Endometrial Osseous Metaplasia-A Rare Cause of Infertility with Unknown Etiology.

Background: Osseous tissue in the endometrium is a rare find, and it is most often discovered when the patient presents with infertility. It is frequently associated with dysmenorrhea and abnormal menstrual bleedings. Although its etiology remains unclear, in almost all described cases until now, the patient has an obstetrical history. Case report: In this report, we present a unique case of endometrial osseous metaplasia in a 27-year-old primary infertile patient. The transvaginal ultrasound revealed a 18/13/7 mm hyperechoic endometrial mass with posterior acoustic shadowing and no flow on color Doppler. A hysteroscopic examination found a polygonal calcification on the endometrial posterior face of the uterine cavity, in the corporeal isthmic region, which was extracted. The histopathological evaluation revealed microscopic elements compatible with endometrial calcification. The patient had a good postoperative course and the complex endocrinologic, immunologic and electrolytical investigation failed to prove any abnormality. Follow-up transvaginal ultrasound examinations revealed no modifications. Three years later, the patient conceived spontaneously, had an uneventful pregnancy and delivered a full-term fetus. Conclusion: We assumed that this entity can be a serious cause of infertility since the patient had a long history of (primary) infertility and its resection made the pregnancy's occurrence possible. Finally, since neither history of abortion or chronic inflammation nor any abnormal laboratory test were noticed, we concluded that the etiology of this entity remained unclear.

Cabergoline Failure and a Spontaneous Pregnancy in a Microprolactinoma with High Prolactin Levels.

We report a particular case of a spontaneously occurring pregnancy in a long-term amenorrheic patient due to a prolactinoma with high serum prolactin (PRL) following the failure of dopamine agonist therapy (DA) for infertility. Initially, clinical, laboratory, and genital ultrasounds were normal, but the serum PRL was 10,074 µIU/mL (n.v.: 127−637 µIU/mL), the PEG fraction was 71% (laboratory cut-off > 60%), and luteinizing hormone (LH) was significantly lower. An MRI revealed a pituitary tumor of 12.8/10 mm with a subacute intratumoral hemorrhage. DA was initiated, and menstrual bleeding reappeared with a reduction in the tumor's volume to 1.9/2.2 mm at 12 months. Two years later, the patient renounced DA and follow-ups. After another 2 years, she became spontaneously pregnant. Serum PRL was 18,325 µIU/mL, and an MRI revealed a microprolactinoma of 2.1/2 mm. The patient gave birth to a normal baby at term, and she breastfed for six months, after which she asked for ablactation, and DA was administered. This case highlights the possibility of the occurrence of a normal pregnancy during a long period of amenorrhea induced by a microprolactinoma with a high level of serum PRL, even if DA fails to correct infertility. There was no compulsory relationship between the tumoral volume's evolution and the evolution of its lactophore activity. The hypogonadotrophic hypogonadism induced by high PRL was mainly manifested by low LH, and in this situation, normal levels of FSH and estradiol do not always induce follicle recruitment and development without abnormalities in the ovary ultrasound.

Is there a relationship in-between ovarian endometriosis and ovarian cancer? Immunohistochemical profile of four cases with coexisting ovarian endometriosis and cancer.

Endometriosis (EMs) is a benign disease characterized by the presence of endometrial tissue outside the uterine cavity. EMs associated with ovarian cancer (OC) has a relative low incidence (5% to 10%), sometimes with evidence of a transition stage through atypical EMs (1.6% cases). We have assessed 135 consecutive patients with either EMs or OC and, out of them, our study reports on four cases of ovarian EMs and OC: two cases with endometrioid OC and two cases with high-grade serous OC (HGSOC). Cases with EMs and HGSOC are extremely rarely reported in the literature - we could find not more than 30 cases. The main objective of our research was to observe the possible similarities between EMs and OC. Secondly, we analyzed the differences between EMs associated with endometrioid OC and EMs associated with HGSOC. We evaluated them in terms of clinical status (age, stages of EMs and OC) and immunohistochemical (IHC) expression of estrogen receptor (ER), progesterone receptor (PR), Ki67, p53, p16, Wilms' tumor 1 (WT1), cluster of differentiation (CD) 34 and CD10 immunomarkers - we could not find in the literature all these markers assessed, in the same time, to such samples. Our results indicated that there are no similarities between EMs and OC and no atypical EMs was identified in our cases. We recorded higher values of ER expression in EMs associated with HGSOC than in EMs associated with endometrioid OC. Higher values of ER expression were also recorded in OC than in endometriotic foci. There were no differences in proliferative rate of endometriotic foci associated with endometrioid OC, compared to EMs associated with HGSOC. An aberrant IHC expression for p53 protein and p16 protein was noted only in HGSOC. Also, a positive immunostaining for Wilms' tumor 1 (WT1) was identified only in HGSOC. Higher values of microvessel density were recorded in OC but not in endometriotic foci. We concluded that there were no similarities between EMs and OC for the cases included in our study, but we noticed differences in terms of Ki67 index and also between hormonal receptors expression in EMs associated with HGSOC, comparing with EMs associated with endometrioid OCs. These results may represent a "brick" for future researches on the less understood EMs associated with type II of OCs, especially with HGSOC. Identifying the best marker, which can predict the risk of developing OC for the patients with EMs, may lead to discover new specific therapeutic agents and, therefore, a better, tailored, therapy.

