Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial.

OBJECTIVE: The purpose of this study was to investigate if the levonorgestrel-impregnated intrauterine device (LNG-IUS, Mirena(®) ) is safe and effective as therapy for low-risk and medium-risk endometrial hyperplasia compared with oral medroxyprogesterone (MPA). DESIGN: A multicentre randomised trial. SETTING: Norway. POPULATION: In all, 170 women aged 30-70 years with low- or medium-risk endometrial hyperplasia who met inclusion criteria. METHODS: Patients were randomly assigned to one of three treatment arms: LNG-IUS; oral MPA 10 mg administered for 10 days per cycle, or continuous oral MPA 10 mg daily, for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was normalisation or persisting hyperplasia. RESULTS: After 6 months all three treatment regimens showed significant effect when the outcome was evaluated as therapy response or not (P < 0.001). Responses were obtained for all the women in the LNG-IUS group (53/53, 95% CI 0.93-1.0) and for 96% of the women in the continuous oral group (46/48, 95% CI 0.86-0.99). Only 69% of the women in the cyclic oral group were responders (36/52, 95% CI 0.55-0.81). Adverse effects were relatively common with minimal differences between therapy groups. CONCLUSION: In the first trial of its kind, women treated with the LNG-IUS showed histologically normal endometrium after 6 months of therapy for endometrial hyperplasia. Cyclical progestogens are found to be less effective compared with continuous oral therapy and LNG-IUS and should not be used for this purpose.

Prognostic markers for detection of coexistent carcinoma in high-risk endometrial hyperplasia.

OBJECTIVES: Reliable predictive uterus-sparing methods are crucial for treatment decisions among women who wish to preserve fertility and for seriously ill patients for whom surgery is hazardous. Thus, prediction of myoinvasive carcinoma by objective histomorphometry (4C-rule) and subjective diagnosis (endometrial intraepithelial neoplasia, EIN) were investigated in high-risk endometrial biopsies. PATIENTS AND METHODS: A total of 45 patients retrospectively diagnosed with high-risk hyperplasia, of whom ten were found to have concurrent carcinoma, were investigated. The histomorphometric 4C-rule and the EIN classification system were used for outcome prediction. RESULTS: Myoinvasive disease was predicted with a sensitivity of 87% and a specificity of 79% by using 4C-rule assessment. The sensitivity and specificity of the EIN classification to predict coexistent carcinoma or not was 50% and 97%, respectively. CONCLUSION: Six out of the seven reported cases with myoinvasion were correctly diagnosed with the 4C-rule assessment. In contrast, only three out of the seven myoinvasive cases were diagnosed as cancer using the EIN approach.

Loss of expression of MLH1, MSH2, MSH6, and PTEN related to endometrial cancer in 68 patients with endometrial hyperplasia.

Derangements in the tumor suppressor gene PTEN and the mismatch-repair genes, hMLH1, hMSH2, and hMSH6, have an important role in endometrial carcinogenesis. The purpose of this study was to assess immunohistochemically the pattern of protein expression for these genes in 68 patients with endometrial hyperplasia and to determine the relation of protein expression to cancer development or coexistence of cancers. Loss of expression of these genes also was evaluated as potential tumor markers for clinical use. PTEN and hMLH1 both showed loss of expression in 55% of specimens from 18 patients with subsequent or coexisting carcinoma. D&C specimens from 50 patients who did not develop cancer (10 patients underwent hysterectomy within 2 years; 40 had no hysterectomy; follow-up of 10-20 years), expressed protein at a much higher frequency (92% for PTEN and 98% for hMLH1). The parameter with the strongest independent relation to subsequent or coexisting carcinoma in a stepwise multiple logistic regression analysis was hMLH1. Evaluation of the investigated factors as prognostic markers for tumor development showed high specificity (92% for PTEN, 98% for MLH1) at the expense of sensitivity (56% for PTEN, 56% for MLH1). The results were compared with the results of the computerized image analysis algorithm, the D-score.

Tumor necrosis factor-related apoptosis-inducing ligand induces apoptosis in human articular chondrocytes in vitro.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is produced by immune cells and by mediating apoptosis, TRAIL plays an important role in tumor surveillance. TRAIL binds four different membrane-bound receptors: DR4, DR5, DcR1, and DcR2. The DR4- and DR5-receptors mediate apoptosis, whereas the others do not. We demonstrated by reverse transcriptase-polymerase chain reaction and flow cytometry that, in vitro, normal human articular chondrocytes express the receptors mediating apoptosis (DR4 and DR5) and one of the decoy receptors (DcR2). Also, we demonstrated that chondrocytes were subjected to cell death within few hours after challenge with TRAIL and that cytotoxicity was dose-dependent. Treated cells had apoptotic morphology accompanied by active caspase-3 immunoreactivity. These data indicate that normal human articular chondrocytes are susceptible to TRAIL-mediated apoptosis, which otherwise is typical for transformed cells, and also that death receptors and their respective ligands may have a crucial role in cartilage generation and destruction.

Differential regulation of gamma-glutamyltransferase mRNAs in four human tumour cell lines.

