A partial estrogen receptor agonist with strong antiatherogenic properties without noticeable effect on reproductive tissue in cholesterol-fed female and male rabbits.

Estrogen replacement therapy retards the development of cardiovascular disease and osteoporosis in postmenopausal women. However, long-term unopposed use increases the risk of cancer in endometrium and possibly in breast. The racemic compound ormeloxifene, widely used in India as an antifertility agent, is a partial estrogen receptor agonist with antiosteoporotic properties. The present study was undertaken to investigate the effect of the L-enantiomer (levormeloxifene) and the d-enantiomer (d-ormeloxifene) on the development of atherosclerosis. In a short-term experiment (6 weeks), 4 x 10 ovariectomized female rabbits were fed a 0.25% cholesterol-enriched diet and the effect on plasma cholesterol levels was studied. In a long-term experiment (13 weeks), 4 x 15 ovariectomized female and 4 x 15 shamoperated male rabbits were maintained at a similar plasma cholesterol level of 25 mmol/L and the effect on undamaged and balloon-injured arterial wall was studied. In both experiments, the rabbits were treated with levormeloxifene, d-ormeloxifene, 17 beta-estradiol, or placebo, respectively. In the short-term experiment, levormeloxifene, in contrast to d-ormeloxifene, significantly reduced plasma cholesterol by 30% compared with the placebo group. In the long-term experiment, levormeloxifene, in contrast to d-ormeloxifene, significantly reduced atherosclerosis by 50% in the undamaged arterial wall of both female and male rabbits. Because these rabbits were cholesterol-clamped, the antiatherogenic effect was not mediated via plasma cholesterol lowering. Like estrogen, levormeloxifene did not inhibit atherosclerosis in the endothelium-denuded site of aorta. The antiatherogenic effects of levormeloxifene were thus similar to those of estrogen, but produced in the absence of any noticeable estrogenic effect on uterine or testicular tissue.

Prognostic significance of DNA content in bladder cancer based on flow cytometric analysis of 249 transitional cell carcinomas.

The prognostic significance of DNA index (DI), S-phase fraction, and heterogeneity determined by flow cytometric DNA analysis was assessed in a prospective study of 249 newly diagnosed transitional cell carcinomas of the bladder. The median observation time was 4.8 years. A total of 456 subpopulations were detected. The S-phases could be estimated in 299 subpopulations. A DI > 1.25 or an S-phase above 9.7% were strongly correlated to invasiveness. One hundred and ten patients were treated with transurethral resection (TUR). Relapse-free survival could not be predicted by the DNA-derived parameters. Univariate analysis of survival showed prognostic significance of diploidy (0.98 < DI < or = 1.02, P = 0.02), hypotetraploidy (1.50 < DI < or = 1.96, P = 0.002), and S-phase size (P = 0.008). Multivariate analysis pointed to the T-classification (RR = 1.64) and hypotetraploidy (RR = 1.57) as prognostic parameters for survival of TUR-treated patients. One hundred and thirty-nine patients received radiotherapy (RT). A significantly better response was found for tumors with a subpopulation with a hypertetraploid DNA content (DI > 2.04, P = 0.05), and a significantly worse response for subpopulations with a maximum S-phase > 24.5% (P = 0.04). T-classification and histological grade had no predictive value. A logistic regression analysis indicated an estimated probability of response to RT of 77% for tumors with a DI > 2.04 and an S-phase < 24.5%, whereas tumors with a DI < 2.04 and an S-phase > 24.5% had only a 28% probability of response. The poor response to RT, predicted by an S-phase > 24.5%, translated into a poor survival, whereas the better treatment response found for patients with a DI > 2.04 did not result in a longer survival. Multivariate analysis pointed to S-phase (RR = 1.70), T-classification (RR = 1.60), and grade (RR = 0.65) as independent prognostic parameters for survival of RT-treated patients.

Transport of insulin across rabbit nasal mucosa in vitro induced by didecanoyl-L-alpha-phosphatidylcholine.

