[Non-Hodgkin´s B-lymphoma of the ovaries with an unfavourable prognosis - incidental finding during caesarean section]. / Non-Hodgkinuv B-lymfom ovarií s nepríznivou prognózou - náhodný nález pri císarském rezu.

OBJECTIVE: Presentation of a rare finding non-Hodgkin´s B-lymphoma of the ovary in a patient during caesarean section. DESIGN: Case report. SETTINGS: Department of Obstetrics and Gynaecology, Regional Hospital Liberec, a.s.; First Internal Clinic - Clinic of Hematology, First Faculty of Medicine and General University Hospital, Charles University in Prague; Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University in Praque and Motol University Hospital. RESULTS: Pregnant woman, 31-years old, primiparous, with a history of caesarean section was examinated in our department due to nonspecific abdominal pain during her pregnancy. During the caesarean section of fetal indication we found bilateral ovarian tumours. We performed unilateral adnexectomy. Preliminary diagnosis from frozen section was thecoma, but final diagnosis (after definitive histology, imunohistochemistry and molecular investigation) was high-grade B-cell non-Hodgkin´s lymphoma with c-myc and bcl-6 gene rearrangement (double-hit lymphoma) resulting in an unfavourable prognosis. The patient consequently completed 6 cycles of chemotherapy with a biological treatment, and achieved a complete remission. However, after 6 months, an early generalisation to the CNS appeared, leading to intracranial hypertension refractory to anithypertensive and anti-oedematous therapy, consequently leading to death. CONCLUSION: Non-Hodgkin´s lymphoma of the ovary in pregnancy is a rare adnexal tumour whose treatment requires interdisciplinary cooperation.

A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI147211 given as a 72-h continuous infusion.

GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily pretreated. Phlebitis occurred with infusions through peripheral veins early in this study, necessitating the use of central venous access. Other toxicities included mild nausea and vomiting, fatigue, headache, central venous catheter infections and alopecia. Three partial and two minor responses lasting 8-34+ weeks were noted in patients with ovarian, colon and breast carcinomas and hepatoma. Mean steady-state concentrations of Gl147211 increased with dose over a range of 0.25-1.24 ng ml(-1). The mean terminal elimination half-life was 7.5 h, and the clearance averaged 1074 ml min(-1) m(-2) over the doses studied. The mean fractional excretion of unchanged drug in urine was 0.114. Gl147211 lactone exposure correlated with haematological toxicity. The recommended phase II doses for this regimen are 1.75 mg m(-2) day(-1) and 1.2 mg m(-2) day(-1) for minimally pretreated and heavily pretreated patients respectively. At these doses, steady-state Gl147211 concentrations within the range of those effective in vitro were achieved. Extensive phase II evaluation of this compound and further phase I trials evaluating more prolonged infusions are ongoing.

Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis.

BACKGROUND: Orthotopic liver transplantation in patients positive for hepatitis B virus (HBV) DNA is associated with a high reinfection rate, even with hepatitis B immunoglobulin (HBIG) prophylaxis. Nucleoside analogues that inhibit hepatitis B replication in patients with chronic hepatitis B could prevent reinfection after transplantation. The aim of this study was to analyse the efficacy and safety of prophylaxis both before and after transplantation with the nucleoside analogue lamivudine, without HBIG, in patients undergoing liver transplantation. METHODS: 17 HBsAg-positive patients with decompensated cirrhosis and previous evidence of viral replication were enrolled. 12 were HBV-DNA-positive by a signal amplification assay. Patients were treated with oral lamivudine (100 mg daily) for at least 4 weeks before transplantation and followed up for 18-90 weeks after transplantation. FINDINGS: HBV DNA became undetectable in serum before transplantation in all HBV-DNA-positive patients. Four died before transplantation from complications of cirrhosis; one patient was withdrawn from the study because of a cerebrovascular accident. The remaining 12 patients underwent transplantation. Two patients died after transplantation (one at 3 days and one [suicide] at 20 weeks). HBV DNA reappeared in one patient with histological evidence of recurrent hepatitis (72 weeks). By week 24 the nine remaining patients had lost HBsAg and remained negative for HBV DNA. INTERPRETATION: Lamivudine treatment may prove useful in preventing recurrence of hepatitis B after liver transplantation. The effect on survival of patients after transplantation remains to be assessed.

