The Effect of Metformin on the Endometrium of Women with Polycystic Ovary Syndrome.

OBJECTIVES: To investigate the effect of metformin on endometrial receptivity in women with polycystic ovary syndrome (PCOS). METHODS: Twenty volunteer women with polycystic ovaries and oligomenorrhea were prospectively investigated. All women were treated with exogenous estradiol and progesterone to simulate a normal menstrual cycle (28-day duration) after GnRH-induced pituitary desensitization. Ten of the women received no other medication (group A, control), while the remaining 10 received metformin (group B, metformin). Endometrial biopsy was performed in all women on day 21 of the 2 simulated cycles. RESULTS: The expression of corticotropin - releasing hormone and urocortin in the endometrium was investigated. There was no significant difference between the 2 groups. A 3-day delay in the secretory maturation of the glandular epithelium relatively to the stroma was observed in 7 out of 10 women of group B (70%) as compared to only 1 out of 10 women of group A (10%, p = 0.02). CONCLUSIONS: It is shown for the first time that metformin administration to women with PCOS did not affect the expression of endometrial receptivity markers but delayed histological glandular maturation. It is suggested that metformin may have an impact on the function of the endometrium in PCOS.

Oral tuberculosis in a patient with rheumatoid arthritis after long treatment with methotrexate and adalimumab.

The treatment of rheumatoid arthritis (RA) with tumor necrosis factor α (TNF-α) inhibitors has been associated with an increased risk of tuberculosis (TB). Most patients have extrapulmonary disease. We describe a case of tonsil TB in an RA patient treated with methotrexate for 23 years and adalimumab (TNF-α inhibitor) for the last 3 years after an initial negative PPD (purified protein derivative of tuberculin) skin test. Our patient presented with a tonsil ulcer. PPD skin test was now positive; biopsy result of the lesion revealed Mycobacterium tuberculosis on culture, and a granuloma typical of TB on histologic assessment. The patient received antituberculous treatment with complete resolution of the lesion. This case illustrates that oral TB can occur after long treatment with TNF-α inhibitor and that tuberculous granulomas can be formed in such patients.

Comparative evaluation of non-informative HER-2 immunoreactions (2+) in breast carcinomas with FISH, CISH and QRT-PCR.

The routine assessment of HER-2 expression can be affected by many immunohistological preanalytical and analytical variables. The evaluation of non-informative HER-2 tests, because of 2(+) scores, has been addressed in studies using in situ hybridization (fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH)). There are very few studies that additionally checked 2(+) cases by quantitative reverse transcription-PCR (QRT-PCR). We analyzed totally 195 breast carcinoma cases, 70 of them showing 2(+) immunoreaction, with FISH/CISH and QRT-PCR. Confirmed amplification in 2(+) cases fell within the reported range (12.8% vs. 8-44%) and some of them showed lower mRNA levels indicating a genuine decrease of HER-2 protein as a mechanism for the non-informative score. In other cases, increased mRNA levels could be ascribed to HER-2 polysomy, verifying previous observations of immunohistologically detectable HER-2 polysomy. A remarkable subset of the 2(+) cases showed "normal" mRNA levels without amplification or polysomy and technical parameters as well as heterogeneity could be incriminated. The overall concordance of QRT-PCR and FISH was 93.8%, highest than most previously reported. Yet, the lack of clear cut-off mRNA values and the challenge of sample microdissection hinder QRT-PCR from claiming the status of a gold standard test for HER-2 evaluation.

A Case of Cervical Carcinoid and Review of the Literature.

Uterine cervix carcinoids are distinct neuroendocrine cervical tumors, representing a comparatively small percentage of them. These well-differentiated neoplasms are far less prevalent than small- and large-cell carcinomas, characterized by a more favorable biological course. We report a case of a 43-year-old woman with a nonmetastatic cervical carcinoid, managed with radical hysterectomy. She still remains free of disease. Scant reports in the literature prohibit any reliable prediction of cervical carcinoid prognosis. Thus, prompt identification of the disease and subsequent therapeutic intervention could alter the final outcome.

Prolonged use of gonadotropin-releasing hormone agonist and tibolone as add-back therapy for the treatment of endometrial hyperplasia.