To investigate the short-term effects of didecanoyl-L-alpha-phosphatidylcholine on the nasal mucosa and the mechanism by which didecanoyl-L-alpha-phosphatidylcholine enhances the nasal absorption of insulin, an in vitro model was developed. The mucosa from the posterior part of the rabbit nasal septum was mounted in an Ussing chamber and incubated in bicarbonate Ringer solution at 37 degrees C. Potential difference, transmucosal conductance, and unidirectional tracer fluxes were measured across an exposed tissue area of 0.44 cm2. Morphological and physiological examinations revealed a typical respiratory epithelium containing amiloride-sensitive Na+ channels and diphenylamine-2-carboxylate-sensitive Cl- channels. Spontaneous potential difference (10.8 +/- 0.4 mV [n = 50]; serosa positive) and transmucosal conductance (10.5 +/- 0.4 mS/cm2 [n = 50]) were stable for several hours. Mucosal addition of 0.1-0.5% didecanoyl-L-alpha-phosphatidylcholine increased transmucosal conductance (by 43-53%) and decreased potential difference (to 0-2 mV) to new steady-state values within 10-15 min. Control unidirectional rate constants for permeation of sucrose, polyethylene glycol 4000, and insulin were low and varied according to the molecular size. After addition of didecanoyl-L-alpha-phosphatidylcholine, unidirectional rate constants for the three compounds all increased 3- to 5.5-fold. The didecanoyl-L-alpha-phosphatidylcholine effects on potential difference and transmucosal conductance were reversible after a recovery period of at least 40 min when didecanoyl-L-alpha-phosphatidylcholine had been applied to the mucosal side for 15 min. The results suggest that didecanoyl-L-alpha-phosphatidylcholine may increase the transepithelial absorption of insulin by facilitating a paracellular passage through a reversible opening of tight junctions.

Diagnosis of acute myeloid leukaemia with the use of monoclonal anti-neutrophil elastase (NP57) reactive with routinely processed biopsy samples.

The reactivity of a monoclonal anti-neutrophil elastase antibody (NP57) with routinely processed biopsy samples from various acute leukaemias has been examined and compared with that of chloroacetate esterase and CD15 (hapten X), two other myeloid cell-associated markers detectable in paraffin sections. No staining was seen with these markers in 14 cases of acute lymphoblastic leukaemia. In contrast the neoplastic cells in 27 of 37 acute myeloid leukaemias were NP57 positive. Twenty of these were also positive for chloroacetate esterase, whereas CD15 was expressed in only six cases. These results indicate that detection of elastase with monoclonal NP57 forms a useful supplement to traditional methods for the histopathological diagnosis of acute myeloid leukaemias.

Repeated fine needle aspirations in the diagnosis of soft tissue metastases in breast cancer.

In 36 patients, treated for breast cancer and with a suspected metastasis in the subcutis, the diagnostic efficacy of repeated fine needle aspiration (FNA) has been evaluated in 39 tumours. By increasing FNA from one to three, the diagnostic sensitivity was increased from 0.59 (95% C.L. 0.33-0.82) to 0.83 (95% C.L. 0.52-0.98). Diagnostic specificity for one aspiration was 0.95 (0.77-1.00), and for two and three aspirates it was 0.96 (0.80-1.00) if suspicious aspirates were considered as positive, and 1.00 for one, two and three aspirations when only aspirates with tumour cells were considered positive. Statistically, three aspirates were significantly better than one in establishing the diagnosis of a soft tissue tumour in patients with breast cancer.

Clinical and radiologic characteristics of bone metastases in breast cancer.

Metastatic bone disease was evaluated in 380 consecutive patients at the time of first metastasis of breast cancer. Studies included radiographic examination, radionuclide examination, and bone marrow biopsy. Radiographs of the skeleton demonstrated metastases in 120 patients (32%), and in 40 of these patients (13%) the bone was the only site of metastases. The diagnostic efficiency was 82% for bone scanning, 80% for pain evaluation, 59% for s-calcium analyses, and 77% for s-alkaline phosphatase analyses. Bone scanning is an effective method to exclude metastatic bone disease (sensitivity: 96%). A positive scan, however, requires radiologic confirmation (specificity: 66%). Bone scanning of the skeleton should be the initial staging procedure in all patients with recurrent breast cancer with no clinical or biochemical signs of bone metastases. Bilateral posterior iliac crest bone marrow aspirations and bone biopsies were positive in 82 out of the 320 patients who underwent biopsy. The frequency of positive bone marrow biopsy was significantly correlated with both the site of radiographic metastases and with the total number of involved bone regions. Routine bone marrow biopsies are indicated in patients with a positive bone scan, but a negative x-ray examination. In these cases biopsies should be performed bilaterally.