Phase I study of intravenous fosquidone (GR63178A-NSC D611615) using a three times a week schedule.

In a Phase I study fosquidone was administered to 23 patients (15 female, 8 male; mean age 53.6 years) with various solid tumours. Increasing doses (50-325 mg/m2) were given intravenously three times a week for 3 weeks. The MTD was established a 325 mg/m2 dose, the dose limiting factor being phlebitis in two of three patients. The other main side-effects were headache (9 patients), pain (11 patients) and nausea and vomiting (16 patients). The majority of these were mild (WHO grade 1-2), but two patients reported WHO grade 3 and 4 pain. There was no clear relationship between dose, severity and frequency of side-effects. Four tumour regressions (three minor and one partial response) were achieved at varying dose levels (50, 100, 160 and 325 mg/m2) in patients with different tumours (laryngeal, colorectal and lung). The recommended dose for Phase II studies is 250 mg/m2 given intravenously three times a week for 3 week.

Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study.

OBJECTIVE: To compare the efficacy and side effects of ondansetron with those of high-dose metoclopramide in treating acute and delayed cisplatin-induced nausea and vomiting. DESIGN: Randomized, double-blind, crossover trial. SETTING: Conducted at two university hospitals, a cancer institute, and six community hospitals. PATIENTS: Of 125 patients, 95 were evaluable for the acute phase and 79 for the delayed phase. Major reasons for not being evaluable were no second course (14 patients), protocol violation (5 patients), and change in cisplatin dose (3 patients) for the acute phase, and rescue medication on day 1 (7 patients), protocol violation (3 patients), and inadequate data (4 patients) for the delayed phase. INTERVENTIONS: All patients received cisplatin, 50 to 100 mg/m2 body surface area (median, 75 mg/m2); none had previously received chemotherapy. Thirty minutes before the cisplatin administration, ondansetron was given intravenously over 15 minutes, at a loading dose of 8 mg followed by a continuous infusion of 1 mg/h for 24 hours. Metoclopramide was given at a loading dose of 3 mg/kg body weight, followed by a continuous infusion for 8 hours (4 mg/kg). For the delayed phase (days 2 through 6), the first oral dose was given as soon as the infusion was completed; the oral dose consisted of either metoclopramide, 20 mg three times daily, or ondansetron, 8 mg three times daily for another 5 days. MEASUREMENTS AND MAIN RESULTS: In the acute phase, a major or complete response was seen in 72% of the ondansetron-treated and 41% of the metoclopramide-treated patients (P less than 0.001). Nausea was significantly better controlled among the ondansetron-treated patients (P = 0.04). In the delayed phase, no statistically significant difference was seen between ondansetron- and metoclopramide-treated patients. Nausea was significantly better controlled with metoclopramide (P = 0.016). CONCLUSIONS: Ondansetron is significantly more effective than metoclopramide in preventing acute nausea and vomiting. In the delayed phase, the results of both drugs were disappointing, although metoclopramide's effect on delayed nausea was superior. Patients preferred ondansetron.

The effects of sequential treatment with ethynyloestradiol and medroxyprogesterone acetate on oestrogen and progestogen receptors in breast cancer.

