Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen.

BACKGROUND: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. OBJECTIVES: To determine the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. SEARCH METHODS: We searched the following databases on 29 June 2020; The Cochrane Gynaecology and Fertility Group specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature. We searched the Cochrane Breast Cancer Group specialised register on 4 March 2020. We also searched two trials registers, checked references for relevant trials and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of women with breast cancer on adjuvant tamoxifen that compared the effectiveness of the LNG-IUS with endometrial surveillance versus endometrial surveillance alone on the incidence of endometrial pathology. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer), diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. We rated the overall certainty of evidence using GRADE methods. MAIN RESULTS: We included four RCTs (543 women analysed) in this review. We judged the certainty of the evidence to be moderate for all of the outcomes, due to imprecision (i.e. limited sample sizes and low event rates). In the included studies, the active treatment arm was the 20 µg/day LNG-IUS plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS probably reduces the incidence of endometrial polyps compared to the control group over both a 12-month period (Peto odds ratio (OR) 0.22, 95% confidence interval (CI) 0.08 to 0.64, I² = 0%; 2 RCTs, n = 212; moderate-certainty evidence) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). For long-term follow-up, this suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS with endometrial surveillance would be between 3.8% and 10.7%.  The LNG-IUS probably slightly reduces the incidence of endometrial hyperplasia compared with controls over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). This suggests that if the chance of endometrial hyperplasia following endometrial surveillance alone is assumed to be 2.8%, the chance following LNG-IUS with endometrial surveillance would be between 0.1% and 1.9%. However, it should be noted that there were only six cases of endometrial hyperplasia. There was insufficient evidence to reach a conclusion regarding the incidence of endometrial cancer in tamoxifen users, as no studies reported cases of endometrial cancer. At 12 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting compared to the control group (Peto OR 7.26, 95% CI 3.37 to 15.66; I² = 0%; 3 RCTs, n = 376; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the chance following LNG-IUS with endometrial surveillance would be between 5.6% and 21.5%. By 24 months of follow-up, abnormal vaginal bleeding or spotting occurs less frequently than at 12 months of follow-up, but is still more common in the LNG-IUS group than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10; I² = 0%; 2 RCTs, n = 233; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 4.2%, the chance following LNG-IUS with endometrial surveillance would be between 4.4% and 23.9%. By 60 months of follow-up, there were no cases of abnormal vaginal bleeding or spotting in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). As a result, there is probably little or no difference in these outcomes between the LNG-IUS treatment group and the control group.  AUTHORS' CONCLUSIONS: The LNG-IUS probably slightly reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. Data were lacking on whether the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available RCTs that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.

Prevention of Benign Endometrial Polyp Recurrence Using a Levonorgestrel-releasing Intrauterine System in Premenopausal Patients: A Retrospective Cohort Study.

STUDY OBJECTIVE: To evaluate the levonorgestrel-releasing intrauterine system (LNG-IUS) to prevent the recurrence of endometrial polyps (EPs) after hysteroscopic polypectomies in premenopausal female patients. DESIGN: A retrospective cohort study. SETTING: A tertiary-care women's hospital. PATIENTS: A total of 451 premenopausal female patients underwent hysteroscopic polypectomies between January 1, 2016, and December 31, 2017. INTERVENTIONS: Treatment with LNG-IUS after hysteroscopic polypectomies. MEASUREMENTS AND MAIN RESULTS: After the hysteroscopic polypectomies and placement of LNG-IUS, transvaginal ultrasounds were performed every 6 months to measure the recurrence of EPs. Overall, 5 (3.47%) of 144 patients in the LNG-IUS cohort and 49 (15.96%) of 307 patients in the control cohort experienced EP recurrence within the follow-up period of up to 3 years. The recurrence exhibited a strongly negative correlation when LNG-IUS was inserted (relative risk, 0.218; 95% confidence interval, 0.089-0.535; p <.05), but this did not significantly correlate with age, polyp size, number of polyps, previous history of polypectomy, and abnormal uterine bleeding. For the LNG-IUS and control cohorts, the recurrence in the first postoperative year was 1.39% and 6.19%, respectively, and 5.41% and 19.23% in the second postoperative year, respectively. CONCLUSION: LNG-IUS reduces the recurrence of postoperative EPs in premenopausal patients.

