Biomedical subjects
Publications and source records attributed to R Tepper.
Tamoxifen is widely used as adjuvant therapy for postmenopausal breast cancer patients with positive estrogen receptors. Data on a possible association of endometrial pathologies with tamoxifen treatment have been accumulating. In this review, we examine the current literature and include our own experience with this occurrence. We recommend close supervision of these patients.
Three patients with findings suggestive of invasive gestational trophoblastic neoplasm and lung metastasis were assessed by color Doppler transvaginal ultrasound, before and during chemotherapy. The sonographic findings were correlated with beta-hCG levels measured at various stages of treatment. Results were compared with blood flow indices found during normal first trimester pregnancies, and those following elective termination of pregnancy. The mean resistance indices were significantly lower in the patients treated with chemotherapy (0.410 +/- 0.04) than in the early pregnancy control group (5-8 weeks gestation; n = 20, resistance index = 0.494 +/- 0.06). The difference between the groups was statistically significant (chi 2; p < 0.05). No pathological flow patterns could be discerned in 10 patients, who after termination of pregnancy had beta-hCG levels below 5 IU/ml. The response of gestational trophoblastic neoplasms to chemotherapy could be reliably assessed by observing the changes in flow resistance, which paralleled the gradual decrements in serial measurements of beta-hCG levels. Thus, the statistically significant results of our study are very encouraging and may indicate that color Doppler flow is a noninvasive, reproducible, useful and highly reliable new diagnostic approach for the diagnosis and management of patients suffering from uterine malignant gestational trophoblastic disease.
As there are no proven optimal serum estradiol levels, we sought to evaluate the pharmacokinetic profiles of serum estradiol levels following a single oral dose of 2 mg estradiol and 1 mg of estriol (Trisequens) among 26 surgically induced, postmenopausal patients. Their serum estradiol levels were periodically measured over 24 h following oral administration of the drug. They were divided into two groups according to the computed hourly mean estradiol values: group A, < 250 pg/ml/h ( < 918 pmol/l/h) and group B, > 250 pg/ml/h ( > 918 pmol/l/h). The mean peak estradiol concentrations were noted 2 h after drug administration and amounted to 595 +/- 190 pg/ml (2,184 +/- 697 pmol/l) in the entire cohort; 435 +/- 117 pg/ml (1,597 +/- 430 pmol/l) in group A and 712 +/- 142 pg/ml (2,614 +/- 521 pmol/l) in group B (p < 0.001). The mean total area under the curve in group A was 4,887 pg/ml (17,940 pmol/l), which was significantly lower than that of 7,995 +/- 652 pg/ml/24 h (29,350 +/- 2,393 pmol/l/24 h) found for group B (p < 0.001). The mean body mass index showed a significant difference (p < 0.003) between group A and group B (29.4 +/- 0.56 vs. 24.3 +/- 0.24). We found that 57% of our patients were exposed to excessively high levels of estradiol during the 24-hour period following drug ingestion. We advise monitoring estradiol levels and individualizing estrogen replacement therapy, to avoid the long-term exposure of postmenopausal patients to superphysiological estradiol levels.
To the best of our knowledge, this is the first report of in vivo endometrial estrogen and progesterone receptor induction as a result of tamoxifen exposure in a postmenopausal breast cancer patient. The following observations, that the postmenopausal endometrium is sensitive to tamoxifen, that this agent can act as an estrogen-like substance, and that it may cause proliferation of the endometrium in the absence of progestin, may explain the endometrial decidual changes described herein as a protective mechanism against possible neoplastic endometrial changes.
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A prospective pilot study was conducted to evaluate the usefulness of uterine artery blood flow in the detection of various pathologic endometrial conditions in 39 asymptomatic postmenopausal breast cancer patients who were treated with tamoxifen. No specific pattern was seen for the uterine artery pulsatility index values in the tamoxifen-treated patients that could be related to any specific endometrial lesions, nor were any specific changes observed in the pulsatility index value with increasing severity of the pathologic endometrial conditions. Similarly, no correlation was found between ultrasonographically measured endometrial widths and uterine artery pulsatility index values. Thus, although pulsed Doppler flow ultrasonography has been shown previously to be effective in the detection of uterine cancer in non-tamoxifen-treated post-menopausal patients, it probably does not contribute to the assessment of endometrial lesions in post-menopausal breast cancer patients treated with tamoxifen.
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Seventy-two asymptomatic, postmenopausal women treated with tamoxifen for breast cancer were studied prospectively with vaginal ultrasonography, followed by endometrial sampling. Seventy-one patients demonstrated an endometrial echo of more than 5 mm, and one displayed an endometrial echo of less than 5 mm. No patient with an endometrial echo of less than 5 mm displayed any endometrial pathology. Different endometrial pathologic conditions were found when the endometrial echo was over 5 mm. When classifying those patients whose ultrasonic endometrial widths were wider than 5 mm, on the basis of different endometrial histologic findings, no obvious correlation was found between the various pathologic endometrial findings and endometrial thickness. Thus, a "thicker" endometrial sonographic image did not necessarily correlate with pathologic endometrial findings. When ultrasonic endometrial thickness of 5 mm was considered the upper limit of normal, the sensitivity of ultrasonography in correlating to positive histologic findings was 91% and the specificity was 96%. These findings suggest that there is good correlation between endometrial width measured by ultrasonographic assessment and histologic findings.