A unique case of recurrent fetal cystic hygroma: first fetus with an inherited heteromorphism of chromosome 1 (1qh+) and the second fetus with 69XXX triploidy.

The authors report a unique recurrent septated cystic hygroma (CH), on two successive pregnancies, at five years interval. The chromosome analysis of the first fetus showed an increase in length of heterochromatin on the long arm of chromosome 1 - 1qh+, a chromosomal polymorphism inherited from mother, 46XX,1qh+,14ps+,21ps+. The karyotype of the second CH, with more severe ultrasound (US) imaging, showed a 69XXX triploidy. The patient took no risk and underwent each time a termination of pregnancy (TOP). The first karyotype is generally considered "normal", although there are few reports linking 1qh+ with low fertility, but this was not the case, the patient having, from a previous marriage, a healthy boy and two TOPs. So, this "particular", but "healthy" karyotype was not a cause for the first CH. The second karyotype highlights a possible causality between the 69XXX triploidy, usually associated with partial hydatidiform mole, and a more severe septated CH in the last fetus. Neither the CHs' appearance nor their recurrence seemed to be family linked, as the two CHs had distinct genetic profiles. We recommend that, once CH is diagnosed, a careful US examination is compulsory for the determination of subcutaneous edema, ascites, pleural and pericardial effusions and cardiac or renal abnormalities; an early genetic work-up is mandatory, by chorionic villus sampling or amniocentesis. However, a "healthy" karyotype does not exclude a severe form, as in our first case of CH. Due to the very poor outcome of fetuses with CH, the patient must be thoroughly informed about the short and the long-term fetal prognosis.

The role of non-invasive scores in determining the liver fibrosis in NAFLD and psoriatic patients.

According to recent data, psoriatic patients have an increased prevalence of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome, compared with the general population. In some published studies, the severity and presence of psoriasis disease were correlated with the severity of NAFLD. In the current study, we aimed to compare the sensibility and specificity of the non-invasive scores and liver biopsy in determining fibrosis in patients with NAFLD and moderate to severe psoriasis. We performed the scientific research from June 2014-December 2017 and we included 71 patients: 40 patients with NAFLD and 31 patients with moderate to severe psoriasis according to Psoriasis Area and Severity Index (PASI) score and NAFLD, who received Etanercept treatment for at least one year. Based on the clinical and laboratory data, we calculated the following scores for fibrosis: body mass index (BMI), aspartate aminotransferase (AST)∕alanine aminotransferase (ALT) ratio, diabetes (BARD) score, Fibrosis-4 (FIB-4) score, and NAFLD fibrosis score (NFS). For liver biopsy, we used the Menghini technique. By calculating Kendall's test, we also observed a strong direct correlation between the degree of fibrosis and FIB-4 (tau=0.558) and NFS (tau=0.490) scores, with a critical statistical impact, and the lack of a correlation with the BARD score (tau=0.095; p=0.332). The hepatic biopsy allowed the more accurate establishment of the role of the non-invasive tests in the diagnosis of the lesions of steatosis, steatohepatitis, and hepatic fibrosis. The non-invasive tests are most useful for the exclusion of the evolution lesions and for the confirmation of the advanced stages of the disease. Among these, the NFS score proved a high statistically significant correlation (p<0.0001) with the fibrosis histological lesions.

