Search

The International Society of Gynecological Pathologists recently agreed on a classification of endometrial hyperplasia into two main groups; hyperplasias with and without atypia. The lesions were further subdivided into simple and complex hyperplasia. These guidelines were subsequently adopted by the World Health Organization. The disease is a result of oestrogen/gestagen imbalance with oestrogen overexpression. The most important prognostic factor is cellular atypia. Progress to invasive cancer is seen in about 20% of the patients with atypical hyperplasia, and most frequently occurs in postmenopausal women. The treatment of endometrial hyperplasia depends on histologic type, patients' age and whether the hyperplasia is a result of endogenous or exogenous oestrogen overexpression. The risk for progression to invasive cancer is minimal in oestrogen treated patients with simple or complex hyperplasia without atypia. Women under 40 years of age in this group can safely be treated with gestagens. In postmenopausal women with simple or complex hyperplasia with atypia, the recommended treatment is surgery including removal of the uterus and the ovaries.

The influence on uterine contractility of inflammatory cytokines like interleukin-6 is widely unknown. We were able to demonstrate in 16 human myometrial strips obtained during caesarean section in the organ chamber a highly significant (P0.001) increase of the activity of uterine strips after addition of IL-6. This further emphasizes the importance of subclinical infections for the etiology of so called idiopathic preterm labour.

Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer. Retinoic acid receptor-gamma (RAR-gamma) has been shown to mediate the antiproliferative activity of retinoids. To further test this hypothesis we examined the effects of different RAR-gamma selectively binding retinoids (CD2325, CD2247, CD666 and CD437) on breast cancer cell lines. With exception of CD2247, all retinoids inhibited proliferation of MCF-7, SKBR-3, T47D and ZR-75-1 breast cancer cell lines, similar to the natural compound all-trans retinoic acid (ATRA). In addition, all 4 compounds were able to act synergistically with interferon-gamma (IFN-gamma) in all breast cancer cell lines including the retinoid-resistant BT-20 and 734-B lines. In functional transactivation assays we demonstrated that only in the MCF-7 cell line, TPA-mediated AP-1 activity was suppressed only by ATRA and CD2325, whereas in SKBR-3, another RA-sensitive breast cancer cell line, it was not. The synergistic antiproliferative activity involving retinoids and IFN-gamma could not be explained by an enhanced anti-AP-1 activity. No correlation was found between expression of RARs and cellular retinoic acid binding proteins (CRABPs) and antiproliferative effects of the retinoids. RAR-gamma selectively binding retinoids are potent inhibitors of breast cancer cell proliferation, alone and in combination with IFN-gamma. For this reason and because of a possible low toxicity, as compared with retinoic acid, we speculate that these RAR-gamma selective binding retinoids might be of clinical importance.

90K is a tumor-associated antigen. Using myelomonocytic cell line THP-1 we determined neopterin production and tryptophan degradation after exposure of cells to 90K in the presence and the absence of interferon-gamma. Interferon-gamma is a well known stimulus for THP-1 cells inducing e.g. neopterin production and tryptophan degradation. Treatment of cells with 50 micrograms/ml 90K induced significant neopterin formation, and the exposure of cells to 90K in addition to 100 U/ml interferon-gamma amplified neopterin production compared to the sole effect of interferon-gamma. In parallel, a significant degradation of tryptophan was observed in culture supernatants leading to the formation of kynurenine. When the cells were treated with the combination of 90K and interferon-gamma the degradation of tryptophan was further enhanced. The data demonstrate that tumor-associated antigen 90K interferes with immunocompetent target cells and is able to induce a biochemical response in monocytic cells.

