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Biomedical subjects

S Kullander

Publications and source records attributed to S Kullander.

At least 19 recordsLinked to original sources

Treatment of endometrial cancer with GnRH analogs.

Given the small number of side effects, GnRH may be a useful and ideal drug for new therapeutic hormonal approaches in many cases of both invasive and noninvasive endometrial cancer. The hypoestrogenic state thus induced as well as a local effect may lead to pronounced regression of the tumor. Any future therapy should, however, always be tailored to meet individual needs. The use of GnRH agonists may be advocated in the following circumstances: 1. In pronounced endometrial hyperplasia and adenomatous hyperplasia (particularly relevant in those cases where hysterectomy is not desirable, e.g., in young patients who have not yet completed their families). 2. In patients with endometrial cancer where surgery is contraindicated or refused. 3. In addition to or as a substitute for radium treatment preoperatively to reduce uterine volume (myomas) to make surgery technically easier; to devitalize the tumor, stop menorrhagia, and improve anemia. 4. In advanced cases as an adjunct to radiotherapy and gestagens. It is possible that this will produce synergistic effects. 5. As adjuvant treatment (replacing gestagens?) in primary stages. 6. In relapses of endometrial cancer, refractory to conventional therapy, and in pulmonary metastases.

Adult

Intracellular actions of steroid hormones and their therapeutic value, including the potential of radiohalosteroids against ovarian cancer.

The biological activities of steroid hormones are effected via intracellular receptors. The receptors are part of a ligand-activated family of transcription regulator proteins that are critical for steroid-regulated cell differentiation. With recombinant cDNA technology, yeast and cultured animal cells can be made to express mammalian cDNA steroid receptors from cDNA clones that contain deletions and substitutions. Among the leading problems addressed in these models is the characterization of sequences that promote association or interaction with other transcription regulating molecules, including oncogene products. Recently it has been found that heat shock proteins may serve not only to stabilize the receptor proteins but also to precondition the activation imparted by ligand binding. Aberrant receptor proteins can be found in ovarian cancer. Whether aberrant receptor proteins are associated with transformation in general or with a variable clinical response to steroidal or anti-steroidal therapy is not known. Even after chemotherapy, steroid receptors are expressed in the metastases of ovarian cancers seen clinically, and they may have potential uses for localization and treatment of receptor-rich cancers. Radioligand pharmaceuticals appropriate for imaging or for site-directed radiocytotoxicity can be sequestered to the nuclei of receptor-rich cancers. Initial clinical imaging and therapy trials with such pharmaceuticals have been approved and begun. In the use of halogenated estrogen radiopharmaceuticals, liver metabolism and enterohepatic recirculation are important considerations. Ascites prolongs retention of a radiohalogenated estrogen in the abdominal cavity. Distant metastases have been localized with [123I]-estrogen in breast cancer patients in pre-operative procedures. Receptor-mediated cytotoxicity occurs when estrogen receptor radioligand pharmaceuticals that are Auger electron emitters are used in vitro.

Animals

Specific low affinity binding sites for gonadotropin-releasing hormone in human endometrial carcinomata.

Specific low-affinity high-capacity binding sites for gonadotropin-releasing hormone (GnRH) have recently been discovered in human breast and ovarian carcinomata. We checked whether similar binding sites are present in human endometrial cancer. Plasma membrane preparations were incubated with [125I,D-Ala6-desGly10]-GnRH-ethylamide in the presence or absence of unlabelled GnRH agonists or other peptides. GnRH-binding could be demonstrated in all 12 tumor samples tested. The mathematical analysis of the binding data was consistent with a single class of low affinity (Ka = (0.8-1.4) x 10(5) M-1) and high-capacity (Bmax = (134-142) x 10(-12) M/mg membrane protein) binding sites. Native GnRH had a similar affinity to the binding sites as the GnRH agonist used. Other peptides such as oxytocin, somatostatin and thyrotropin-releasing hormone did not crossreact with the binding sites. A photolabelled derivative of [D-Lys6]-GnRH was prepared with the bifunctional photolabile reagent (4-azidobenzyl)-N-hydroxysuccinimide. Photoaffinity labelling of endometrial carcinoma membranes and subsequent sodium dodecyl sulfate electrophoresis in 10% polyacrylamide gel revealed the presence of a single molecular mass component of 62 +/- 1.9 kDa. The appearance of this photolabelled binding site could be largely suppressed by the addition of unlabelled GnRH-agonist (10(-4) M) and thus represents the specific binding site for GnRH in endometrial cancer.

