for all operations. Simultaneous aortocoronary bypass surgery did not enhance the operation risk. During the follow-up period of 23 +/- 22 months a total of 21 patients died (12%). Only 4% of the survivals showed clinical deterioration by at least one NYHA class. Clinical tendency to improvement was as clearly evident among the patients of over 70 years of age as among the entire group. Preoperative invasive and noninvasive data do not display any significant correlation with the result of surgery. Significantly higher (P less than 0.05) mortality rates or inferior functional operation results were seen only with higher age, a preceding valve operation, and preoperative NYHA class IV. CONCLUSION: In elderly patients indication for valve replacement should not be more restrictive than in younger ones. Postponement of valve replacement in these age groups until the patient experiences symptoms when at rest (NYHA class IV) will adversely affect the chances of success and increase the mortality risk.

DNA-grading of malignant lymphomas. I. Prognostic significance, reproducibility and comparison with other classifications.

The prognostic significance of the DNA Malignancy Grade (DNA-MG) was tested for 83 malignant non Hodgkin lymphoma patients in comparison with three different subjective morphological classification systems (New Working Formulation for Clinical Usage, Rappaport and Kiel Classification). Monolayer smears prepared from paraffin embedded tissue and imprint smears from fresh cut lymph-nodes were investigated. Feulgen staining was performed automatically. The scalar DNA-MG was determined by rapid interactive DNA-cytometry, using an automatic microscope and a TV-image analysis system. A strong influence of the DNA-MG on length of survival was found. Compared with morphological classification systems, the DNA-MG was of greater prognostic validity as revealed by different statistical tests. Significant differences of survival probabilities between some groups with differences of 0.5 DNA-MG only were found. The interobserver reproducibility of this new prognostic index was found to be 95% within a range of +/-0.4 DNA-MG.

[A new echocardiographic procedure for calculation of the accurate volume of the right atrium]. / Ein neues echokardiographisches Verfahren zur exakten Volumenberechnung des rechten Vorhofes.

The right atrial (RA) volume can be determined angiographically from two perpendicular projections. Up to now volume calculations by means of two-dimensional echocardiography (2-DE) have only been attempted in a single plane, the apical four-chamber view. Our study reports a new method for RA volume calculation using two intersecting cross-sectional echocardiographic views. For this purpose silicone rubber casts of 20 human necropsy hearts were obtained and thin walled natural rubber moulds of the RA casts were prepared. Totally filled with and immersed in water, the mouls could be visualized in the apical four-chamber view and an additional echocardiographic plane, the latter corresponding to the subcostal view in vivo. In this view the vertical extension of RA could be estimated. Areas and length of RA were determined in the respective planes and RA volume was calculated by applying the formula: - Area X Length - to two intersecting planes. Finally, the latex moulds were filled with diluted contrast agent and the volume was determined angiographically using a biplane disc method. Real volume of RA was 112 +/- 23 ml (mean +/- 1 SD). Angiographically, an overestimation resulted: the calculated volume amounted to 119 +/- 24 ml, the mean difference was 7 +/- 2 ml (p less than 0.001). The regression equation was y = 1.04 X + 2.34, r = 0.995, SEE = 2.3 ml. Volume determination from the apical four-chamber view using a monoplane disc method resulted in a mean volume of 62 +/- 17 ml. The mean difference to the real RA volume was 50 +/- 17 ml, p less than 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA grading of urothelial carcinoma of the bladder.

The prognostic influence of the nuclear DNA distribution pattern of human urothelial carcinomas of the bladder was investigated in 25 patients. Nuclear DNA content was measured by scanning microphotometry in Feulgen-stained histologic sections. A DNA malignancy grade (DNA-MG) ranging from 0.01 to 3 on a continuous scale was computed for each patient from the single cell DNA values. With the aid of the Cox proportional hazard regression model, DNA-MG was revealed as having a strong influence on survival time (p = 0.0004). Possible influences of other parameters (histological grade, stage, endoscopical tumor size and multiplicity, age) on survival could not be assessed in this model. This may be explained by the low number of cases and by the weakness of the influence of these parameters. Divided into two groups of patients according to their DNA-MG (group I: DNA-MG less than 1.5, group II: DNA-MG greater than or equal to 1.5), the histological grade had an influence on survival (p = 0.021). There was a good association of DNA-MG and histological grade (p = 0.05). In comparison to the histological grade DNA-MG seems to allow a more precise prognostic statement for the individual patient as it reveals additional information on survival for patients categorized according to their histological grade. We conclude that DNA-MG is an objective and scalar index for the prognosis of bladder carcinoma patients.

