Ki67 immunohistochemistry: a valuable marker in prognostication but with a risk of misclassification: proliferation subgroups formed based on Ki67 immunoreactivity and standardized mitotic index.

AIMS: Counting mitotic figures is considered to be a reliable prognosticator, but evaluation of Ki67 immunohistochemistry has become more popular in evaluating proliferation. Our previous studies suggested an occasional discrepancy between mitotic figures and Ki67 fraction. The aim of this study was to investigate this more closely and also to study the associations between bcl-2 and p53 expression and proliferation. METHODS AND RESULTS: Two hundred and sixty-five infiltrating breast carcinomas were immunostained for Ki67, p53 and bcl-2. The standardized mitotic index (SMI) was determined. Four proliferation groups were based on Ki67 positivity fraction and SMI at optimal cut-off points. Cox's multivariate model was used to test the power of the prognosticators. SMI and nodal status were the most powerful individual prognosticators. Ki67 was an independent prognosticator if nodal status, tumour size, age and histological grade were included in the analysis but not if analysed with SMI. The group with low SMI and low Ki67 fraction had the best prognosis. Groups with high SMI had the poorest prognosis. The group with low SMI and high Ki67 fraction had a favourable prognosis. Bcl-2 negativity and p53 positivity correlated with proliferation. CONCLUSIONS: We have found a 'wrong positive' Ki67 group with favourable prognosis. SMI cannot be replaced by Ki67 because of the danger of misclassification of some patients.

Drug-related deaths in a university central hospital.

OBJECTIVES: The objectives were to determine the incidence of drug-related deaths in a university hospital and to find out which drugs are most commonly involved in these cases. METHODS: The files of 1511 death cases (97.7% of all death cases in the Helsinki University Central Hospital during the year 2000) were scrutinised. In the cases of suspected drug-related deaths excluding suicides, the medication, its duration and indications, the route of drug administration, and the type of the adverse reactions were determined. The probability of a fatal adverse drug reaction was classified according to WHO's classification. In addition, the incidence of drug-related deaths was calculated from the death certificates. RESULTS: Scrutiny of the patients' files showed that 75 of the death cases (5.0% of all deaths) were certainly or probably drug-related. This corresponds to about 0.05% of all hospital admissions. The most common adverse reactions were neutropenia caused by antineoplastic agents and gastrointestinal or intracranial haemorrhage due to anticoagulants or nonsteroidal anti-inflammatory drugs (NSAIDs). The incidence of drug-related deaths is only 0.5% when based on the International Classification of Diseases (ICD) codes in death certificates. CONCLUSIONS: Adverse drug reaction is a significant cause of death. Most of the deaths occurred in seriously ill patients with high-risk medication and they are seldom preventable. Incidence figures based on death certificates only may seriously underestimate the true incidence of fatal adverse reactions.

Nuclear volume and breast cancer prognosis.

BACKGROUND: In breast cancer, nuclear volume estimates can be expected to be better prognosticators than nuclear profile areas because biological variation is wider in volume estimates than in area measurements. MATERIALS AND METHODS: 191 invasive breast cancer samples were available for nuclear volume measurements. To estimate the volume weighted mean nuclear volume, point-sampled linear intercepts were used on micrographs. The nuclear profile area was measured from 148 cases matching volume measurements and run by the Prodit morphometry program. Measurements were compared as prognosticators after a follow-up of 5 years. A computerized method on a randomly selected large number of nuclei was also applied in 17 cases. Bcl-2 immunostaining was compared with nuclear measurements. RESULTS: The correlation of volume and area measurements was statistically significant, but the correlation coefficients were low. The nuclear area showed a significant difference in survival at the 75 percentile cut-point but the volume-weighted mean nuclear volume did not allow distinction of different prognostic groups. Computerized volume measurements based on a large number of nuclei and measurements based on the simpler method did not show statistically significant correlation. Bcl-2 staining did not show any correlation with volume or area measurements. CONCLUSIONS: Although the prognostic value of nuclear area was shown in our study, the volume-weighted mean nuclear volume did not show prognostic significance. Improvement of the methodology which could decrease method variation and increase reproducibility of measurements is urgent for verification of the prognostic value of nuclear volume measurements. Bcl-2 immunostaining and nuclear area measurements were independent prognostic variables.

Bcl-2 immunostaining: a way to finding unresponsive postmenopausal N+ breast cancer patients.

BACKGROUND: Bcl-2 staining positivity has shown limited prognostic value. However, we have decided to study this issue in the era of mammography screening, and adjuvant treatment protocols. METHODS: Paraffin sections of 414 breast cancers were stained for bcl-2 and staining intensity graded. Association of bcl-2 with established prognosticators was analysed with chi 2 test and odds ratios in 2 x 2 tables. Kaplan-Mayer analysis and Cox's regression were used to evaluate the prognostic value of bcl-2 and other prognosticators. RESULTS: Bcl-2 immunostaining was associated with tumor size, lymph node status, histological type, multivariate prognostic index, standardized mitotic index, Ki-67 fraction, DNA-index, proportion of cells with DNA above 5c, estrogen receptor status, and histological grade. ER status showed the best association with bcl-2 positivity (odds ratio 11.3, 95% CI 5.6-22.7). In the whole group of patients bcl-2 positivity was not an independent prognosticator. However, among N+ patients bcl-2 staining was significant, and among postmenopausal N+ patients bcl-2 immunostaining was a stronger independent prognosticator than tumor size. CONCLUSIONS: The prognosis of N+ breast cancers can potentially be evaluated with bcl-2 positivity, in association with tumor size, and mitotic activity. Among postmenopausal N+ patients, most of whom have received anti-estrogen therapy, bcl-2 positivity is an independent prognosticator. Also, the close association of bcl-2 positivity with ER status supports the view that bcl-2 negativity reveals a patient group which might benefit from additional treatment in association with anti-estrogen therapy.