Human gamma-glutamyltransferase (GGT) belongs to a multigenic family and at least three mRNAs are transcribed from the gene that codes for an active enzyme. Four human tumour cell lines (HepG2, LNCap, HeLa and U937) with different GGT levels were used to investigate how GGT activity, total GGT mRNA and each individual GGT mRNA subtype responded to tumour necrosis factor-alpha (TNF-alpha), 12-O-tetradecanoylphorbol 13-acetate (TPA) or sodium butyrate treatment. Butyrate reduced the GGT activity in HepG2 cells, and the level of total GGT mRNA accordingly, whereas TNF-alpha and TPA did not alter these parameters. In LNCap cells, TNF-alpha, TPA, and butyrate reduced the activity as well as the level of GGT total mRNA. In HeLa cells no significant changes were observed either in activity or in mRNA level whereas TPA induced both GGT activity and mRNA levels in U937 cells. The distribution of each GGT mRNA subtype (A, B and C) was found to be cell specific: type B mRNA was the major form in HepG2 cells, while type A was the major form in LNCap and HeLa, type A and type C were expressed almost at the same level in U937 cells. The GGT mRNA subtypes were also differently modulated in these cells after TNF-alpha, TPA or butyrate treatment, suggesting that they are regulated by distinct and cell type specific mechanisms.

The haemodialysis machine as a lifeline: experiences of suffering from end-stage renal disease.

AIM: The aim of this study was to describe patients' experiences of suffering from end-stage renal disease (ESRD). RATIONALE: The rationale was to investigate how persons find meaning or make sense of their situation and how they experience suffering. The theoretical basis for the study was to view suffering at three levels. The first level was related to sickness and treatment. The second level was related to the care provided and the third level was related to each person's unique life experience and existence. METHOD: Data were collected by interviews focusing on questions concerning daily life, needs, and expectations for the future. A qualitative interpretative content analysis was used. Fifteen patients between the ages of 50-86 participated in the study. FINDINGS: Two main themes were identified describing these patients suffering. The first theme, 'the haemodialysis machine as a lifeline' consisted of three subthemes: 'loss of freedom', 'dependence on the caregiver', and 'disrupted marital, family and social life'. The second theme 'alleviation of suffering' consisted of two subthemes: 'gaining a sense of existential optimism' and 'achieving a sense of personal autonomy'. CONCLUSION: This study indicated that, in the lives of patients on haemodialysis, the main areas of suffering were related to loss of freedom expressed as dependence on the haemodialysis machine as a lifeline and, the caregivers. This time-consuming and tiring dependence affected marital, family and social life. Alleviation of suffering could be achieved by accepting dependence on the haemodialysis machine and maintaining autonomy by being seen as an individual by the caregivers.

Cytogenetic diagnosis of the fragile X syndrome: efficiency, utilization, and trends.

In order to assess the impact of the increasing awareness of the fra(X) syndrome and a broader approach to fra(X) testing, we analyzed our laboratory experience for 1980-1988. In 1981-1986, there was an average of 80 cases/year (62 male; 18 female). The 103 (74 male; 29 female) cases in 1987 represent a 45% increase over the prior 3 years; this sustained in 1988 with 106 cases. The fra(X) positive yield decreased from a high of 49% in 1980 to an average of 20% (range 15-24%) in 1981-1984, 10% (range 9-11%), in 1985-1987 and 7% in 1988. The positive rate for males and females was nearly identical in both time periods. The positive yield for mentally retarded individuals with a family history of mental retardation dropped from an average of 20% for 1981-1984 and 33% for 1985-87 to 13% for 1988; however, the positive fra(X) rate for mentally retarded individuals decreased from an average of 23% in 1981-1984 to 9% in 1985-1987 and 7% in 1988. The decreasing fra(X) yield and increasing case load are directly attributable to the relaxation of criteria for referral and testing related to the referral of all mentally retarded patients, and to the perceived malpractice liability for not doing a "complete" evaluation. Although the burden for cytogenetic laboratories is considerable, the yield of positive fra(X) cases is still worthwhile, and may be maximized by the use of improved screening criteria.

Acrocallosal syndrome: additional manifestations.

The acrocallosal syndrome (ACS) is a probable autosomal recessive condition of macrocephaly, craniofacial and hand and foot abnormalities, absence of the corpus callosum, and mental retardation. This patient had characteristics of the ACS but also had a severe congenital heart defect and other visceral malformations. After comparing the ACS with and contrasting it to other disorders, we concluded that the internal organ abnormalities found in this patient probably represent further manifestations of the ACS.

Methotrexate measurements in plasma: comparison of enzyme multiplied immunoassay technique, TDx fluorescence polarization immunoassay, and high pressure liquid chromatography.

One hundred nine patient plasma samples were examined for methotrexate (MTX) levels by enzyme multiplied immunoassay technique (EMIT), fluorescence polarization immunoassay (TDx), and high pressure liquid chromatography (HPLC). EMIT analysis was performed twice within a time span of 18 months. All three methods measure MTX with a high degree of specificity, sensitivity, and precision. There was no evidence of decay of MTX concentrations in samples stored at -20 degrees C for 1.5 years. EMIT, TDx, and HPLC are adequate methods for MTX quantification in the clinical laboratory.