Progesterone ameliorates the endometrial polyp by modulating the signaling pathway of Wnt and ß-catenin via regulating the expression of H19 and miR-152.

BACKGROUND: MicroRNAs and long noncoding RNAs are believed to play important roles in the pathogenesis of various diseases. This study aimed to explore the potential mechanism of the involvement of H19 and miR-152 in an endometrial polyp. METHODS: Luciferase assay was conducted to determine the effect of progesterone. Real-time polymerase chain reaction (PCR) and western blot were performed to detect the influence of progesterone on miR-152 and Wnt1. MTT assay and flow cytometry (FCM) were utilized to detect the effect of progesterone on cell proliferation and apoptosis. In silicon analysis, luciferase assay, real-time PCR, and immunohistochemistry (IHC) were performed to explore the regulatory relationship between H19 and miR-152 or miR-152 and Wnt1. RESULTS: Progesterone dose-dependently increased the H19 expression level through driving the promoter efficiency of H19. Then, progesterone upregulated Wnt1 level and downregulated miR-152 in a dose-dependent manner in ECC1 and HEC1A cells. Administration of progesterone inhibited cell viability and promoted cell apoptosis. H19 negatively regulated miR-152 expression by binding to miR-152. Furthermore, Wnt1 was identified as a virtual target gene of miR-152 and was inhibited by miR-152. Progesterone receptors mRNA and miR-152 were lowly expressed in participants with an endometrial polyp, while the levels of H19 and Wnt1 were much higher in the endometrial polyp group compared with normal controls. H19 negatively regulated miR-152 and miR-152 negatively regulated Wnt1, with the negative correlation coefficients being -0.500 and -0.500, respectively. Using IHC, it was found that Wnt1 and Bcl-2 protein were highly expressed in the endometrial polyp group compared with normal controls. CONCLUSION: The results suggested that H19 was associated with endometrial polyp via mediating cell proliferation and apoptosis.

Celecoxib use and circulating oxylipins in a colon polyp prevention trial.

Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E2 are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Currently, the contribution of individual variability in ARA metabolism in response to the COX-2 inhibitors and potential adverse effects remains poorly understood. Using patient samples from the randomized, placebo-controlled phase III selenium/celecoxib (Sel/Cel) trial for the prevention of colorectal adenomatous polyps, we analyzed plasma concentrations of 74 oxylipins in a subset of participants who received celecoxib (n = 90) or placebo (n = 95). We assessed the effect of celecoxib (with and without low dose aspirin) on circulating oxylipins and systolic blood pressure (SBP). Individual CYP450- and LOX- but not COX-derived metabolites were higher with celecoxib than placebo (P<0.05) and differences were greater among non-aspirin users. LOX derived 5- and 8-HETE were elevated with celecoxib and positively associated with systolic blood pressure (P = 0.011 and P = 0.019 respectively). 20-HETE, a prohypertensive androgen-sensitive CYP450 metabolite was higher with celecoxib absent aspirin and was positively associated with SBP in men (P = 0.040) but not women. Independent of celecoxib or aspirin, LOX derived metabolites from ARA were strongly associated with SBP including 5- and 8-HETE. These findings support oxylipins, particularly the ARA LOX-derived, in blood pressure control and indicate that pharmacologic inhibition of COX-2 has effects on LOX and CYP450 ARA metabolism that contribute to hypertension in some patients.

Effect of Helicobacter pylori eradication on the regression of gastric polyps in National Cancer Screening Program.