As part of a clinical study designed to modulate oestrogen and progestogen receptor (ER and PR) binding site concentrations prior to chemotherapy ER and PR levels have been estimated immediately before treatment, after ethynyloestradiol (EE, 10 micrograms/day, 1 week) and after medroxyprogesterone acetate (MPA, 500 mg/day i.m., 2 weeks) in tumour tissue from 14 women with advanced breast cancer. There was no consistent change after EE treatment. MPA tended to decrease ER and PR levels, though some increases were also seen. Responses (10 complete and 3 partial remissions) to sequential cyclical hormono-chemotherapy were not related to ER or PR levels prior to chemotherapy.

A direct assay for oestrone sulphate and its use to investigate the effect of ampicillin on plasma levels of oestrone sulphate.

A direct radioimmunoassay for measuring plasma levels of oestrone sulphate has been developed using 8-anilino-2-naphthalene sulphonic acid to displace oestrone sulphate from plasma binding proteins. Oestrone sulphate was assayed by using an antiserum raised against glucuronide which cross-reacted 100% with oestrone sulphate. The direct assay gave a good analytical recovery of oestrone sulphate and there was a good correlation (r = 0.82, P less than 0.001) for plasma levels of oestrone sulphate measured by the direct assay and a method involving steroid conjugate extraction and enzyme hydrolysis. The mean (+/- S.D.) plasma level of oestrone sulphate in men was 1100 +/- 280 pg/ml. The effect of taking the antibiotic, Ampicillin, on plasma levels of oestrone sulphate was investigated in four men. Plasma levels of oestrone sulphate were significantly reduced after taking Ampicillin for 5 days. Ampicillin may act to lower plasma levels of oestrone sulphate by reducing the growth of bacteria in the gut or by inhibiting oestrogen sulphotransferase activity.

The effect of ethynyloestradiol and medroxyprogesterone acetate on the in vivo uptake and metabolism of 3H-oestradiol by breast tumour tissue in postmenopausal women.

The uptake and metabolism of 3H-oestradiol by breast tumour tissue was studied in three postmenopausal women before, after 1 week of treatment with ethynyl-oestradiol (EE, 10 micrograms/day) and again two weeks later after treatment with medroxyprogesterone acetate (MPA, 500mg/day, i.m.). Treatment with EE reduced the tissue: plasma gradients for both 3H-oestradiol and 3H-oestrone and little further change in these ratios occurred after MPA treatment. The proportion of oestrogen present as 3H-oestrone increased in tumours from 2/3 women after treatment with MPA but not EE, although no increase in the activity of oestradiol 17 beta-hydroxysteroid dehydrogenase (E2DH) was detected. Plasma and tissue concentrations of 5-androstenediol, dehydroepiandrosterone and dehydroepiandrosterone sulphate were all reduced after MPA treatment. The results from this study show that treatment with EE and MPA can reduce the uptake of oestradiol by breast tumours. No increase in E2DH activity was detected but it is possible that MPA influences other enzymes involved in oestradiol metabolism.

The effect of cortisol or ACTH on plasma concentrations of free fatty acids.

The effect of infusion of cortisol (14 mumol) or ACTH (Synacthen, 250 micrograms) injection on plasma levels of free fatty acids has been examined in normal men. The increment in plasma cortisol levels after infusion of cortisol (+182%) was much less than after ACTH injection (up to 262%). Mean plasma levels of free fatty acids were only significantly increased after ACTH injection. However, some inter-subject variation occurred and a small but significant increment in plasma levels of free fatty acids was seen for one control subject and for a subject who received an infusion of cortisol. It is possible that the reported diurnal variations in plasma levels of free fatty acids may be related to changes in plasma levels of ACTH or cortisol throughout a 24h period.

Peripheral oestrogen metabolism in postmenopausal women with or without breast cancer: the role of dietary lipids and growth factors.

