Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up.

OBJECTIVES: Levonorgestrel (LNG), delivered locally into the uterine cavity has a profound effect on the endometrium. The aim of the study was to use a LNG intrauterine system to treat non-atypical and atypical endometrial hyperplasia in women and to evaluate the long-term cure (remission) rate. METHODS: Each of the 20 women in the study, of whom eight were diagnosed with atypical hyperplasia, received a LNG-IUS, releasing 20 microg LNG/day. The study is a non-comparative study with long-term follow-up (range 14-90 months). RESULTS: All women developed a normal endometrium, except one asymptomatic woman with atypical hyperplasia who still had focal residual non-atypical hyperplasia at 3 years follow-up in the presence of a thin (< 4 mm) endometrium. CONCLUSION: Continuous intrauterine delivery of LNG appears to be a promising alternative to hysterectomy for the treatment of endometrial hyperplasia and could enhance the success rate when compared with other routes of progestagen administration as well as intrauterine progesterone delivery. The significant reduction of the PR expression observed during treatment with the LNG-IUS appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression.

Endometrial safety after 5 years of continuous combined transdermal estrogen and intrauterine levonorgestrel delivery for postmenopausal hormone substitution.

OBJECTIVE: To investigate endometrial histology and thickness of the endometrium after long-term use of continuous transdermal estrogen substitution combined with intrauterine release of levonorgestrel (LNG) in postmenopausal women. DESIGN: A 5-year non-comparative prospective clinical trial. SUBJECTS: Out of 182 symptomatic postmenopausal women using estrogen substitution therapy (EST) combined with a novel T-shaped LNG-releasing intrauterine system (Femilis Slim LNG-IUS), to prevent endometrial proliferation and bleeding, only those women (n=102) who used two consecutive LNG-IUSs, were isolated with the aim to study the long-term effects on the endometrium. The mean age of the women was 57 years (range 47-71). The majority of women received percutaneous 17beta estradiol, 1.5mg daily, or an equivalent dose by patch or orally, on a continuous basis. MAIN OUTCOME MEASURES: Endometrial histology and ultrasonographic evidence of endometrial suppression, after a period of approximately 5 years of use. The mean duration of use of the regimen was 70 months (range 25-98). RESULTS: The dominant endometrial histologic picture was that of inactive endometrium characterized by glandular atrophy and stroma decidualization (Kurman classification 5b). No cases of endometrial hyperplasia were found. On transvaginal ultrasound, this corresponds with a thin endometrium (< or = 5 mm). CONCLUSION: The results of this 5-year study in 102 postmenopausal women using EST demonstrates that the LNG-IUS effectively opposes the estrogenic effect on the endometrium resulting in strong suppression during the entire period of EST. Due to its high efficacy and absence of systemic effects on organ tissues (e.g., breasts), target delivery in the uterine cavity could be a preferred route to administer a progestagen in women using EST.

Endometrial safety with a low-dose intrauterine levonorgestrel-releasing system after 3 years of estrogen substitution therapy.

OBJECTIVE: To evaluate the pharmacodynamic effects of a novel intrauterine drug delivery system, FibroPlant-levonorgestrel (LNG), on the endometrium in 24 postmenopausal women using estrogen substitution therapy (EST) to suppress climacteric symptoms. DESIGN: A 3-year non-comparative prospective clinical trial. SUBJECTS: The treatment with the FibroPlant-LNG intrauterine system (IUS), releasing 14 microg of LNG per day, was part of a regimen for estrogen substitution therapy in symptomatic postmenopausal women to prevent endometrial proliferation and bleeding. The majority of women received percutaneous 17 beta estradiol, 1.5 mg daily, or an equivalent dose by patch or orally, on a continuous basis. OUTCOME MEASURES: Menstrual pattern, endometrial histology and ultrasonographic evidence of endometrial suppression, after 3 years of use. RESULTS: The endometrial histology specimen showed profound endometrial suppression with glandular atrophy and stroma decidualization in all women. On transvaginal ultrasound, this corresponds with a thin endometrium (<5 mm) and clinically with a "bleed-free" menstrual pattern or amenorrhoea. CONCLUSION: The results of this 3-year study in 24 postmenopausal women using EST suggest that the FibroPlant-LNG IUS is effective in causing strong suppression of the endometrium during the entire period of EST. Target delivery in the uterine cavity could be the preferred route of administering a progestin to oppose estrogen stimulation of the endometrium.