Since magnesium regulates calcium transport, and magnesium replacement in magnesium-deficient postmenopausal patients resulted in unexpected improvement in documented osteoporosis, we investigated the effect of magnesium treatment on trabecular bone density in postmenopausal osteoporosis. Thirty-one postmenopausal patients (mean age +/- SD = 57.6 +/- 10.6 years), consecutively admitted to the Back Rehabilitation Unit with musculoskeletal pain of non-malignant origin and bone density values of < or = 1.19 g/cm3 (measured by Compton Bone Densitometer), received two to six tablets daily of 125 mg each of magnesium hydroxide (Magnesium Magma USP/; 'Mazor', Israel) for 6 months and two tablets for another 18 months in a 2 year, open, controlled therapeutic trial. Twenty-three symptom-free postmenopausal women (mean +/- SD = 61.2 +/- 6.2 years) whose bone density was concurrently assessed at the same laboratory and who were found to have osteoporosis but refused treatment, served as controls. No new fractures occurred. Twenty-two patients (71 per cent) responded by a 1-8 per cent rise of bone density. The mean bone density of all treated patients increased significantly after 1 year (P < 0.02) and remained unchanged after 2 years (P > 0.05). The mean bone density of the responders increased significantly both after one year (P < 0.001) and after 2 years (P < 0.02), while in untreated controls, the mean bone density decreased significantly (P < 0.001). The disparity between the initial mean bone density and bone density after one year in all osteoporotic patients and in the responders differed significantly from that of the controls (both P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVE: To evaluate the effect of hormone replacement therapy on platelet function in postmenopausal women. METHODS: In 51 postmenopausal women, platelet aggregation and adenosine triphosphate (ATP) release were studied before and after estrogen and progestogen treatment and compared with that in untreated patients. An incubation study evaluated platelet function after incubation with estrogen and progestogen. RESULTS: Significant decreases in adrenaline-induced platelet aggregation (P < .01) and ATP release (P < .02) were observed 3 months after initiation of estrogen replacement. Patients receiving replacement regimens consisting of estrogen opposed by progestogen or progestogen alone showed nonsignificant changes in platelet aggregation and release. The most pronounced decrease in platelet function in the incubation assay was detected after incubation with estrogen plus progestogen. Results were similar in the spontaneous- and surgical-menopause patients. CONCLUSION: Estrogen replacement therapy may inhibit the atherosclerotic process by suppressing platelet function.
This compassionate-use study examined the efficacy of foscarnet in patients with AIDS and cytomegalovirus (CMV) gastrointestinal disease who had failed ganciclovir induction. Nineteen male homosexuals with AIDS and biopsy-proven CMV gastrointestinal disease who had twice failed standard ganciclovir induction (defined as progression of clinical CMV disease) were studied. Foscarnet 60 mg/kg every 8 h was administered intravenously for 14 days, then maintenance was utilized at 90 or 120 mg/kg every day with 1 L normal saline daily. Endpoints included endoscopic appearance, blinded histopathologic analysis of biopsies for CMV inclusions, and changes in symptoms by 50% from baseline. Patients were evaluated before and 2-3 wk after foscarnet. Histopathologic improvement was seen in 67%, whereas 74% improved clinically after a median duration of 7.5 days (1-12). Among the nine with esophageal disease, six patients (68%) had a clinical response and six of eight (75%) had a pathologic response. Among the 10 with colonic disease, eight patients (80%) had a clinical response and six (60%) had a pathologic response. Reversible elevations in creatinine were seen in two of 17 (12%). Three patients with esophageal disease developed strictures late in therapy requiring dilation. Median survival after foscarnet induction was 5.0 months. Foscarnet appears to induce remission of CMV gastrointestinal disease in 67% of patients when ganciclovir induction has failed. Reversible nephrotoxicity occurred in 12%. Strictures may be a late complication of CMV esophagitis.
Basal morning plasma levels of immunoreactive-beta-endorphin (ir-beta-EP), and 17-beta estradiol (E2) were assessed in 25 adolescents with anorexia nervosa (AN) in comparison to 24 healthy controls. All subjects were drug free for at least 6 weeks. The mean plasma level of ir-beta-EP was significantly higher (84%) in the AN patients when compared with the control subjects. The elevated plasma ir-beta-EP may be relevant to the suppression of appetite, tolerance of fasting, and to the hypothalamic hypogonadism in AN.