BACKGROUND/AIMS: Western guidelines recommend Helicobacter pylori eradication in H. pylori-associated gastric polyps; however, there is no standard guideline in Korea. The aim of this study is to assess the effect of H. pylori eradication on the regression of gastric hyperplastic polyps in National Cancer Screening Cohort, representative of general population. METHODS: Among participants in National Cancer Screening Program, subjects who had H. pylori positive gastric hyperplastic polyps less than 10 mm and underwent follow-up endoscopy and H. pylori testing were enrolled. The effect of H. pylori eradication on hyperplastic gastric polyps was estimated using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 183 H. pylori infected subjects with hyperplastic polyp at baseline underwent follow-up endoscopy and H. pylori test after mean of 2.2 years. Successful H. pylori eradication markedly induced the disappearance of hyperplastic polyps comparing to non-eradication group (83.7% vs. 34.1%, p = 0.001). Successful eradication increased the possibility of disappearance of hyperplastic polyps (adjusted OR, 5.56; 95% CI, 2.63 to 11.11). Polyp size was inversely related with the disappearance of hyperplastic polyps (adjusted OR, 59; 95% CI, 0.48 to 0.71). CONCLUSIONS: Eradication of H. pylori infection may induce disappearance of gastric hyperplastic polyps in National Cancer Screening Cohort.

Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice.

Intestinal cyclic guanosine monophosphate (cGMP) signaling regulates epithelial homeostasis and has been implicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5 (PDE5) inhibitor sildenafil to prevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS) inflammation-driven colorectal cancer model. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrier dysfunction. In mice treated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cell infiltration and reduced expression of iNOS, IFNγ, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration of sildenafil suppresses polyp formation and inflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans. Cancer Prev Res; 10(7); 377-88. ©2017 AACRSee related editorial by Piazza, p. 373.

Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen.

BACKGROUND: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. OBJECTIVES: To determine the effectiveness and safety of levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. SEARCH METHODS: We searched the following databases: Cochrane Menstrual Disorders and Subfertility Group Specialised Register (MDSG), Cochrane Breast Cancer Group Specialised Register (CBCG), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Abstracts of Reviews of Effects (DARE), The Cochrane Library, clinicaltrials.gov, The World Health Organisation International Trials Registry, ProQuest Dissertations & Theses, MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science, OpenGrey, LILACS, PubMed, and Google. The final search was performed in October 2015. SELECTION CRITERIA: Randomised controlled trials of women with breast cancer on adjuvant tamoxifen that compared endometrial surveillance alone (control condition) versus the LNG-IUS with endometrial surveillance (experimental condition) on the incidence of endometrial pathology. DATA COLLECTION AND ANALYSIS: Study selection, risk of bias assessment and data extraction were performed independently by two review authors. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer) diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. The overall quality of evidence was rated using GRADE methods. MAIN RESULTS: Four randomised controlled trials involving 543 women were identified and are included in this review. In the included studies, the active treatment arm was the 20 µg/day levonorgestrel-releasing intrauterine system (LNG-IUS) plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS led to a reduction in the incidence of endometrial polyps over both a 12-month period (Peto OR 0.22, 95% CI 0.08 to 0.64, 2 studies, n = 212, I² = 0%) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39, 4 studies, n = 417, I² = 0%, moderate quality evidence). Also the LNG-IUS led to a reduction in the incidence of endometrial hyperplasia over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67, four studies, n = 417, I² = 0%, moderate quality evidence). However, it should be noted that the number of events of endometrial hyperplasia was low (n = 6). None of the trials were sufficiently powered to detect whether LNG-IUS leads to significant changes in the incidence of endometrial cancer in tamoxifen users. At 12 months of follow-up abnormal vaginal bleeding or spotting was more common in the LNG-IUS treatment group (Peto OR 7.26, 95% CI 3.37 to 15.66, 3 studies, n = 376, I² = 0%, moderate quality evidence). By 24 months of follow-up, abnormal vaginal bleeding or spotting occurred less frequently compared to 12 months of follow-up in the LNG-IUS treatment group but was still more common than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10, 2 studies, n = 233, I² = 0%, moderate quality evidence). By 60 months of follow-up, no cases of abnormal vaginal bleeding or spotting were reported in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). There was no evidence of a difference between the LNG-IUS treatment group and controls for these outcomes. The quality of the evidence was judged as moderate, due to limited sample sizes and low event rates for the outcome comparisons. AUTHORS' CONCLUSIONS: The LNG-IUS reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS increased abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. There is no clear evidence from the available randomised controlled trials that the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available randomised controlled trials that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.