GPER and ERα expression in abnormal endometrial proliferations.

UNLABELLED: G-protein coupled estrogen receptor 1 (GPER), a particular extranuclear estrogen receptor (ER), seems not to be significantly involved in normal female phenotype development but especially associated with severe genital malignancies. This study investigated the GPER expression in different types of normal and abnormal proliferative endometrium, and the correlation with the presence of ERα. GPER was much highly expressed in cytoplasm (than onto cell membrane), contrary to ERα, which was almost exclusively located in the nucleus. Both ERs' densities were higher in columnar epithelial then in stromal cells, according with higher estrogen-sensitivity of epithelial cells. GPER and ERα density decreased as follows: complex endometrial hyperplasia (CEH) > simple endometrial hyperplasia (SHE) > normal proliferative endometrium (NPE) > atypical endometrial hyperplasia (AEH), ERα' density being constantly higher. In endometrial adenocarcinomas, both ERs were significant lower expressed, and widely varied, but GPER÷ERα ratio was significantly increased in high-grade lesions. CONCLUSIONS: The nuclear ERα is responsible for the genomic (the most important) mechanism of action of estrogens, involved in cell growth and multiplication. In normal and benign proliferations, ERα expression is increased as an evidence of its effects on cells with conserved architecture, in atypical and especially in malignant cells ERα's (and GPER's) density being much lower. Cytoplasmic GPER probably interfere with different tyrosine÷protein kinases signaling pathways, also involved in cell growth and proliferation. In benign endometrial lesions, GPER's presence is, at least partially, the result of an inductor effect of ERα on GPER gene transcription. In high-grade lesions, GPER÷ERα ratio was increased, demonstrating that GPER is involved per se in malignant endometrial proliferations.

Ovarian teratomas in a patient with Bardet-Biedl syndrome, a rare association.

Bardet-Biedl syndrome (BBS) represents a rare ciliopathy recessive autosomal inherited. The main clinical features are retinal dystrophy, postaxial polydactyly, obesity, different degrees of cognitive deficit, renal impairment, hypogonadism and genital malformations. The genetic explanation consists in BBS genes mutations, which encode modified proteins, altering the function of the immotile cilia. As a multitude of BBS genes mutations were described, the phenotypic aspect of these disorders varies according to that. We present the case of a 22 years old female patient, known with BBS since the age of 11 and which was diagnosed and operated for bilateral ovarian dermoid cysts, at the age of 21. We did not find a similar case in literature, regarding the association between the two disorders. We consider that our case points towards the importance of periodic imagistic evaluations [magnetic resonance imaging (MRI), computed tomography (CT) or ultrasound] of these patients, not only clinical and biological. Usually, the moment they are diagnosed with hypogonadism or genital malformations (in childhood or adolescence), the genital evaluation is neglected thereafter. We also consider that our therapeutic approach can be helpful in other similar clinical situations. Another important conclusion is represented by the importance of genetic counseling of the relatives of a BBS patient, unfortunately insufficiently provided in our region.

The immunohistochemical analysis of the proliferative activity and the maturity degree of lymphatic vessels in oral squamous cell carcinomas.

Oral cancers still represent a major health problem; regional lymph node metastases occur in 30-40% of head and neck squamous cell carcinomas and are associated with unfavorable prognosis and decreased survival. The study included 35 cases of oral squamous cell carcinomas (OSCC), which were analyzed by double reactions to determine the proliferative activity (anti-human D2-40/Ki67) and the maturity degree (anti-human D2-40/α-SMA) of lymphatic vessels, both intratumoral (IT) and in the advancing edge (AE), and in relation to clinicopathological prognostic parameters. The mean values of D2-40 lymphatic vessel density (LVD) were higher in AE then in IT level. Poorly differentiated carcinomas, T3/T4, presented the highest LVD values, both IT and in the AE. LVD was higher in advanced stages and metastasizing carcinomas. Ki67 was positive in all cases, Ki67 proliferation index (IP) indicated higher values in poorly differentiated carcinoma, T3/T4, metastasizing ones, both IT and in the AE. LVD and IP Ki67 showed a positive linear correlation. D2-40/Ki67-positive vessels were identified only at the AE or close to it. D2-40/Ki67 LVD had highest values in advanced stages carcinoma, with metastases. D2-40/α-SMA-positive vessels were identified only in the neighborhood of the tumor and LVD highest values were present in early-stage carcinomas and without metastases. A negative linear correlation between proliferation and maturity of the lymphatic vessels was found. The study indicated a strong association between lymphatic proliferative activity and lymph node metastases, suggesting the need for targeted antilymphangiogenic therapies in OSCC.