High-dose preoperative radiotherapy does not alter the strength of unilaterally irradiated colon anastomoses in rats.

PURPOSE: We studied the influence of preoperative radiotherapy on the strength of colon anastomoses in rats. We compared a conventional (2 Gy/fraction; 1 fraction/day; 5 days/week; cumulative doses of 40.0, 60.0, and 80.0 Gy) and a hyperfractionated schedule (1.6 Gy/fraction, 2 fractions/day, 5 days/week, cumulative doses of 41.6, 60.8, and 80.0 Gy). We compared unilaterally with bilaterally irradiated anastomoses for two conventional radiation schedules. METHODS AND MATERIALS: The rectosigmoid was always irradiated. Depending on the experiment, the cecum was irradiated or not. A side-to-side anastomosis between rectosigmoid and cecum was constructed the day following the last irradiation. The strength of the anastomosis was evaluated by means of a bursting pressure (BP) measurement after 10 days. A control group and a sham-treated group were carried out. RESULTS: Compared to controls, the strength of unilaterally irradiated anastomoses was not altered and BP values were independent of the radiation schedule and of the cumulative dose. In case of bilaterally irradiated colon anastomoses, anastomotic strength was significantly reduced at 80 Gy, but not at 40 Gy. CONCLUSIONS: After high doses of preoperative radiotherapy, colon anastomoses in rats can be safely constructed if only one anastomotic segment is irradiated. The strength of bilaterally irradiated colon anastomoses is dose-dependent.

A comparative phenotypical analysis of rheumatoid nodules and rheumatoid synovium with special reference to adhesion molecules and activation markers.

OBJECTIVES: (1) To analyse the in situ expression of adhesion molecules in rheumatoid nodules. (2) To compare the endothelial expression of adhesion molecules in synovial tissue and subcutaneous nodules obtained from the same patients. (3) To compare the expression of adhesion molecules and activation markers on T cell lines from nodules and synovium. METHODS: (1) Immunohistochemical analysis by APAAP technique of E selectin, CD44, ICAM-1, PECAM-1, and VCAM-1 was performed on 10 rheumatoid nodules from seven patients with rheumatoid arthritis (RA); nodules and synovium were simultaneously analysed from three patients. (2) T cell lines were generated from RA nodules (n = 7) and synovium (n = 7) by interleukin 2 expansion, and subsequently characterised by flow cytometry for surface expression of alpha E beta 7, alpha 4 beta 7, CD44, L selectin, LFA-1a, PECAM-1, and CD30. RESULTS: (1) In rheumatoid nodules, the palisading layer strongly stains for ICAM-1 and PECAM-1, but less pronounced for CD44. VCAM-1 staining was usually negative. ICAM-1 is upregulated in the vessels surrounding the central zone of fibrinoid necrosis. The immunohistological picture in different nodules derived from the same patient was similar. (2) The endothelial expression of adhesion molecules is comparable in RA nodules and synovium on an individual level, except for E selectin, which is overexpressed in nodule endothelium. (3) T cell lines from nodules and synovium display similar adhesion molecule profiles. However, the expression of CD30, a T cell activation marker linked with Th2 subsets, is higher in nodules compared with synovium. CONCLUSION: These data support a recirculation hypothesis of T cells between articular and extra-articular manifestations in RA, although the activation state of the T cells in each of these localisations may differ.

Coexistence of an adrenocortical carcinoma with an abdominal ganglioneuroma in a child.

We report a 3-year, 5-month-old boy with an adrenocortical carcinoma. These tumours are rare and highly malignant in childhood. In most cases they are functional, secreting adrenocortical hormones. In this case there was a misleading coexistence with a second abdominal neoplasm, which was a ganglioneuroma; this is a rare benign tumour arising from the sympathetic nervous system. The imaging investigations and their findings are discussed and correlated with pathology.