Studies we have carried out have revealed significant differences in oestrogen production and metabolism between normal women and postmenopausal women with breast cancer. The free, biologically available fraction of oestradiol is elevated in plasma from women with breast cancer and we have found that metabolic clearance rates and production rates of oestradiol are also increased. In vitro studies have suggested that lipids can influence the distribution of sex steroids in plasma and we have therefore examined the effect of dietary lipids on the distribution of sex steroids in plasma in vivo. Consumption of a meal with a high saturated fat content or the oral or i.v. administration of "Intralipid", a stabilised emulsion of soya bean oil that is high in unsaturated free fatty acids, had little effect on the available fractions of oestradiol in plasma. However, results from a preliminary study suggest that long-term changes in dietary fat intake can alter the distribution of steroids in plasma. It is concluded that dietary lipids may influence the availability of sex steroids to tissues. Such a mechanism could account for the significant correlation that has been found between dietary fat consumption and the incidence of breast cancer on a world-wide basis.

Estrogen production and metabolism in normal postmenopausal women and postmenopausal women with breast or endometrial cancer.

The metabolic clearance rates of estradiol in postmenopausal women with breast cancer (1269 +/- 370 1/24 hr, mean +/- S.D.) or endometrial cancer (1320 +/- 238 1/24 hr) were significantly higher than in normal postmenopausal women (922 +/- 238 1/24 hr). The metabolic clearance rates of estrone were elevated in women with endometrial cancer (2012 +/- 749 1/24 hr) or with conditions associated with an increased risk for breast or endometrial cancer (1830 +/- 413 1/24 hr) compared with values for normal postmenopausal women (1321 +/- 301 1/24 hr). The production rate of estradiol was only increased in women with breast cancer. Significant correlations were found between subjects' percentage of ideal body wt and the metabolic clearance rates of estrone and estradiol and also the production rate of estrone. The increased clearance rates may reflect differences in either the binding of estrogens to plasma proteins or the tissue metabolism of estrogens in cancer patients.

The role of tissue steroids in regulating aromatase and oestradiol 17 beta-hydroxysteroid dehydrogenase activities in breast and endometrial cancer.

We have observed that oestradiol concentrations in breast and endometrial tumours are relatively higher than oestrone, in contrast to peripheral tissues. Infusion of radiolabelled oestrogen also suggested there was a difference in metabolism between normal and tumour tissue. We have therefore looked for factors which could modulate tissue steroid metabolism and conclude that progesterone may influence aromatase, and that the adrenal androgens can inhibit oestradiol dehydrogenase activity. The latter mechanism, in particular, may be important in increasing tissue exposure to oestradiol.

The effect of glucocorticoids on the in vivo conversion of androstenedione to oestrone.

In vitro studies have previously shown that the activity of the aromatase enzyme system, which is responsible for the conversion of androstenedione to oestrone, can be stimulated by natural and synthetic glucocorticoids and also by ACTH. In view of the potential physiological importance of such a regulatory mechanism we have examined the effect of administration of dexamethasone, and of ACTH on the conversion of androstenedione to oestrone in vivo. The transfer constants for the conversion of androstenedione to oestrone [( rho]AEBU) measured in two women before administration of dexamethasone were 1.0% and 1.1% and after were 0.9% and 1.2%. Similarly no increase in conversion of androstenedione to oestrone [( rho]AE1BB) was detected after ACTH stimulation (pre = 0.74%, post = 0.77%). It is concluded from this study that glucocorticoids and ACTH do not have a role in regulating aromatase activity in vivo.

A comparison of the in vivo uptake and metabolism of 3H-oestrone and 3H-oestradiol by normal breast and breast tumour tissues in post-menopausal women.

After infusion of 3H-oestradiol or 3H-oestrone into post-menopausal women with breast cancer, there was a significant uptake of both steroids by breast tumour and normal tissue. The proportion of oestrogen present in tumour tissue as 3H-oestradiol after infusion of 3H-oestradiol (89.4 +/- 3.5%, mean +/- SD, n = 4) was significantly higher (p less than 0.001) than in normal breast tissue (72.8 +/- 3.3%) obtained from the same women. Similarly, after infusion of 3H-oestrone, the proportion of oestrogen present as 3H-oestradiol (48.4 +/- 14.4%) was significantly higher than in normal breast tissue (19.1 +/- 6.4%). These results suggest that conversion of oestrone to oestradiol is enhanced in breast tumour tissue with little metabolism of oestradiol. This would account for the higher concentrations of oestradiol reported in breast tumour tissue in the presence of increased oestradiol 17 beta-hydroxysteroid dehydrogenase activity.