Salivary and serum biomarkers for the study of side effects of aripiprazole coprescribed with mirtazapine in rats.

The aim of this study was to investigate whether the co-administration of aripiprazole and mirtazapine could determine weight gain and lipid metabolism disorders in Wistar rats, compared to the same side effects produced by mirtazapine alone, and the risk of hepatotoxicity due to the combination of the two substances. Tumor necrosis factor alpha (TNF-α), liver fatty acid binding protein (L-FABP/FABP1) and repulsive guidance molecule C/hemojuvelin (RGM-C/HJV) levels were determined in serum and in saliva. Also, serum levels for total cholesterol (TC), low and high-density lipoprotein (LDL, HDL), triglycerides (TG), aspartate aminotransferase (ASAT) and alanine amino transferase (ALAT) were assessed. We found positive and statistically significant correlations between serum and salivary levels of TNF-α, L-FABP/FABP1 and RGM-C/HJV. Mirtazapine determined significantly differences of TNF-α and L-FABP serum levels; final body weight; TC and LDL levels, leading to higher concentrations than its association with aripiprazole. Although not statistically significant, mirtazapine group experienced higher values for salivary levels of TNF-α, TG and ASAT, and lower values for HDL, compared to aripiprazole + mirtazapine group. The results suggest that aripiprazole might improve some of the disturbances caused by mirtazapine, and that the two drugs combination cause no additional alterations in liver function. Also, the findings indicate that TNF-α, L-FABP/FABP1 and RGM-C/HJV levels can be helpful as biomarkers for metabolic disturbances and impaired function of hepatocytes, and that their salivary determination can replace serum determination.

Large pancreatic mucinous cystic neoplasm during pregnancy: what should be done?.

Pancreatic mucinous cystic neoplasms are uncommon and their occurrence in pregnancy is extremely rare. The authors report the unique case of a newborn weighing 3,620 g, delivered vaginally with no complications by a patient with a large 'silent' pancreatic mucinous cystic neoplasms, and analyze the very few other reports. With no available protocol, this case highlights an interesting dilemma on the management of pregnancy and delivery as well on the timing of pancreatic surgery. Despite its limitations, MRI remains the most accurate investigation either for differentiating the mucinous from nonmucinous cysts or for evaluating the malignancy, but echography is also very useful. Without symptoms, all low-grade malignant potential tumors, independent of the moment of their diagnosis during pregnancy, should be resected 2-3 months after delivery and we believe that the best option is a term vaginal birth, even in the presence of a large cyst and large fetus. On the contrary, all high-grade malignant potential tumors, discovered in the first two trimesters of pregnancy should be resected during the second trimester, and followed by a vaginal delivery at term. If high-grade malignant potential tumor is diagnosed in the third trimester, an early vaginal delivery followed by surgery is recommended. Finally, the patient's preference is crucial.

Recurrent partial hydatidiform mole, with a first twin pregnancy, after treatment with clomiphene citrate.

We present a patient, treated for 3 months with clomiphen citrate after 5 years of infertility. This treatment resulted in a twin pregnancy, one degenerated into a partial hydatidiform mole and the other into a very early embryo death. The karyotype was a mosaic one: 63% of metaphases showed triploidy - 69 XXX and 37% diploidy - 46 XX. Despite all medical advice, she returned 8 months later with a new pregnancy, which proved to be a new partial hydatidiform mole, this time a single one. Karyotype was, also, a triploidy - 69 XXX. The genetic map of both genitors was performed, showing no aberrations. Unfortunately, the patient came back, once again, 5 months later, with a new positive pregnancy test. Ultrasonography revealed a new very early embryo death, the histopathological analysis establishing to be a single 'pure' stop in evolution of the pregnancy. As all the three pregnancies obtained after treatment with clomiphene were abnormal, two being partial hydatidiform moles and one being a premature miscarriage, without any genetic aberrations of the genitors, it seems very possible that clomiphene, apart from improving fertility, also increases the risk of abnormal ovum appearance.