Ovarian cancer arises mostly from the ovarian surface epithelium. The aim of our study was to compare the effects of cytokines in ovarian surface epithelial (OSE) cells and in ovarian carcinoma cells. Proliferation and expression of surface antigens (CA-125 and classes I and II antigens of the major histocompatibility complex [MHC]) were measured in OSE cells obtained from 7 different patients and 7 ovarian carcinoma cell lines. Proliferation of OSE cells remained unaffected by interferon (IFN)-alpha or IFN-gamma, whereas interleukin-1 (IL-1) and tumor necrosis factor (TNF) increased cell growth. Proliferation of ovarian carcinoma cells was reduced by both types of IFN as well as TNF but was not affected by IL-1. Expression of the tumor marker CA-125 was increased by IFN-gamma in ovarian carcinoma cells but not by any other treatment. None of the cytokines affected CA-125 surface expression in OSE cells. Expression of MHC-I was augmented in OSE and in carcinoma cells by both IFNs but not by the other cytokines. Both types of cell were negative for MHC-II, but IFN-gamma induced its expression in both OSE and carcinoma cells. Significant concentrations of the cytokines evaluated here have been measured in blood and follicular fluid by several authors. The different actions of these cytokines in OSE and carcinoma cells could therefore be important in understanding the role of such molecules in the regulation of physiological and pathological processes in the ovary, such as ovulation or malignant proliferation.

Peritoneal mesothelial cells are uniquely located to regulate cellular events in the peritoneal cavity and are a potentially important source for various cytokines. The present study was designed to elucidate the capacity of human peritoneal mesothelial cells (HPMCs) to synthesize and secrete the transforming growth factor (TGF)-beta isoforms 1, 2, and 3 and to characterize their regulation by inflammatory cytokines. HPMCs constitutively released appreciable amounts of TGF-beta 1 and low amounts of TGF-beta 2 as detected by specific immunoassays. TGF-beta 1 levels secreted within 48 hours (45 +/- 8.9 pg/10(5) cells) were 60-fold higher than TGF-beta 2 levels (0.9 +/- 0.1 pg/10(5) cells), respectively. Treatment of HPMCs with interleukin (IL)-1 beta (10 ng/ml) resulted in a significant increase of both TGF-beta 1 (mean, 5-fold; P < 0.001) and TGF-beta 2 (mean, 6-fold; P < 0.01) generation. After 48 hours of IL-1 beta treatment the levels were 185 +/- 17.1 pg/10(5) cells for TGF-beta 1 and 5.3 +/- 1.5 pg/10(5) cells for TGF-beta 2, respectively. Neither tumor necrosis factor (TNF)-alpha nor interferon (IFN)-gamma (both 10 ng/ml) affected TGF-beta 1 or TGF-beta 2 synthesis by HPMCs. TGF-beta 3 could not be detected in any of the supernatant media. Stimulation of HPMCs with IL-1 beta increased steady-state levels of TGF-beta 1- and TGF-beta 2-specific mRNA. Western blot analysis of supernatants revealed the presence of an immunoreactive band at 25 kd. Indirect competition assays confirmed receptor-binding activity of HPMC-derived TGF-beta. Appreciable amounts of TGF-beta were present in a bioactive form. Our results demonstrate that HPMCs synthesize the TGF-beta isoforms 1 and 2 and that the levels of mRNA and protein release can be up-regulated by the proinflammatory cytokine IL-1 beta.

Neopterin is a sensitive marker of macrophage activity, and elevated urine excretion has been observed in viral and bacterial infections. Including 48 patients, we investigated whether neopterin could be a valid parameter for classification of PID. Urinary Neopterin was determined pretherapeutically and throughout the follow-up by means of high pressure liquid chromatography. In about one third of the patients elevated levels of neopterin were observed and these were characterized by higher PID-scores, accelerated erythrocyte sedimentation rate and higher levels of C-reactive protein. The results indicate that in patients with PID macrophages are regularly activated. Neopterin may give additional information for classification of PID although because of lack of sensitivity and specificity it may not be helpful for differential diagnosis or follow-up of these patients.