Long-term effects of levonorgestrel-releasing intrauterine system on tamoxifen-treated breast cancer patients: a meta-analysis.

OBJECTIVE: The aim of the study is to assess the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) on the tamoxifen-induced endometrial lesions in breast cancer patients. METHODS: PubMed and EMBASE databases were searched for eligible studies. Odds ratios were obtained to estimate the association between the LNG-IUS and tamoxifen-induced endometrial lesions. The fixed effects or random-effects model was used to combine data depending on heterogeneity. RESULTS: With three eligible randomized clinical trials involving 359 patients, this analysis demonstrated tamoxifen-treated breast cancer patients using the LNG-IUS derived benefit from de novo polyps prevention (P < 0.0001, OR 0.18, 95% CI: 0.08-0.42). However, the LNG-IUS only showed a trend of maintaining endometrial proliferation or secretory status (P = 0.05, OR 0.36, 95% CI 0.13-1.02) and no statistical difference in atrophic or inactive changes (P = 0.13, OR 0.24, 95% CI 0.04-1.53) or endometrial hyperplasia without atypia (P = 0.08, OR 0.20, 95% CI 0.04-1.18). The LNG-IUS didn't have an increased incidence in breast cancer recurrence (P = 0.28, OR 1.75, 95% CI: 0.64-4.80) and cancer-induced death (P = 0.71, OR 1.22, 95% CI: 0.42-3.52). Bleeding in the treatment group was statistically more frequent than that in the control group (OR 6.20, 95% CI: 2.99-12.85, P < 0.00001). CONCLUSIONS: This analysis verifies the efficacy of the LNG-IUS in preventing tamoxifen-induced polyps. The LNG-IUS didn't have an increased incidence in breast cancer recurrence and cancer-induced death. Long-term, large randomized studies of the LNG-IUS will be necessary to determine the benefit and risk in tamoxifen-treated breast cancer patients.

[Effects of levonorgestrel intrauterine system on endometrial tissue after endometrial polyps resection by hysteroscopy].

OBJECTIVE: To explore the changes of endometrial tissues after the insertion of levonorgestrel intrauterine system (LNG-IUS). METHODS: The endometrial tissues were harvested from 21 cases after endometrial polyps resection by hysteroscopy. And the patients received a 1-year follow-up. The immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), Ki-67, bcl-2 and bax were used for semi-quantitative analyses. The changes of endometrial thickness were monitored and uterine weight was observed with a 3-year follow-up. RESULTS: The endometrial thickness and uterine weight declined continuously after the insertion of LNG-IUS. The endometrial thickness decreased from the preoperative level of (9.8 ± 1.2) mm to (3.5 ± 1.0) mm while the uterine weight dropped from the preoperative level of (98.8 ± 8.6) g to (66.6 ± 9.8) g. The expressions of ER, PR and Ki-67 were significantly lower than those of the para-polyps endometrial tissue (P < 0.05). The expressions of bcl-2 and bax were significantly higher than those of the para-polyps endometrial tissue (P < 0.05). CONCLUSION: LNG-IUS may prevent the recurrence of uterine endometrial polyps through its inhibited expressions of ER, PR and Ki-67 and induced endometrial apoptosis.

Gynecologic conditions in participants in the NSABP breast cancer prevention study of tamoxifen and raloxifene (STAR).

OBJECTIVE: This study reports the gynecologic conditions in postmenopausal women (intact uterus on enrollment) in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of tamoxifen and raloxifene (STAR)/P-2 trial. STUDY DESIGN: This study, with a median follow-up period of 81 months, evaluated the incidence rates/risks of gynecologic conditions among women who were treated with tamoxifen and raloxifene. RESULTS: Compared with women who received tamoxifen therapy, women who received raloxifene therapy had a lower incidence of uterine cancer (relative risk, 0.55)/endometrial hyperplasia (relative risk, 0.19), leiomyomas (relative risk, 0.55), ovarian cysts (relative risk, 0.60), and endometrial polyps (relative risk, 0.30) and had fewer procedures performed. Women receiving tamoxifen therapy had more hot flashes (P < .0001), vaginal discharge (P < .0001), and vaginal bleeding (P < .0001). CONCLUSION: Our results suggest that tamoxifen has more of an estrogenic effect on the gynecologic reproductive organs. These effects should be considered in counseling women on options for breast cancer prevention.