Interference of IgM rheumatoid factor with nephelometric C-reactive protein determinations.

Different nephelometric assay systems for quantitation of C-reactive protein (CRP) were compared with radial immunodiffusion (RID) and tested for their susceptibility to interference by serum IgM rheumatoid factor (RF). In 3 nephelometric assays, RF was found to elevate CRP values. Sera with high RF content from patients with rheumatoid arthritis gave significantly higher CRP values by nephelometric assay than by RID; the addition of purified RF to RF-negative sera increased CRP values markedly; and removal of RF from sera corrected falsely elevated CRP values. This interference by RF is explained by the action of human RF as a (secondary) antibody reacting with complexed mammalian IgG anti-human CRP in the assay. In this way the nephelometric signal is enhanced to give falsely elevated CRP values. In contrast, the gel diffusion RID method does not suffer from this non-specific interference.

DNA grading of malignancy and tumor regression in prostatic carcinoma under hormone therapy.

The prognostic value of the DNA malignancy grade (DNA-MG) and of the DNA regression index (DNA-RI) for survival was tested in 19 patients with prostatic carcinoma under hormone therapy. Measurements were performed on repeated Feulgen-stained transrectal aspiration biopsy smears by DNA image cytometry. The DNA-MG was demonstrated to be an objective scalar index of high prognostic value for the individual patient. The prospective tumor response to hormone therapy could be predicted from the DNA-MG. Independently of the DNA-MG, the DNA-RI provided additional prognostic information concerning tumor regression and survival of prostatic cancer patients under conservative therapy. The determination of DNA-RI allows the early identification of an ineffective conservative therapy.

[Determination of the size of the right atrium in patients with pulmonary hypertension using 2-dimensional echocardiography]. / Grössenbestimmung des rechten Vorhofes bei Patienten mit pulmonaler Hypertonie mittels zweidimensionaler Echokardiographie.

Normal values for right atrial area and tricuspid annular diameter and their percentage shortening measured from the two-dimensional echocardiographic four-chamber view are now available. In this study right atrial size of patients with pulmonary hypertension is evaluated and the results compared with the M-mode findings of the right ventricle in order to detect pulmonary hypertension. Hemodynamics and echocardiograms of 60 patients (mean age 57 +/- 10 years) with mitral stenosis III-IV NYHA and concomitant pulmonary hypertension were examined. 20 patients in group I with atrial fibrillation had additional functional tricuspid incompetence. Unlike the 20 patients in group II, who had atrial fibrillation, the remaining 20 in group III were still in sinus rhythm. The mean pulmonary artery pressure was 44.1 +/- 9.3 mmHg in group I, in group II 33.9 +/- 6.3 mmHg (grp. I vs. grp. II p less than 0.001) and in group III 33.2 +/- 7.1 mmHg (grp. II vs. grp. III ns). The end-systolic index of the right atrial area in group I was 19.6 +/- 5.7 cm2/m2 and thus significantly greater than in group II with 10.6 +/- 2.3 cm2/m2 (p less than 0.001) and in group III with 9.1 +/- 2.5 cm2/m2 (p less than 0.001). The maximal diameter of the tricuspid annulus measured 24.6 +/- 5.5 mm/m2 in group I, 18.9 +/- 3.5 mm/m2 in group II (grp. I vs. grp. II p less than 0.001) and 20.2 +/- 2.2 mm/m2 in group II (grp. I vs. grp. II p less than 0.001) and 20.2 +/- 2.2 mm/m2 in group III.(ABSTRACT TRUNCATED AT 250 WORDS)