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Airway responsiveness to methacholine and other bronchoconstrictors is highly variable within and among species. The aim of the experiments in this report was to evaluate the importance of the quantity of airway smooth muscle as a determinant of intra- and inter-species variability in airway responsiveness. To do this we established concentration-response curves to methacholine in a sample of normal guinea pigs as well as in rat, rabbit, and dog. After challenge we excised the lungs for the quantitation of smooth muscle by morphometry. Animals were anesthetized with pentobarbital and mechanically ventilated using a Harvard ventilator. Aerosols of methacholine were administered in progressively doubling concentrations from 0.0625 to 256 mg/mL for a period of 30 s for each concentration. The maximal response, determined from pulmonary resistance (RL), and the concentration of methacholine required to effect 50% of the maximal RL were determined. After provocation testing the lungs were removed and fixed with 10% Formalin. Midsagittal sections and parahilar sections were stained with hematoxylin-phloxine-saffron for microscopic examination of smooth muscle. The images of all airways in the sections were traced using a camera lucida side-arm attachment and digitized using commercial software. The area of the airway wall occupied by smooth muscle was determined and standardized for airway size by dividing it by the square of the epithelial basement membrane length. The variability in airway smooth muscle in the intraparenchymal airways was significantly greater between than within individual guinea pigs (n = 13). This was not true of extraparenchymal airways.(ABSTRACT TRUNCATED AT 250 WORDS)
We assessed pulmonary mechanics in six open-chest rabbits (3 young and 3 adult) by the forced oscillation technique between 0.16 and 10.64 Hz. Under control conditions, pulmonary resistance (RL) decreased markedly between 0.16 and 4 Hz, after which it became reasonably constant. Measurements of alveolar pressure from two alveolar capsules in each rabbit showed that the large decrease of RL with increasing frequency below 4 Hz was due to lung tissue rheology and that tissue resistance was close to zero above 4 Hz. Estimates of resistance and elastance, also obtained by fitting tidal ventilation data at 1 Hz to the equation of the linear single-compartment model, gave values for RL motion that were slightly higher than those obtained by forced oscillations at the same frequency, presumably because of the flow dependence of airways resistance. After treatment with increasing doses of aerosolized methacholine, RL and pulmonary elastance between 0.16 and 1.34 Hz progressively increased, as did the point at which the pulmonary reactance crossed zero (the resonant frequency). The alveolar pressure measurements showed the lung to become increasingly inhomogeneously ventilated in all six animals, whereas in the three younger rabbits lobar atelectasis developed at high methacholine concentrations and the alveolar capsules ceased to communicate with the central airways. We conclude that the low-frequency pulmonary impedance of rabbits exhibits the same qualitative features observed in other species and that it is a sensitive indicator of the changes in pulmonary mechanics occurring during bronchoconstriction.
The influence of a local injection of 0.05 ml/kg weight of 8 mg/ml methotrexate (MTX) was evaluated in 6 rabbit oviducts and compared with saline injections to the contralateral oviducts. Cell cultures of bovine oviducts were incubated in vitro for 7 days and then incubated for 24 h with 100-nmol MTX. Forty-eight and 72 h following the exposure to MTX, the treated and control cultures were harvested. Specimens and cultures were examined by light and scanning electron microscopy. In the in vivo cohort, no differences were observed between MTX and control groups. However, in MTX-treated cell culture, ciliated cells demonstrated partially adherent cilia in about 30% of the cells. The effect of MTX observed only in vitro treated cells may be due to the rapid proliferation of epithelial cells in culture which does not represent the physiological role of the oviduct in vivo.
The association between plasma calcitonin and beta-endorphin has been shown in various studies with analgesic and thermoregulatory effects. In the present study, we sought a similar association between those chemicals and physiological menopausal hot flush. Plasma calcitonin and beta-endorphin levels were measured in 5 women in physiologic menopause who suffered from frequent episodes of hot flushes. An increase in plasma calcitonin levels was noted during the hot flushes, although it was not significant. In contrast, plasma beta-endorphin levels fell significantly at onset of the hot flush, as compared to their levels 5-20 min earlier (p less than 0.005), and rose 5-15 min following the hot flush episode.
Natural cell-mediated cytotoxicity (CMC), spontaneous release of tumor necrosis factor (TNF-alpha) by mononuclear cells in vitro, and PHA-induced interferon (IFN-gamma) production were examined by standard methods in 14 females with anorexia nervosa (AN) and marked weight loss and in 16 normal matched controls. The results were confirmed by neutralization with monoclonal antibodies. In the anorectic patients there was a significant increase in TNF production (16 +/- 5 vs 4 +/- 3 mu/ml), and depressed CMC (4 +/- 2 vs 10 +/- 3 lytic units per 50/10(6) cells) and IFN-gamma production (172.5 +/- 25 vs 367 +/- 34 mu/ml). Following successful refeeding and nutritional rehabilitation, all values returned to normal. Thus there are changes in cytokines and defective natural cytotoxicity in AN, apparently related to undernutrition and not to neuroimmunomodulation. The increased TNF-release may further suppress food intake and enhance tissue catabolism, suggesting that nutritional rehabilitation should be the earliest therapeutic goal in anorexia nervosa.