A case of gastric polyposis in antral area of stomach following prolonged proton-pump therapy.

We describe the clinical scenario of a young male with history of non ulcer dyspepsia who had endoscopic evidence of gastric polyposis in antral area. The polyps disappeared four months after proton pump inhibitors were stopped. Proton pump inhibitors have been linked to gastric fundal polyposis and not antral gland polyposis. This is the first report originating from an Asian country describing antral gland polyposis (AGPs) in a patient on long-term PPI therapy with no evidence of Helicobacter pylori. A case report with brief review is presented.

Is it necessary to perform prophylactic cholecystectomy for asymptomatic subjects with gallbladder polyps and gallstones?

BACKGROUND AND AIMS: The purpose of the present study was to determine the clinical characteristics of subjects with gallbladder polyps and cholelithiasis compared with those with gallbladder polyps only. METHODS: Between August 1999 and December 2005, 176 subjects with gallbladder polyps and cholelithiasis (study group) by transabdominal ultrasonography performed during a medical check-up at our institution were recruited and compared with a control group of 185 subjects who had gallbladder polyps only. RESULTS: No significant difference in the mean interval change (delta) of polyp size during the follow-up period between the study and control groups (0.85 +/- 1.39 mm vs 0.84 +/- 1.58 mm, respectively, P = 0.927) was noted. A significantly higher proportion (9/176 [5.1%]) of examinees in the study group had attacks of acute cholecystitis compared with the control group (1/185 [0.5%], P < 0.01). By multivariate logistic regression analysis, gallbladder wall thickening on initial ultrasonography (odds ratio, 13.7; 95% confidence interval, 1.1-178.0; P = 0.046) and the interval increase in the size of the gallbladder polyps (odds ratio, 14.7; 95% confidence interval, 1.7-126.9; P = 0.014) were independent risk factors for cholecystectomy. No gallbladder cancer occurred during the follow-up period. CONCLUSIONS: There was no significant difference in delta polyp size between the examinees with gallbladder polyps and cholelithiasis and those with gallbladder polyps only. Hence, a small proportion of subjects with gallbladder polyps and cholelithiasis, such as those with thickened gallbladder walls and an interval increase in the size of the gallbladder polyps are candidates for prophylactic cholecytectomy.

Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen.

BACKGROUND: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with estrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial hyperplasia, polyps, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. OBJECTIVES: To determine the effectiveness of the levonorgestrel intrauterine system in preventing the development of endometrial hyperplasia, polyps, and adenocarcinoma in pre and postmenopausal women taking adjuvant tamoxifen following breast cancer. SEARCH STRATEGY: All reports which described randomised controlled trials of effects of the levonorgestrel intrauterine system on the endometrium in breast cancer patients taking adjuvant tamoxifen were obtained through searches of the Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009), MEDLINE (1996 to August 2009), EMBASE (1980 to August 2009), CINAHL (Cumulative Index to Nursing and Allied Health Literature) (1982 to August 2009). SELECTION CRITERIA: Randomised controlled trials of women with breast cancer on adjuvant tamoxifen that compared endometrial surveillance or placebo alone versus the LNG-IUS. Women with known endometrial pathology or contraindications to LNG-IUS were excluded. DATA COLLECTION AND ANALYSIS: Only two randomised controlled trials were identified and are included in this review. Risk of bias assessment and data extraction were performed independently by two review authors. The outcome measures were endometrial pathology (including polyps, endometrial hyperplasia, or adenocarcinoma) diagnosed at hysteroscopy or endometrial biopsy; any reported side effects of treatment; and abnormal vaginal bleeding. MAIN RESULTS: In both included studies, the active treatment arm was the Mirena 20 mug/day levonorgestrel-releasing intrauterine device (Bayer Health Care, US). The LNG-IUS in tamoxifen users led to a significant reduction in the incidence of endometrial polyps (Peto odds ratio 0.14, 95% confidence interval 0.03 to 0.61). Neither trial was sufficiently powered to detect whether LNG-IUS leads to significant changes in the incidence of endometrial hyperplasia or adenocarcinoma in tamoxifen users, nor whether LNG-IUS leads to any increased risk of breast cancer recurrence. There appeared to be more vaginal bleeding in the Mirena treatment group, in the first six months only. However, the bleeding patterns at 12 months were fairly similar for both groups. AUTHORS' CONCLUSIONS: The Mirena LNG-IUS appears to prevent the development of benign endometrial polyps in breast cancer patients taking tamoxifen, over a one-year period. There is no clear evidence from the available randomised controlled trials that LNG-IUS prevents endometrial hyperplasia or adenocarcinoma in these patients. Larger studies are necessary to assess the effects of LNG-IUS in preventing endometrial hyperplasia and endometrial cancer, and to determine whether LNG-IUS might have an impact on the risk of breast cancer recurrence.