The measurement of the endometrial thickness by means of transvaginal sonography has been discussed as a tool for cancer screening. The aim of the study was to evaluate such a sonomorphological characterization of the endometrium performed by physicians in training.A transvaginal sonography was performed in 400 patients before histological examination (dilatation and curettage or hysterectomy). The endometrial thickness measured as double layer and the sonographic patterns were determined.The endometrial thickness correlated with the histological findings: the median thickness was 6 mm for the normal endometrium and increased to 9 mm for polypiform hyperplasias 9.5 for cervical mucous polyps, and to 14 mm for glandular-cystic hyperplasias and carcinomas (p0.001 vs. normal). The sonomorphological grading score was also associated with the histology. For the sonomorphological grading, the sensitivity decreased to 80%, but the specificity increased to 62%.The sonomorphological pattern is superior to the sole determination of the endometrial thickness. This method is practicable under routine conditions performed by physicians in training. However, the specificity of both methods is too low to recommend them for cancer screening.

The value of the TAG-72 (CA 72-4) serum marker in primary diagnosis was investigated in 110 patients with histologically diagnosed ovarian cancer. A reference group consisted of 103 patients with benign pelvic masses. Compared to the well-established CA-125, TAG-72 showed a low sensitivity of 42% in the detection of ovarian cancer. By contrast, when the cut-off level for TAG-72 was set at 6 U/ml, it showed a very high specificity of 99%. When the measurement of TAG-72 was combined to that of CA-125, improvements in both the specificity (as compared to a single CA-125 determination) and the sensitivity (as compared to a single TAG-72 assay) were observed. In such a combined assay, our results suggest that the best predictive value (positive and negative) was obtained if CA-125 is assigned a relatively high cut-off value (65 U/ml) in conjunction with a low cut-off level (3.2 U/ml or 4 U/ml) for TAG-72. In the present study, at threshold values of 65 U/ml respectively, a sensitivity of 86%, a specificity of 83% and a positive and negative predictive value of 85% were obtained. In mucinous carcinomas of the ovary, however, the additional TAG-72 determination did not lead to a better predictive power than did CA-125 measurement alone.

The role of inflammatory cytokines on regulation of hCG biosynthesis was studied.JAR choriocarcinoma cells were cultured and treated with interleukin-1 (IL-1), IL-3. IL-4, stem cell factor (SCF), tumor necrosis factor (TNF), and granulocyte or granulocyte-macrophage-colony stimulating factor. hCG concentration was determined by immunoradiometric methods and cell number was enumerated by means of an electronic particle counter.Il-1 and TNF increased biosynthesis of holo-hCG as well as the free alpha- and free beta-subunit and the beta-core protein. Proliferation was not affected by any cytokine tested.Inflammatory cytokines are able to increase the biosynthesis of hCG.

Laparoscopic surgery has become an important tool in the treatment of tubal pregnancy. Skillful operative technique should prevent tissue spread and thus avoid persistence of ectopic trophoblastic cells.A laparotomy with complete salpingectomy was performed in a patient with rising serum hCG levels after a previous laparoscopic partial salpingectomy for ampullary tubal pregnancy. The only residual trophoblastic tissue found was an implant in the abdominal wall at the site of auxiliary puncture.Extra-abdominal dispersion of active trophoblastic cells may lead to increasing hCG levels, mimicking persistent tubal pregnancy.

The effects of cytostatic agents on proliferation and epidermal growth factor receptor (EGF-R) expression were examined in the ovarian carcinoma cell line OVCAR-3. These cells were found to express about 84,000 high-affinity EGF binding sites per cell. Treatment of OVCAR-3 cells with cisplatin, etoposide or epirubicin for two hours resulted in a marked augmentation of EGF-R expression and growth inhibition, on the other hand, incubation with substances blocking RNA or protein synthesis, actinomycin-D and cycloheximide, resulted in a reduction of both EGF-R expression and growth rate. An up-regulation of EGF-R has thus been shown only for DNA-affecting agents, but not for those inhibiting transcription or translation. This response may be explained as a frustrated escape mechanism of the cancer cell to cytotoxic agents.