The gut associated addressins: lymphocyte homing in the gut.

The process of lymphocyte trafficking is mainly regulated by receptors that belong to a group of molecules referred to as adhesion molecules. These molecules can be divided, according to their molecular structure, into three broad families: the integrins; the selectins; and the immunoglobulin superfamily members. The alpha 4 beta 7 integrin is expressed on some lymphocytes with hallmarks of gut tropism. alpha 4 beta 7, among others, serves as a ligand for the mucosal vascular addressin MadCAM-1, which is selectively expressed on mucosal lymphoid organ high endothelial venules and on gut lamina propria venules. It is tempting to believe that related integrin receptors play a crucial role in the recirculation of activated lymphocytes between the gut mucosa and the synovial membrane.

The role of T cells in rheumatoid arthritis.

The most striking arguments in favor of a T cell dependent nature of RA are the strong association of the disease with selected class II HLA haplotypes (the "shared epitope" hypothesis) and the fact that, in experimental animal models such as adjuvant arthritis, the disease can be transferred by isolated T cell lines. It is true that T cell activation at the site of inflammation is not excessive. However, there is now unequivocal evidence for focal synthesis of IL-2 and IFN-gamma in the RA synovial membrane and one may realise that a limited but specific T cell activation may be sufficient to induce or perpetuate the immune process. This same argument may explain the lack of clear TCR restriction at the sites of inflammation. Until now, no antigen has been demonstrated to initiate and/or perpetuate RA. Different antigens though have been incriminated in the pathogenesis of RA, including cartilage antigens (collagen, proteoglycans, chondrocyte antigens), heat shock proteins or exogenous (viral/bacterial) antigens. Unless one can pick up the right antigen and clone the relevant T cells, it will be very hard to directly prove a T cell-dependent nature of the disease.

Immunohistochemical analysis of E-cadherin expression in human colorectal tumours.

The homotypic homophilic cell-cell adhesion molecule E-cadherin is crucial in the organization and maintenance of most epithelia. The expression of E-cadherin was studied immunohistochemically in various human colorectal tumours. Therefore we stained 1 tubular adenoma with low grade dysplasia, 18 adenocarcinomas with different histologic degrees of differentiation and invasion, and 1 metastasis using a modified peroxidase-anti-peroxidase technique. In the adenoma as well as in all well differentiated adenocarcinomas we found E-cadherin immunopositivity at the cell membrane of almost all cancer cells. The immunopositivity of E-cadherin was clearly weaker and sometimes even absent in isolated neoplastic cells and glands of less differentiated adenocarcinomas. The moderately differentiated adenocarcinomas showed an intermediate staining pattern. These findings are in line with experimental evidence that downregulation of E-cadherin favours invasion, eventually leading to metastasis.

Expression of T cell receptors alpha beta and gamma delta in the ileal mucosa of patients with Crohn's disease and with spondylarthropathy.

The expression of the alpha beta and gamma delta heterodimer of the T cell receptor (TCR) was studied in normal human ileal mucosa or in ileal biopsies featuring Crohn's disease or acute and chronic spondylarthropathy-related gut inflammation. With an immunohistochemical technique we demonstrated that the increase of mucosal lymphocytes per mm mucosa in Crohn's disease and spondylarthropathy-related ileitis is exclusively due to expansion of the alpha beta + T cell compartment. In Crohn's disease and chronic ileitis observed in some spondylarthropathy patients the alpha beta + T cells were increased amongst intraepithelial lymphocytes (IEL). The lamina propria lymphocytes (LPL) were augmented in all studied inflammatory conditions. The gamma delta + T cells showed no changes in IEL or LPL and their proportions were not altered. They were evenly dispersed throughout the ileal mucosa and did not seem to participate in the inflammatory process. This study confirms that gamma delta T cells are a distinct subset in the intestinal mucosa. The increase in alpha beta + T cells suggests augmented mucosal antigen handling and involvement of the major histocompatibility complex in the pathogenesis of spondylarthropathy-related gut inflammation and Crohn's disease.