Prevention of tamoxifen induced endometrial polyps using a levonorgestrel releasing intrauterine system long-term follow-up of a randomised control trial.

OBJECTIVES: In a RCT, we have previously shown that the levonorgestrel intrauterine system (LNG-IUS, Mirena) produces a decidual response protecting the endometrium at one year follow-up. We here report on the long-term follow-up of this group of women, to test the hypothesis that a LNG-IUS could prevent the pro-proliferative uterine responses of tamoxifen for up to 4.5 years. METHODS: A randomised-controlled trial of postmenopausal women who had taken at least one year of adjuvant tamoxifen therapy. RESULTS: One hundred twenty-two women were recruited. Nine were found to be ineligible after randomisation. The average duration of follow-up was 26.25 months (IQR 14.5-36 months) in the surveillance group and 24.2 months (IQR 13.75-32.5 months) in the LNG-IUS group. Women with LNG-IUS in situ at the time of final assessment had decidualised endometrium, and no polyps. In the surveillance group new polyps arose in 8 cases. There were 3 new polyps in the group initially randomised to LNG-IUS, one in a patient who did not have the device inserted and 2 occurred in patients following the removal of the LNG-IUS. Univariate Cox proportional hazards regression models identified only endometrial thickness at trial entry as a statistically significant variable (HR 1.12, 95% CI 1.02 to 1.22, p=0.01) for the development of polyps. CONCLUSION: This study confirms that LNG-IUS induces benign endometrial changes and prevents endometrial polyps but only during its use in women taking tamoxifen. Endometrial thickness is a risk factor for the development of polyps.

A randomised controlled trial of prophylactic levonorgestrel intrauterine system in tamoxifen-treated women.

OBJECTIVE: To study the prophylactic use of levonorgestrel intrauterine system (LNG-IUS) in the prevention of endometrial pathology in women having breast cancer treated with tamoxifen. DESIGN: Randomised controlled trial. SETTING: A tertiary teaching hospital. POPULATION: One hundred and thirteen women (66 premenopausal/47 postmenopausal) who required adjuvant tamoxifen for breast cancer after the completion of postoperative radiotherapy and chemotherapy. METHODS: Women were randomised to treatment group (prophylactic LNG-IUS insertion before the commencement of tamoxifen) or control group. Uterine cavity was examined by outpatient hysteroscopy and endometrial biopsy before and at 12 months after commencement of tamoxifen. MAIN OUTCOME MEASURES: De novo endometrial pathology at 1 year of tamoxifen. RESULTS: Women in the treatment group had a much lower incidence of endometrial polyp (1.8 versus 15.5%, P= 0.017) (relative risk: 0.12; 95% CI: 0.02-0.91) at 12 months. There was no significant difference in the incidence of submucosal fibroid between the two groups (1.8 versus 3.4%, P= 1.0). LNG-IUS was retained in 95% women in the treatment group at 1 year. CONCLUSION: LNG-IUS reduces the occurrence of de novo endometrial polyp in women treated with tamoxifen for breast cancer.