Affinity Labels

Prolonged clearance of intraperitoneal 16 alpha-[125I]iodo-17 beta-estradiol in presence of ascites.

Radioestrogens have potential as adjunct therapeutic agents against ovarian carcinoma, because selected radionuclides can deposit lethal doses of radiation to tumor cells and many ovarian carcinomas and their metastases express estrogen receptors. Because intraperitoneal administration is a possible approach, we investigated absorption from the peritoneal cavity of a radioiodoestradiol after intraperitoneal application in rats with and without ovarian tumors and ascites and compared the distribution of the radioactivity with that obtained after intravenous injection. In the absence of ascites, 70% of the intraperitoneal dose was cleared into the intestine within 2 hours after injection, indicating fast absorption from the peritoneal cavity. In the presence of ascites, clearance of intraperitoneal radioiodoestradiol was considerably slower; at 2 hours after injection, 50% of the injected dose remained in the ascites, mostly as radioiodoestradiol. Uptake of radioactivity in estrogen receptor-rich tissues, e.g., uterus, after intraperitoneal injection was high (about 20:1 over blood), regardless of the presence of ascites, but moderately lower than that observed after intravenous injection of radioiodoestradiol.

Animals

Bacterial infection in relation to pain and irregular bleeding in women using IUD.

Pain and metrorrhagia in women using IUDs are often the reason for removing the IUD. In 54 women where the IUD was removed, uterine fluid for bacteriologic cultures was taken from the removed IUD. There was a correlation between positive cultures and symptoms of pain and metrorrhagia. Spotty bleeding caused by microtraumata and increased fibrinolytic activity of the IUD might thus consitute a substrate for bacterial invasion resulting in endometritis and in turn increased bleeding and pain. In 18 male consorts of females with positive cultures, asymptomatic bacteriospermia was found. Treatment offered alleviated symptoms. Removal of the IUD need thus not be necessary.

Bacterial Infections

Bromocriptine treatment of the premenstrual syndrome.

Bromocriptine, 2.5 mg twice a day was tested for its effect on premenstrual tension in a random double-blind cross-over trial. 1. The compound tended to lessen the symptoms, especially mastodynia. 2. Serum prolactin levels around the upper limit of the normal range were significantly lowered. Patients with the highest starting prolaction levels had the most severe symptoms and in these patients the fall in the levels was greatest. 3. Serum FSH and LH levels were significantly reciprocally influenced compared with serum prolactin. Serum estradiol-17-beta and progesterone did not change during treatment. 4. The bromocriptine-treated cycles were all ovulatory according to basal temperature levels. The luteal phase was prolonged when serum FSH was raised.

Adult

Heterogeneous response of disseminated human ovarian cancers to cytostatics in vitro.

Cell suspensions from nine human ovarian primary cancers, their metastases and ascitic cells were treated in vitro with amethopterin and melphalan. Effects were measured by incorporation of H3-TdR or H3-UdR into the cells. There was significant heterogeneity of cytostatic effects on cells from the three sources in a given patient. Ascitic cells did nt represent a "mean" of the cancer cell clones. The implications of these findings should be considered if cytostatic in vitro prediction tests are used to guide cytostatic treatment of patients.

Ascitic Fluid

On improved outcome of twin pregnancies.

During the past four years, an attempt has been made in Malmö to reduce the frequency of preterm termination of twin pregnancies. For this purpose, the entire pregnant population of this medium-sized city was subjected to general ultrasonic screening in the second trimester. This detected 88 per cent of the twin pregnancies. The screening has a methodological error of 2 per cent. Eightysix of the women with twin pregnancy were subjected to bedrest in hospital for more than two weeks in the second half of gestation. The incidences of twins born with birth weight below 1 500 g and of twins light-for-gestational-age were reduced compared with those a decade earlier. Also the group of twins born before the 37th week decreased, and the perinatal mortality rate fell to the same level as in singleton pregnancies. Early detection of twin pregnancies followed by rest for the pregnant women seems to contribute to an improved outcome of these gestations.

Birth Weight

On receptors for estrogens (E2) and androgens (DHT) in human endometrial carcinoma and ovarian tumours.

