Significance of progesterone receptors (PR-A and PR-B) expression as predictors for relapse after successful therapy of endometrial hyperplasia: a retrospective cohort study.

OBJECTIVE: After successful progestin therapy for endometrial hyperplasia (EH), the risk of relapse remains. We aimed to assess if immunohistochemical (IHC) expression of progesterone receptor isoforms, PR-A and PR-B, in endometrial glands and stroma in pre-treatment endometrial biopsies was related to relapse of EH. DESIGN AND SETTING: Biopsy material originated from women with low-risk and medium-risk EH recruited to a recent Norwegian multicentre randomised trial. Participants (n = 153) had been treated for 6 months with three different progestin regimens. POPULATION: One hundred and thirty-five of the 153 women achieved therapy response and underwent follow up for 24 months after therapy withdrawal. Fifty-five women relapsed during follow up. Pre-treatment endometrial biopsies from 94 of the 135 responding women were available for IHC staining. METHODS: Immunohistochemical staining was performed separately for PR-A and PR-B and IHC expression was evaluated in endometrial glands and stroma by a histological score (H-score) using light microscopy. MAIN OUTCOME MEASURE: Immunohistochemical expression of PR-A and PR-B in endometrial glands and stroma in women with or without relapse of EH. RESULTS: Low PR-A in endometrial glands (P = 0.013) and stroma (P < 0.001), and high PR-B in endometrial glands (P = 0.001) in pre-treatment endometrial biopsy have a statistically significant association with relapse of EH. Women with a pre-treatment ratio of PR-A:PR-B ≤ 1 have a higher risk of relapse (71%) compared with women with a ratio of PR-A:PR-B > 1 (19%; P < 0.001). CONCLUSION: Immunohistochemical expression of PR-A and PR-B in pre-treatment endometrial biopsy proves valuable as a predictor of relapse in EH. TWEETABLE ABSTRACT: Pre-treatment endometrial expression of PR-A and PR-B is a valuable predictor of relapse in endometrial hyperplasia.

Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel-impregnated intrauterine system or oral progestogens.

OBJECTIVE: To investigate relapse rates after the successful treatment of patients with non-atypical endometrial hyperplasia who were randomised to either a levonorgestrel-impregnated intrauterine system (LNG-IUS; Mirena(®) ) or two regimens of oral medroxyprogesterone acetate (MPA) after primary histological response. DESIGN: A multicentre randomised trial. SETTING: Ten different outpatient clinics localised in hospitals and seven gynaecological private practices in Norway. POPULATION: One hundred and fifty-three women aged 30-70 years with low- or medium-risk endometrial hyperplasia met the inclusion criteria, and 153 completed the therapy. METHODS: Patients were randomly assigned to one of the following three treatment arms: LNG-IUS; 10 mg of oral MPA administered for 10 days per cycle for 6 months; or 10 mg of oral MPA administered daily for 6 months. The women were followed for 24 months after ending therapy. MAIN OUTCOME MEASURES: Histological relapse of endometrial hyperplasia. RESULTS: Histological relapse was observed in 55/135 (41%) women who had an initial complete treatment response. The relapse rates were similar in the three therapy groups (P = 0.66). In the multivariable analyses relapse was dependent on menopausal status (P = 0.0005) and estrogen level (P = 0.0007). CONCLUSIONS: The risk of histological relapse of non-atypical endometrial hyperplasia is high within 24 months of ceasing therapy with either the LNG-IUS or oral MPA. Continued endometrial surveillance and prolonging progestogen therapy should be considered. TWEETABLE ABSTRACT: Relapse of endometrial hyperplasia after successful treatment is independent of therapy regime.

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.

Un arma terapéutica alternativa: perros entrenados para asistencia o terapias / No disponible

No disponible

Artritis reactiva secundaria a inmunoterapia intravesical con bacilo / Reactive arthritis secondary to intravesical

Presentamos un caso de artritis reactiva secundaria a inmunoterapia intravesical con bacilo de Calmette-Guerin (BCG) como tratamiento del cáncer de vejiga superficial. Esta complicación es muy infrecuente de modo que sólo ocurre en el 0,5% de los pacientes tratados. Aparece tardíamente, tras la cuarta o quinta instilación y afecta de forma asimétrica preferentemente a la rodilla, el tobillo y la muñeca. El tratamiento de elección son los antiinflamatorios no esteroideos (AINE)

We present a case of reactive arthritis secondary to intravesical bacillus Calmette-Guerin (BCG) immunotherapy as treatment of superficial bladder cancer. This complication is very rare as it only occurs in 0.5% of the patients treated. It appears late, after the fourth or fifth instillation and mainly affects the knee, ankle and wrist asymmetrically. Treatment of choice is non-steroid anti-inflammatory drugs (NSAIDs)

Genetic derangements in the tumor suppressor gene PTEN in endometrial precancers as prognostic markers for cancer development: a population-based study from northern Norway with long-term follow-up.