[The effect of postmenopausal hormone replacement therapy on endometrial bleeding]. / A postmenopausalis hormonpótló kezelés hatása a változókorban jelentkezo vérzészavarra.

OBJECTIVE: The aim of this study was to determine the effect of postmenopausal hormone replacement therapy (exclusively oestrogen or sequential/continuous combined oestrogen-progestogen treatment) on endometrial bleeding, including the histological alteration of the endometrium. PATIENTS: From January 2000 to December 2005, 5893 women were treated by the authors in the menopause unit of their department. They examined the frequency of menopausal bleeding in treated and control groups. In case of bleeding, dilatation and fractional curettage was always carried out and the tissues were histologically evaluated. RESULTS: In menopausal patients who did not obtain hormone replacement therapy, bleeding occurred twice as frequently as in the treated group. Proliferating or hyperplastic endometrium was observed mainly among the treated patients, suggesting that in due time, even before the age of menopause, hormonal treatment might decrease hyperplasia and indirectly the chance of occurrence of adenocarcinoma. Hyperplasia was found more frequently in patients obtaining only oestrogen. According to the authors' view, unbalanced oestrogen treatment might further aggravate the existing hyperplasia of the endometrium. In the group treated with hormonal therapy, only simplex hyperplasia was observed. No case of complex hyperplasia with atypia was found among these patients. In the majority of patients on continuous balanced hormonal therapy, the myometrium underwent atrophy and the frequency of hyperplasia, including the chance of bleeding, mostly decreased. Endometrial polyps most frequently were found under hormonal therapy, but no acceptable explanation can be provided. The rate of cervical polyps was also higher in this group. CONCLUSIONS: According to the observations of the authors, hormone replacement therapy does not increase the risk of endometrial carcinoma. Combined preparations decrease the frequency of hyperplasia and consequently the chance of occurrence of adenocarcinoma.

Introducing inulin-type fructans.

Inulin is a generic term to cover all beta(2-->1) linear fructans. Chicory inulin is a linear beta(2-->1) fructan (degree of polymerisation (DP) 2 to 60; DPav=12), its partial enzymatic hydrolysis product is oligofructose (DP 2 to 8; DPav=4), and by applying specific separation technologies a long-chain inulin known as inulin HP (DP 10 to 60; DPav=25) can be produced. Finally, a specific product known as oligofructose-enriched inulin is obtained by combining chicory long-chain inulin and oligofructose. Because of the beta-configuration of the anomeric C2 in their fructose monomers, inulin-type fructans resist hydrolysis by intestinal digestive enzymes, they classify as 'non-digestible' carbohydrates, and they are dietary fibres. By increasing faecal biomass and water content of the stools, they improve bowel habits, but they have characteristic features different from other fibres. They affect gastrointestinal functions not because of their physico-chemical properties but rather because of their biochemical and physiological attributes. In the colon, they are rapidly fermented to produce SCFA that are good candidates to explain some of the systemic effects of inulin-type fructans. Fermentation of inulin-type fructans in the large bowel is a selective process; bifidobacteria (and possibly a few other genera) are preferentially stimulated to grow, thus causing significant changes in the composition of the gut microflora by increasing the number of potentially health-promoting bacteria and reducing the number of potentially harmful species. Both oligofructose and inulin are prebiotic. They also induce changes in colonic epithelium stimulating proliferation in the crypts, increasing the concentration of polyamines, changing the profile of mucins, and modulating endocrine as well as immune functions. From a nutrition labelling perspective, inulin-type fructans are not only prebiotic dietary fibres; they are also low-calorie carbohydrates [6.3 kJ/g (1.5 kcal/g)]. Supported by the results of a large number of animal studies and human nutrition intervention trials, the claim 'inulin-type fructans enhance calcium and magnesium absorption' is scientifically substantiated, but different inulin-type fructans have probably a different efficacy (in terms of effective daily dose), the most active product being the oligofructose-enriched inulin. A series of animal studies demonstrate that inulin-type fructans affect the metabolism of lipids primarily by decreasing triglyceridaemia because of a reduction in the number of plasma VLDL particles. The human data largely confirm the animal experiments. They demonstrate mainly a reduction in triglyceridaemia and only a relatively slight decrease in cholesterolaemia mostly in (slightly) hypertriglyceridaemic conditions. Inulin appears thus eligible for an enhanced function claim related to normalization of blood triacylglycerols. A large number of animal data convincingly show that inulin-type fructans reduce the risk of colon carcinogenesis and nutrition intervention trials are now performed to test that hypothesis in human subjects known to be at risk for polyps and cancer development in the large bowel.