A total of 110 patients with upper ureteral calculi was admitted to a prospective trial and randomly allocated to 2 groups: 1 group treated with in situ extracorporeal shock wave lithotripsy (ESWL) and 1 group treated with ureteral manipulation before ESWL. All patients had solitary upper ureteral calculi without urinary infection. The stones had to be smaller than 1 cm. and located more than 2 cm. lateral to the spine. ESWL was performed with the Dornier HM3 lithotriptor. One patient in the in situ ESWL group had to be treated twice because disintegration of the stone was insufficient after the initial treatment session. All other patients underwent only 1 treatment session. Because 16 patients were lost to followup, 94 were evaluable for the analysis of immediate and long-term results. For disintegration of the stones in situ ESWL needed significantly more shock waves (1,844 +/- 639 versus 1,297 +/- 473, p < 0.001) and a higher voltage (19.5 +/- 1.4 versus 18.7 +/- 0.9 kv., p < 0.001). There were no severe complications in either treatment group. At 3 months 44 of 46 patients (96%) after in situ ESWL and 45 of 48 (94%) after ureteral manipulation before ESWL were free of stones. In view of these results it is suggested that uncomplicated upper ureteral calculi (as defined previously) should be treated first with in situ ESWL, thus, avoiding an invasive procedure.

In analogy to Kühnle et al. (1984) the role of etoposide in patients with cisplatin-refractory ovarian cancer was evaluated. 45 patients were treated with 150-200 mg of etoposide per sa. m. on days 1-3. Acute toxicity was tolerable except alopecia grade III. Remarkable, however, was the induction of two fatal cases of leukaemia following etoposide treatment. The first patient, who was 27 years old, with FIGO stage IIb serous cystadenocarcinoma, which was treated with cisplatin/epirubicin and after a latent period of 45 months, a local recurrence was treated with 8 cycles of etoposide. Twenty-three months after discontinuation of etoposide therapy, the patient showed acute myelogenous leukaemia (AML) of M5b-subtype according to the FAB classification. Two days after diagnosis, the patient died of the disease. The second patient, a 55-year old woman with FIGO stage IIa serous cystadenocarcinoma, was treated with cisplatin/cytoxan; 8 cycles of etoposide were given as a second line therapy. This patient, 21 months after discontinuation of etoposide therapy showed a pre-pre-B-acute lymphocytic leukaemia with coexpression of the myeloid antigens. Two months after diagnosis, the patient died of the disease. In 4 out of 38 patients, a complete and in 7 patients a partial remission was induced by etoposide treatment and survival of these responding patients was prolonged in comparison with the nonresponder. The survival was also dependent on CA-125 serum level and the cumulative dose of etoposide administered. Etoposide treatment is an acceptable option as salvage therapy in refractory ovarian cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with recurrent gynaecological carcinomas have a poor prognosis, with a survival of a few months. Three patients with a recurrent vulva carcinoma, one patient with a recurrent cervical carcinoma, one patient with a recurrent endometrial carcinoma, and one patient with a recurrent breast carcinoma underwent PDT after parenteral or topical sensitisation with Photosan 3. From these patients, two of them showed a complete response with no evidence of disease for 32 and 29 months. One patient responded partially with two recurrences, which were treated twice after tropical sensitisation, living now 21 months. The remaining three patients showed partial response and died 3 to 8 months after PDT. The energy applied was derived from an argon-dye-laser ranging between 225 and 750 joule/cm2. Photosan 3 was given intravenously at a dose of 2.5 mg/kg body weight and was tolerated without any allergic reaction. The response rate in three of six patients in recurrent gynaecological malignancies encourages us to pursue PDT in gynaecological disease.

The value of magnetic resonance imaging (MRI) was studied in a case of a gestational trophoblastic tumour. In addition to the tumour size, MRI made it possible to measure necrotic areas, which are assumed to be a sign of response to chemotherapy. Moreover, uterine zonal anatomy and subserosal uterine veins yielded important information on tumour biology. Complete remission was induced in high-risk patients by etoposide, methotrexate, and actinomycin D treatment.