OBJECTIVES: To investigate the response of the various hyperplastic disorders of the endometrium to a prolonged treatment with leuprolide acetate, a gonadotropin-releasing hormone agonist (GnRH-a), plus tibolone, as add-back therapy, and further to study if the tibolone addition reduces the hypoestrogenic actions of the GnRH-analogue. METHODS: We treated 26 women with histologically confirmed simple (n = 9), complex (n = 15) or atypical (n = 2) endometrial hyperplasia (EH) for 12 months with monthly injections of 1Ampulle/3.75 mg of leuprolide acetate, followed by tibolone, 2.5mg per day per os. Every woman underwent a hysteroscopic evaluation and biopsy of the endometrium after 3 (in cases with atypical EH), 6 and 12 months of treatment, as well as after 12 and 24 months of follow-up. The clinical, paraclinical and laboratory course of the disease was followed-up by using of a climacteric scoring system and by testing of various parameters. RESULTS: The histopathologic evaluation of the endometria revealed regression of EH in all women after 12 months of treatment, however, during the first 2 years of follow-up EH reappeared in four women (4/21, 19%). Bone mineral density and serum parameters did not show significant changes during treatment, whereas only a mild suffering from hypoestrogenic side-effects was noted. CONCLUSIONS: It seems that the combined GnRH-a/tibolone treatment in women with EH is a potent alternative, so far as the endometrial status and the clinical course of the disease are concerned, whereas tibolone appears to act sufficiently as add-back therapy to prolonged GnRH-a treatment. The probability of relapse of the disease during the follow-up period makes the close monitoring of the endometrium after cessation of the treatment absolutely necessary.

Solitary rectal cap polyp: Case report and review of the literature.

Rectal bleeding combined with the presence of a rectal mass has been traditionally associated with the presence of malignant disease. Cap polyposis is a relatively young and still undefined rare entity which mainly involves the rectosigmoid. It is characterized by the presence of inflammatory polyps. In this case report, we present a patient who was diagnosed with a solitary cap polyp of the rectum during the investigation of a bleeding rectal mass. The patient's age and the absence of family history were not in favor of malignancy, despite the strong initial clinical impression. After confirmation of the diagnosis, the patient underwent a snare excision and remains asymptomatic. Cap polyposis, although rare, should be suspected and, when diagnosed, should be treated according to location, number of polyps and severity of symptoms.

Correlation between cyclin B1 immunostaining in cervical biopsies and HPV detection by PCR.

In recent years, experimental data on the roles of viruses and cyclin B1 in G2/M arrest has accumulated. The aim of our study was to immunohistochemically examine a series of cervical squamous intraepithelial lesions for the presence of cyclin B1 and test for a possible correlation with morphologic findings or human papillomavirus (HPV) types detected by polymerase chain reaction. One hundred and three biopsies and/or conization specimens were examined, including high-grade lesions (25), low-grade lesions (52), biopsies showing nondiagnostic atypia (15), and biopsies without histopathologic alterations (11). Three patterns of immunopositivity were recognized, according to the level of epithelium exhibiting positively stained cells. Immunoreactivity for cyclin B1 above the basal/parabasal cells correlated with HPV presence. Cyclin B1-stained cells may represent "prekoilocytes," whose eventual progression to koilocytes would depend on several parameters related to the intricacies of HPV infection. In cases of nondiagnostic atypia immunoreactivity, cyclin B1 could be considered as a surrogate test.

Fascin in ovarian epithelial tumors.

Fascin contributes to the formation of actin-based protrusions involved in cell migration. Fascin has emerged as a prognostic marker in some carcinomas. We examined ovarian neoplasms to check any correlation between fascin expression and established clinicopathologic parameters. Fascin immunoreactivity was semiquantitavely scored in 100 ovarian tumors (62 carcinomas, 15 borderline tumors and 23 cystadenomas). Double staining for fascin and Ki-67 was performed in selected carcinomas. Western Blotting was done in frozen samples. Fascin immunoreactivity was highest in carcinomas, lowest in cystadenomas and intermediate in borderline tumors; these results were in accordance with those from Western blotting analysis. Fascin was statistically increased in carcinomas of advanced stage and in serous carcinomas. It was also increased in metastatic foci and in tumor foci with lower Ki-67 labeling. We conclude that in ovarian tumors fascin is associated with certain features of increased tumor aggressiveness. Future studies could determine if fascin may become a routinely helpful marker in gynecological pathology or clinical oncology.

The protective effect of alpha-tocopherol and GdCl3 against hepatic ischemia/reperfusion injury.