[Nonsteroidal anti-inflammatory drugs and the risk of polyposis, colon carcinoma and rectal carcinoma].

OBJECTIVE: To probe the risk of colorectal polyp, colon and rectal carcinoma and the intake of NSAIDs. METHODS: Case-control study participants were from patients who underwent colonoscopy at different hospitals, the persons with the above disease was as cases, and those without the above diseases was as controls. Use of NSAIDs was assessed by interviewing the participants with a questionnaire which include a list of NSAIDs and related dietary and life style factors and family history. RESULTS: There are 37 cases of colorectal polyp, 105 cases of colon carcinoma and 142 cases of rectal carcinoma and 66 controls. Adjusted for potential confounders, the risk of colorectal polyposis, colon carcinoma and rectal carcinoma were markedly reduced by NSAIDs. The OR values were 0.21 (95% CI 0.07-0.65, P = 0.007), 0.13 (95% CI 0.05-0.35, P < 0.001), 0.15 (95% CI 0.11-0.58, P < 0.001) respectively. The risk of the above diseases were also reduced markedly by aspirin, the OR values were 0.265 (95% CI 0.07-0.96, P = 0.044), 0.10 (95% CI 0.03-0.35, P < 0.001), 0.15 (95% CI 0.04-0.49, P = 0.002) respectively. The risk of colon carcinoma was also reduced by profen, with the OR being 0.11 (95% CI 0.02-0.64, P = 0.014). CONCLUSIONS: Aspirin and other NSAIDs could reduced the risk of colorectal polyp, colon carcinoma and rectal carcinoma markedly. Aspirin was the most prospective chemopreventive agents for colorectal polyp, colon and rectal carcinoma for its capability of reducing the risk of cardio-cerebral vascular disease as well.

Response of Apc(min) and A33 (delta N beta-cat) mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

There is growing interest in the potential health benefits of tea, and a recent report described the potent antimutagenic activity of white tea in comparison with green tea against several heterocyclic amines, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) [Mutat. Res. 495 (2001) 61]. We compared the inhibitory effects of white and green teas with sulindac, a nonsteroidal anti-inflammatory agent, in two different mouse models of intestinal tumorigenesis. In the Apc(min) mouse, white and green teas given at human-relevant concentrations (1.5% w/v, 2-min brew), and sulindac (80 ppm in the drinking water), each suppressed polyp formation by approximately 50%, and the combination of white tea plus sulindac was more effective than either treatment alone (P=0.05). Mice expressing an N-terminally truncated, oncogenic version of beta-catenin (A 33(delta N beta-cat) mutant mice) developed colonic aberrant crypt foci (ACF) spontaneously, but PhIP treatment increased the incidence and number of ACF per colon. In the normal-looking intestinal mucosa of Apc(min) and A 33(delta N beta-cat) mice, white tea plus sulindac treatment markedly attenuated the expression of beta-catenin protein, and this was recapitulated in vitro in cells transiently transfected with beta-catenin plus Tcf-4 and treated with tea or the major tea polyphenol epigallocatechin-3-gallate (EGCG). Expression of a beta-catenin/Tcf reporter was inhibited by EGCG in the transfected cells, and the beta-catenin/Tcf target genes cyclin D1 and c-jun were downregulated in vivo by tea plus sulindac treatment. Collectively, the data support a chemopreventive role for tea and sulindac against intermediate and late stages of colon cancer, via effects on the beta-catenin/Tcf signaling pathway.