The effect of epidermal growth factor, transforming growth factor and breast tumour homogenates on the activity of oestradiol 17 beta hydroxysteroid dehydrogenase in cultured adipose tissue.

The effect of epidermal growth factor (EGF), transforming growth factor (TGF alpha) and breast tumour homogenates on oestradiol 17 beta hydroxysteroid dehydrogenase (E2DH) activity has been examined using cultured human breast adipose tissue. EGF (100-1000 ng/ml) inhibited E2DH activity (E1----E2) in a dose dependent manner. TGF alpha (250 and 500 ng/ml) stimulated E2DH activity, with conversion of E1----E2 increasing to a greater degree than E2----E1 activity. Breast tumour homogenates (2-10% w/v) also influenced E2DH activity. It is concluded that growth factors, produced by breast tumours, may modulate E2DH activity in tissues surrounding the tumour and thereby influence tumour growth.

Oestrogen production and metabolism in peri-menopausal women.

The metabolic clearance rates and production rates of oestrone and oestradiol have been measured in a group of peri-menopausal women either with breast or endometrial cancer or having an increased risk of developing one of these diseases. The results were compared with values for normal post-menopausal women in whom the menopause was established. The transfer constants for the conversion of oestrone to oestradiol and of oestradiol to oestrone were also measured. Metabolic clearance rates for oestrone (1946 +/- 406 1/24 h) and oestradiol (1296 +/- 261 1/24 h) for peri-menopausal women, and production rates of oestrone (90 +/- 38 micrograms/24 h) and oestradiol (45 +/- 33 micrograms/24 h) were significantly higher than for normal post-menopausal women. Transfer constants for the conversion of oestrone to oestradiol and of oestradiol to oestrone were similar in the peri- and post-menopausal women. Plasma progesterone concentrations were less than 0.4 ng/ml in both groups of women. It is possible that the higher oestrogen production and clearance rates of peri-menopausal women, at a time when progesterone production is greatly reduced, may in part account for the higher risk that post-menopausal women have for developing breast or endometrial cancer.

Free fatty acids: a possible regulator of the available oestradiol fractions in plasma.

Consumption of dietary fats has been linked to the high incidence of breast cancer found in Western women. In vitro studies we have carried out show that unsaturated free fatty acids can increase the biologically available oestradiol fractions in plasma. It is possible therefore that the increased risk for breast cancer associated with a diet high in fats may be related to an elevation in the biologically available oestradiol fractions in plasma.

Metabolism of [3H]oestradiol in vivo by normal breast and tumour tissue in postmenopausal women.

Tumour and normal breast tissue was obtained from postmenopausal breast cancer patients following [3H]oestradiol infusion (50 mu Ci over a 12 h period). The fraction of radioactivity present as oestradiol or oestrone was measured and the results expressed both as the ratio of oestradiol-oestrone and as the percentage oestrogen present as oestrone, and the findings compared with in vitro measurements of 17 beta-hydroxysteroid dehydrogenase activity. Concentrations of 5-androstene-3 beta, 17 beta-diol, dehydroepiandrosterone and its sulphate and testosterone were measured and related to oestradiol metabolism. The study demonstrated that tumour tissue is less able to metabolise oestradiol to oestrone than is normal breast tissue and indicated that the ability of the tissue to detoxify oestradiol may be dependent on cofactor availability. The results also supported the possibility that increased tissue concentrations of adrenal androgens inhibit oestradiol and thus increase tissue exposure to oestradiol.