13 patients between 19 and 35 years, 12 of them with histologically verified trophoblastic disease, were examined by MRI, to prove the diagnostic value of this method. In line with the excellent results of MRI described in the literature with respect to the differentiation of tissue characterisation, vascularisation and localisation of tumours, the response to chemotherapy was evaluated comparatively to HCG-titres (5 patients). The results showed, that a decrease of HCG-titres correlated with significant tumour reduction. MRI was performed with 1.5 Tesla machines. Axial, sagittal and coronal images of pelvis and abdomen in T1, proton density and T1 sequences, one after administration of Gd-DTPA, were carried out. Except for one case with decreasing titres, GTP was proven by MRI. The tumour showed a remarkable lack of homogeneity and signal increase in 7 cases in T2-weighted images. In one case, the tumour showed a marked signal enhancement after applying Gd-DTPA, compared with the normal myometrium. In 5 cases, destruction of the zonal anatomy of the uterus and dilatation of subserosal uterine and pelvis veins were found. The uterus was larger in size than expected for the duration of gravidity. In correlation with the clinical examination and HCG titres, MRI has the potential of multiplanar imaging and signal characterisation of tissue, and is therefore useful to evaluate the tumour extent and to detect residuals. Gradient echo-technique and the use of contrast media will reduce the duration of examination, but more experience is required.

To determine the serum concentrations of human chorionic gonadotropin (hCG), its free beta-subunit (hCG beta), and the free alpha-subunit (free alpha) common to all human glycoprotein hormones under physiological and pathological conditions, we developed monoclonal antibody-based immunoenzymometric assays. Free alpha-subunit was detected in the sera of all healthy individuals of both sexes; hCG was measurable in sera of 54% of the men, and 46% were positive for free hCG beta; in nonpregnant women, 69.5% were positive for hCG, 68.4% for the free beta-subunit. Pathological conditions, i.e., hCG-producing tumors, were studied in vitro and in vivo. In vitro, the concentrations of hCG, free hCG beta, and free alpha in tissue-culture supernates of a choriocarcinoma cell-line ("JAR") showed a parallel pattern during time-course analysis. In vivo, in long-term follow-up studies of 13 patients with testicular cancer, serum concentrations of the three analytes paralleled each other, whether the disease was in remission or not. Because of a selective increase of free hCG beta and free alpha in 27% of seminomatous tumor patients and in 13% of the nonseminomatous patients, the percentage of tumor-marker-positive sera was increased from 15% to 42% and 57% to 70%, respectively, by the additional measurement of free hCG beta and free alpha. Thus hCG, free hCG beta, and free alpha are physiologically present in a high percentage of the sera from healthy men, and the determination of free hCG beta and free alpha, although not of prognostic value, improves the diagnostic possibilities in patients with testicular cancer.

The aim of this study was to elucidate whether proliferation of ovarian carcinoma cells may affect the biosynthesis and release of CA-125. In a cell culture model the tumour marker CA-125 expression in cytosol, surface membrane, and release into culture medium was studied in six human carcinoma cell lines. Cell cycle analysis of propidium iodide stained nuclei was performed using a fluorescent activated cell sorter. The turnover of CA-125 is very rapid, within 24 h the equivalent amount found in each cell was also released in the supernatant culture medium. A good relation between cytosolic, membrane, and released CA-125 was observed. CA-125 expression was associated predominantly with the G0/G1 phase of the cell cycle and was dependent on cell density. The results presented here demonstrate that factors associated with tumour cell proliferation could influence the CA-125 serum level in ovarian cancer patients.

The combination of intracavitary and external-beam radiation is the treatment of choice in advanced cervical cancer. Low-dose regimens using radium were widely abandoned in favour of high-dose-rate afterloading systems. We compared in this retrospective analysis of 550 patients the 2 different treatment modalities. We could observe neither in overall survival, nor in the incidence of side effects, any significant difference. Although the change from low- to high-dose-rate radiation therapy was not accompanied by a benefit in survival, the latter modality displayed several advantages e.g. a reduced exposure of personnel to radiation and shorter duration of confinement to bed. Patient survival rate was dependent mainly on parameters of tumour burden (FIGO stage), i.v. pyelogram or CT scan of paraaortic lymph nodes. On the other hand, neither the histological classification as epidermoid or adenocarcinoma nor the WHO grading, were useful predictors of patient outcome.