OBJECTIVES: The purpose of the current study was to characterize the role of PTEN in malignant transformation and to evaluate the significance of mutated PTEN exons as prognostic markers in the carcinogenesis of endometrial hyperplasia. A comparison of PTEN mutations as prognostic markers with former investigated prognosticators was also intended. METHODS: Histological material from 68 patients with endometrial hyperplasia and 10-20 years of follow-up of whom 18 later developed cancer was examined. PCR amplification and DNA sequencing were performed, screening the most frequently mutated exons 5a-8b of the PTEN gene. RESULTS: Mutations were demonstrated in 13.2% of the patients. Of the patients with cancer development, five showed to have PTEN mutations corresponding to 28%. Of the patients remaining without carcinoma, only 8% had PTEN mutations (P = 0.04). In total, there were three missense, three nonsense, and four frameshift mutations, and twice as many mutations leading to a truncated protein (six) than mutations altering one amino acid in the entire protein (three). Mutations were distributed in the following manner: three in exon 5a, two in exon 5b, two in exon 6, two in exon 7, and one in exon 8b. Only mutations in exons 6, 7, and 8a were connected with cancer development or coexisting cancer and six out of seven mutations within these exons were frameshift or nonsense mutations. CONCLUSIONS: Our results showed that mutations in the PTEN gene were statistically more frequent in cases with cancer development or coexisting cancer. Although the specificity was acceptable, the sensitivity of PTEN mutations was too low to make it suitable as a tumor marker (sensitivity of 27% and specificity of 91%) in clinical practice.

Resection margins in conization as prognostic marker for relapse in high-grade dysplasia of the uterine cervix in northern Norway: a retrospective long-term follow-up material.

OBJECTIVE: The main intention of the current study was to evaluate free resection margins in cervical conization specimens as prognostic marker by investigating the statistical association between clear or unclear resection margins of cervical cones and the risk of recurrence. METHODS: In a retrospective material, 459 women with moderate (CIN II) and severe dysplasia (CIN III) were included. Fifty of the patients were diagnosed with CIN II (10.9%) and 409 with CIN III (89.1%). Cold knife conization was performed in 371 (81%) patients, the rest were treated with CO(2) laser (19%). All the patients had been treated with conization between 1980 and 1984, follow-up time being from 19 to 23 years. Mean age of the patients was 35.2 years (range 18-81 years) at operation. The histopathological material and the results of the follow-up biopsies and smears were accessible as archival material. RESULTS: A total of 379 (82.6%) patients had clear margins in the primary operation specimens, in 80 patients margins were unclear (17.4%). There were three recurrences in the CIN II group (6%) and 39 (9.5%) in the CIN III group. Further there were 42 (9.2%) relapses in the total group, 36 relapses in the cold-knife group and 6 in the laser group. When univariate analysis was performed to investigate the statistical relation between the resection margins and recurrences, there was no significant correlation (P = 0.7, P > 0.05). Nor did variables like CIN group, surgical procedure, age at disease, age at recurrence, and years till recurrence prove to be predictors of relapses. CONCLUSION: In our material, the relation between free margins and relapse was not statistically significant. According to the literature-free resection margin is not an optimal prognostic criterion for recurrence. The search for new prognostic markers for high-risk cases are important to give these patients adequate therapy and avoiding over-treatment of the low risk groups.

Nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone.

OBJECTIVE: To show that local application of the levonorgestrel intrauterine device was a better therapy for endometrial hyperplasia (EH) compared to per-oral gestagen treatment based on subjective (WHO criteria) and objective (prognostic data-based morphometric and stereological method/D score, predicting the risk of cancer development for each single patient) evaluation. METHODS: Women between 30 and 70 years with EH and D score > 0 were treated with levonorgestrel intrauterine device (n = 26) and the results compared to a historic group of women treated with per-oral gestagen (n = 31). In both treatment groups only patients with low risk (D score > 1) and uncertain risk (D score = 0-1) of cancer development were included. Endometrial specimens were investigated prior to treatment and after 3 months of therapy. The endometrial samples from the two groups were examined by light microscopy and objective data-based morphometry to assess tissue characteristics and to evaluate nuclear size variation. RESULTS: After 3 months all patients treated with levonorgestrel intrauterine device showed regression of hyperplasia, whereas 14 of 31 patients in the per-oral group still had persisting disease. The objective morphometric analysis showed reduction in nuclear size for both treatment groups, including the D score > 1 as well as the D score 0-1 patients. However, the reduction was most obvious for the levonorgestrel intrauterine device-treated patients with initial D score of 0-1. CONCLUSION: The present study indicates that levonorgestrel intrauterine device is a superior alternative to per oral treatment of endometrial hyperplasia. By using objective morphometric treatment monitoring we have shown that the hyperplasia patients with the highest malignant potential (D score = 0-1) were those taking most benefit from local high-dose levonorgestrel therapy.

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.