The presence of tumor cells in bone marrow at the time of first recurrence of breast cancer.

The occurrence of bone marrow carcinosis was investigated in 380 patients at the time of first recurrence of breast cancer. Results were related to results from radiographic bone survey, 99mTc MDP bone scintigraphy, clinical examination and serum alkaline phosphatase and serum calcium levels. Eighty-seven patients (23%) had tumor cells in the bone marrow. X-rays showed metastases in 78% of the patients with and in 16% of the patients without bone marrow carcinosis. The diagnostic efficiency of x-rays with bone marrow biopsy as the key diagnostic factor was 83%, and it was superior to that of other investigation methods. Bone tissue biopsies were positive alone in 15 patients (17%) and marrow aspirations were positive alone in seven patients (8%). Imprint preparations were positive alone in 7% of the patients and bone tissue biopsy in 5% of the patients. Heavy tumor infiltration (greater than or equal to 50%) of the bone marrow was associated with the occurrence of numerous regions of radiographically involved bone lesions and with histopathologic evidence of bone destruction. Furthermore, pronounced bone formation and marrow fibrosis were more commonly seen in patients with osteosclerotic bone metastases than in patients with osteolytic bone metastases. This study provides evidence that the primary soil of metastatic bone disease in human breast cancer is the bone marrow and that radiographic evidence of bone metastases is a result of an invasion and destruction of the bone tissue matrix by tumor cells from the marrow cavity.

Incidence and methodologic aspects of the occurrence of liver metastases in recurrent breast cancer.

The occurrence of liver metastases was evaluated by ultrasonic scanning and correlated with prognostic factors, pattern of metastases, clinical examination, biochemical liver function tests from serum, and liver biopsy specimens in 394 consecutive evaluable patients with first recurrence of breast cancer. Fifty-nine patients (15%) had a positive scan, and liver metastases were the only sign of recurrent disease in 11 of these patients. The presence of liver metastases was not associated with age, menopausal status, size of the primary tumor, regional lymph node status, or the length of the recurrence-free interval; but patients with liver metastases were significantly closer to the menopause than those without (P = 0.02). The diagnostic value of clinical examinations was comparable to that of serum bilirubin and serum aspartate aminotransferase (ASAT) analyses, but was significantly better than alkaline phosphatase (AP) and lactate dehydrogenase (LDH) analyses. Analysis of serum AP was not a valuable diagnostic tool in the diagnosis of liver metastases, since it was elevated in 58% of the patients with bone metastases, and since metastases in this site were found in one third of the patients without liver metastases. If all four tests were negative, liver metastases were excluded in 99% of the patients, and if more than two of the four tests were positive, liver metastases were found in 95%. Valid (greater than 80%) diagnosis of liver metastases by serum LDH or serum ASAT alone, required an elevation of three or five times the upper normal limits, respectively. Thirty-nine patients with positive ultrasonography results underwent biopsy. The ultrasonographic diagnosis could not be confirmed histologically in three patients (8%). If ultrasonic scanning had not been performed routinely, only one of 213 patients (0.5%) with soft tissue metastases would have been offered local therapy rather than systemic treatment. These data suggest that ultrasonic scanning of the liver should not be a routine diagnostic tool in examination of patients with first recurrence of breast cancer. However, whenever indicated by clinical signs or elevated blood tests, scanning should be performed to confirm the presence of liver metastases, particularly in patients entering therapeutical trials, since liver metastases demonstrated by ultrasound examinations may serve as a measurable parameter.

Hypereosinophilia in a patient with acute lymphoblastic leukemia.