The overexpression of the protooncogene c-erbB-2 (HER-2/neu) in ovarian and mammary carcinoma is an important indicator for a bad prognosis. In this study we demonstrate that, in three of four ovarian carcinoma cell lines, there is a gamma-interferon-mediated reduction in c-erbB-2 specific protein, and this effect was found to correlate with the antiproliferative action. It is interesting to note that there is no relation between the absolute amount of c-erbB-2 protein expressed and the sensitivity of the ovarian carcinoma cells for an antiproliferative activity of gamma-interferon. Other chemotherapeutic agents did not affect c-erbB-2 expression, although they inhibited the proliferation. The oncogene expression was lowered only in the ovarian carcinoma cell lines and not in three gamma-interferon-sensitive human breast cancer cell lines. Expression of the oncogene c-erbB-2 is the leading prognostic factor in ovarian cancer. Its modulation might represent a mechanism by which gamma-interferon inhibits cell proliferation.

In a retrospective analysis of 429 endometrial carcinoma and 29 malignant mixed Müllerian tumour (MMMT) patients, the prognostic factors were evaluated. More than 80% of endometrial carcinomata were staged as I or II, whereas about 30% of MMMT's already in stage III or IV (p less than 0.05). MMMT patients were 10 years older than the carcinoma group (73a vs 63a; p less than 0.001). The risk factors parity, adipositas, and diabetes were equally distributed in the two groups, the survival was worse in MMMT (p less than 0.0001). Applying univariate analysis stage, grading, myometrial invasion and type of therapy significantly affected the survival of endometrial carcinoma patients. After a Cox regression, only stage and grading remained significantly associated with the prognosis. For MMMT's, the survival was also influenced by stage, myometrial invasion, and kind of therapy. Moreover, the parity was found to affect markedly the course of disease. Cox regression of our data excluded all but stage and parity. The beneficial influence of parity on the prognosis of MMMTs, despite a latency of more than 20 years from the last birth to tumour appearance, is unique in oncology.

Transforming growth factor-beta (TGF-beta) is a multifunctional peptide regulating several processes in ovarian cells. The growth of ovarian carcinoma cell lines (OVCAR-3, HTB-77, 2780 and CRL-1572) was reduced by TGF-beta in a dose related manner. The antiproliferative activity was not improved by combination with other biological response modifiers. Treatment with TGF-beta augmented the expression of interferon-gamma induced class I and II antigens of the major histocompatibility complex. The presentation of another antigen namely the tumor marker CA-125 on the cell surface was markedly reduced by TGF-beta.

The tumour necrosis factor (TNF) stimulates in cultured JAR choriocarcinoma cells the biosynthesis of hCG, including the free alpha and beta chain and the holo-hCG. Although elevated serum TNF levels have been shown by Balkwill et al. (1987) in about 50% of tumour patients, we were unable to confirm these data in the 10 examined patients, who had a choriocarcinoma. Despite its excellent in-vitro action, INF could not be confirmed to exercise an influence on the regulation of hCG in choriocarcinoma patients.

The human endometrial adenocarcinoma cells IK were found to be highly susceptible for TNF but rapidly developed a resistance to this cytokine. Inhibitors of RNA transcription or protein biosynthesis could not overcome this resistance. Moreover TNF resistance was not associated with increased resistance to hydrogen peroxide. The resistant phenotype remained stable and was not communicated to neighbouring cells in a paracrine manner. The TNF treatment did not induce a multidrug resistance on IK cells. Nude mice bearing xenotransplanted endometrial carcinoma cells did not benefit from TNF treatment.

A state of magnesium deficiency has been established in the population of highly industrialized countries in the last few years. This results among other disturbancies, in increasing prematurity. Therefore the tocolytic activity of magnesium was investigated in 29 uterine strips, which were obtained during cesarean section. A highly significant (p less than 0.001) reduction of the uterine activity from 100 to 0 (0-21), 0 (0-0) and 0 (0-0) (median, 20th and 80th percentile) 10, 20 and 60 min after the application of magnesium was observed.

Fragestellung: Bedeutung von inflammatorischen Zytokinen bei der Regulation der hCG Biosynthese. Methoden: JAR Chorionkarzinomzellen wurden mit Interleukin-1 (IL