PURPOSE: To evaluate the combined effect of alpha-tocopherol and gadolinium chloride (GdCl3) in reducing lipid peroxidation after severe hepatic ischemia/reperfusion (IR) injury. METHODS: Sixty male Wistar rats, 200-250 g, were randomly divided into six equal groups. There were two sham operation (SHAM) groups, two untreated IR groups, and two IR groups treated with GdCl3 and alpha-tocopherol (IRGT). After 60 min of total hepatic ischemia and 120 min reperfusion, one of each group was killed, liver samples were taken for malondialdehyde (MDA) and myeloperoxidase (MPO) analysis and light microscopy examination, and blood samples were analyzed for aspartate (AST) and alanine (ALT) transaminase, lactate dehydrogenase (LDH), and alpha-tocopherol content. The remaining groups were monitored for survival rate determination. RESULTS: The mean MDA and MPO values in the SHAM, IR, and IRGT groups, respectively, were 1.117, 1.476, and 0.978 nmol/g wet tissue and 1.49, 6.26, and 1.78 (U/g). The mean alpha-tocopherol values in the SHAM, IR, and IRGT groups, respectively, were 10.4, 1.9, and 12 micromol/l. The mean serum AST, ALT, and LDH values were significantly higher in the IR group than in the SHAM group (P < 0.001), and significantly lower in the IRGT group than in the IR group (P < 0.001). Light microscopy examination revealed more severe congestion and vacuolization in the IR group than in the SHAM group, and minimal congestion and vacuolization in the IRGT group. Survival was significantly higher in the IRGT group than in the IR group. CONCLUSION: The administration of GdCl3 and alpha-tocopherol is likely to protect the liver against lipid peroxidation by suppressing Kupffer cell and polymorphonuclear leukocyte activation and enhancing endogenous antioxidant activity.

High dose intravenous immunoglobulin g pretreatment: effect on lipid peroxidation and reperfusion injury to the liver.

The aim of this study was to examine the effect of intravenous immunoglobulin G (IVIG) compared with that of gadolinium chloride (GdCl3) in the inhibition of Kupffer cell activation on lipid peroxidation after severe total hepatic ischemia/reperfusion (I/R). Male Wistar rats ( n = 40) were randomly divided into four equal groups: a sham-operation group, a control I/R group, and two I/R groups pretreated with either IVIG or GdCl3 intravenously. Following 60 minutes of total hepatic ischemia and 120 minutes of reperfusion, the rats were sacrificed and liver and blood samples collected. Additional animals ( n = 80) were followed up for survival rate determination. Results showed that I/R decreased the survival rate to 10%, increased the levels of aspartate (AST) and alanine (ALT) transaminase and lactate dehydrogenase (LDH) in serum to 2487, 2189, and 4236 IU/L, respectively, and increased malondialdehyde (MDA) levels in liver to 1.552 nmol/g compared with 1.114 nmol/g in the sham operation group. Pretreatment with GdCl3 increased the survival rate to 50% and decreased the levels of AST, ALT, and LDH in serum to 1496, 1298, and 3245 IU/l, respectively. Pretreatment with IVIG increased the survival rate to 60% and decreased the levels of AST, ALT, and LDH in serum to 449, 367, and 1456 IU/l, respectively, and the levels of MDA in liver to 1.153 and 1.148 nmol/g for GdCl3 and IVIG respectively. Histologic examination showed protection of liver parenchyma in the animals treated with GdCl3 or IVIG.

Intramuscular administration of very high dose of alpha-tocopherol protects liver from severe ischemia/reperfusion injury.

The effect of intramuscular administration of high (30 mg/kg body weight for 3 days) or very high (300 mg/kg body weight for 3 days) doses of a-tocopherol to Wistar rats subjected to total severe warm hepatic ischemia and reperfusion was investigated. After a 60-minute period of total hepatic ischemia and 120 minutes of reperfusion, animals were killed, and liver samples were taken for determination of malondialdehyde (MDA) and histological examinations. Blood samples were also taken for assay of serum a-tocopherol, alanine transaminase (ALT), aspartate transaminase (AST), and lactic dehydrogenase (LDH). Additional animals were followed for a 7-day survival rate determination. Results showed that ischemia and reperfusion decreased the survival rate to 10%, whereas the levels of AST, ALT, and LDH in serum were increased compared with levels in animals that were sham operated. The MDA concentrations in liver were also increased, from 1.142 to 1.567 nmoles/g, whereas the levels of a-tocopherol in serum were decreased from 10.20 to 1.80 mmol/L. Pretreatment with a-tocopherol increased the viability to 50% and 70%, for the high and very high doses, respectively, and decreased the levels of AST, ALT, and LDH in serum. It also decreased the MDA concentrations in liver to 0.975 and 0.774 nmoles/g for the high and very high doses of a-tocopherol, respectively, whereas it increased the level of a-tocopherol in serum to 11.25 and 13.02 mmol/L for the high and very high doses, respectively. Histological examinations showed protection of the liver parenchyma in the animals treated with a-tocopherol.