A case of a coincident acute lymphoblastic leukemia and marked eosinophilia is presented. The clinical and pathological features of this case are discussed with special emphasis on the hypereosinophilic syndrome versus secondary hypereosinophilia that can be found to accompany ALL. Special immunological studies may be helpful in the diagnostic procedures.

Fine needle aspiration and Tru-Cut biopsy in the diagnosis of soft tissue metastases in breast cancer.

Soft tissue is a common site of the first recurrence in patients with breast cancer, and soft tissue lesions are often used to assess the efficacy of systemic therapy. It is therefore desirable to obtain histological/cytological verification of such lesions. It is our experience that FNA and TCB in psycho-social respects are superior to a surgical biopsy. Using a surgical biopsy as the key-diagnosis we have compared the diagnostic value of Fine-Needle Aspiration (FNA), Tru-Cut Biopsy (TCB) and clinical evaluation. The FNA was found to be significantly better than TCB in establishing the diagnosis. The diagnostic specificity and sensitivity for FNA was 1.0 and 0.65, while the corresponding figures for TCB and the clinical diagnosis were 1.0 and 0.36 and 0.76 and 0.33, respectively. Since no false positive results were obtained by use of FNA, this procedure seems to be a sufficient diagnostic procedure. However, in case of a negative outcome of the FNA, the diagnosis must be obtained by a surgical biopsy.

The differential diagnosis of intraepidermal malignant lesions using immunohistochemistry.

The malignant intraepithelial proliferations--malignant melanoma level I, bowenoid epithelial dysplasia, and mammary as well as extramammary Paget's disease--may cause differential diagnostic difficulties. We have examined 12 cases of malignant melanoma level I, nine cases of bowenoid epithelial dysplasia, 17 cases of extramammary and five cases of mammary Paget's disease for S100 protein, carcinoembryonic antigen (CEA), cytokeratin, and keratin to evaluate the sensitivity and specificity of these reactions with regard to their differential diagnostic value. Antibodies against S100 reacted specifically with the tumor cells in intraepithelial malignant melanomas; antibodies against CEA reacted specifically with the tumor cells in Paget's disease; and cytokeratin and keratin antibodies reacted with the epithelial tumor cells in Paget's disease as well as in bowenoid epithelial dysplasia. However, only antibodies to CEA and keratin showed 100% sensitivity. We conclude that the investigated antibodies may be of differential diagnostic value in cases of intraepidermal neoplasias, but that a negative reaction does not exclude diagnosis of these diseases.

Simultaneous presence of translocations t(14;18) and t(2;8) in a case of chronic lymphocytic leukemia.

We report a patient with classical chronic lymphocytic leukemia of IgM kappa phenotype and a stable clinical course, in which repeated chromosome analyses of blood lymphocytes revealed the coexistence of t(14;18), a marker often associated with follicular low grade lymphocytic lymphomas, and t(2;8), a variant of the t(8;14) typically seen in Burkitt's lymphoma. Both these translocations involve immunoglobulin gene regions, the t(2;8) being almost always found in patients with kappa light chain restriction. However, in an EBV-immortalized cell line of this patient, most karyotypes contained t(14;18) alone, without the t(2;8). This suggests that t(14;18) was the primary cytogenetic event, and that t(2;8) evolved subsequently. As a secondary cytogenetic event, the t(2;8) may not share the grave clinical consequences of a primary t(2;8) as seen in Burkitt's lymphoma and related disorders.

Metabolic response to subtotal thyroidectomy in propranolol-treated thyrotoxic patients.

Changes in plasma cortisol, glucose, cyclic AMP, blood leucocytes, pulse rate and body temperature were measured during and for 24 h after subtotal thyroidectomy in eight propranolol-treated (120-160 mg per day) mild to moderate thyrotoxic patients and eight patients with a non-toxic goitre. The results showed a similar metabolic response to surgery in the two groups without any trends towards a hypermetabolic response in the toxic group. The accumulating evidence of the safety of preoperative preparation with propranolol in patients with mild to moderate thyrotoxicosis is thus supported by our results.