Some human endometrial carcinomas contain receptors for estrogen (E2) and dihydrotestosterone (DHT). Analysis of 50 primary endometrial carcinomas by agar gel electrophoresis revealed a varying receptor pattern, absence of both receptors, sole presence of E2- or DHT- receptor, or presence of both. Highly differentiated tumours often had receptors of both types (7/18) and poorly differentiated tumours most often lacked them (1/10). Primary tumours with metastases (Stages III-IV) seldom had combined receptors, only in 2 cases out of 9. Growth of the tumour down in the cervical canal (Stage II) implied absence of combined receptors in all of the 13 cases studied. In 8 different ovarian tumours, presence of either E2- or DHT-receptors was found in 6. The findings are discussed in relation to hormonal treatment of the disease.

Female

Human ovarian tumours heterotransplanted to "nude" mice.

22 different human ovarian tumours were heterotransplanted subcutaneously to female "nude" mice. When small tissue pieces were used 10 out of 16 tumours grew. Subcutaneous injections of suspended tumour cells were made to 11 mice: all failed. Metastatic or infiltrative growth was never seen in the mice observed for up to 25-40 days. Material from each tumour was transplanted to four separate sites in two mice. The successful grafts largely retained the original morphological features. As measured with H3-thymidine incorporation, DNA-synthesis was also similar in the original tumours and the growing grafts. This animal in vivo model might be highly informative for the study of inter alia fundamental biology, chemotherapy, and irradiation of ovarian tumours.

Animals

Antineoplastic-drug effect evaluated with a new X-ray stereophotographic measurement of the tumour volume.

A method for determination and follow up of the size of inoperable intraabdominal tumours has been devised. At laparotomy, tantalum balls are deposited into the capsule of the tumour. An X-ray stereophotogrammetric method determines their position, which define a polyhedron whose volume can be computer calculated. The value of the method was proved in four patients with inoperable ovarian carcinoma, which provides a simple way for the continuous follow up of the effect of antineoplastic therapy in advanced malignant tumours.

Abdominal Neoplasms

Intrauterine breathing movements and fetal presentation.

Fetal breathing movements in 14 twin pregnancies were examined with ultrasonic technique. The twin fetuses I in cephalic presentation showed a significantly higher percentage of apnea and periodic breathing compared with twin fetuses II. No such difference was found in twin pairs with Twin ti in breech presentation. Also in the control group of 27 singleton pregnancies, the fetuses in cephalic presentation had a higher incidence of apnea and periodic breathing than those in breech presentation. The position of the fetus seems to be decisive for the character of the breathing movements before birth.

Female

Coagulative and fibrinolytic studies on postmenopausal women treated with a new non-steroidal oestrogen.

Treatment of postmenopausal women with a non-steroid oestrogen (P1496) in a dose of 50 mg a day for 2 ,days before operation for prolapse did not suppress the histochemically determined fibrinolytic activator content of the vessel wall. Neither was any change found in the concentration of P&P-complex (prothrombin, factor VII, factor X), factor VIII, antithrombin III, alpha1-antitrypsin, alpha2-macroglobulin or the inhibitors of urokinase induced plasminogen activation. Nothing suggested a thrombogenic effect of this non-steroidal oestrogenic compound.

Aged

Fever and parturition. An experimental study in rabbits.

The hyperthermic effect of purified lipopolysaccharides (Pyrexal, Wander) was tested and analyzed in pregnant rabbits. The fever produced premature deliveries - probably caused by oxytocin, released from the posterior pituitary - in 50% of 40 tested rabbits on the 31st day of gestation. Injections of Syntocinon had a roughly equally strong effect. In control animals injection of saline did not accelerate delivery. The offspring of several animals, in which hyperthermia had been induced, were born dead. Fever during pregnancy thus can result in premature delivery and in injury to the fetus. Fever and febrile conditions occurring during pregnancy should therefore be treated as promptly and as effectively as possible.

Animals

Ultrasound and human-placental-lactogen screening early detection of twin pregnancies.

In the past five years gradual introduction of ultrasonic screening of pregnant women increased the ante-partum detection of multiple pregnancy from 60% in 1971 to 95% in the first half of 1975. At the same time the average gestational age for dection of multiple pregnancies diminished from thirty-three to twenty-five weeks. The corresponding figures for 1963 were 32% and thirty-six weeks. Plasma human-placental-lactogen concentrations were assessed for their value in selecting a smaller target group for subsequent ultrasonic screening. All but 2 of 39 twin pregnancies examined by single H.P.L. determinations had H.P.L. values more than 1 S.D. above the mean of the normal distribution. The use of plasma-H.P.L. screening might lower the proportion of patients requiring ultrasonography for antepartum diagnosis of multiple pregnancies to 16% of the total pregnant population.

Evaluation Studies as Topic