Elif Pestereli

Preliminary results of the first human uterus transplantation from a multiorgan donor

OBJECTIVE To describe the first-year results of the first human uterus transplantation case from a multiorgan donor. DESIGN Case study. SETTING University hospital. PATIENT(S) A 21-year-old woman with complete müllerian agenesis who had been previously operated on for vaginal reconstruction. INTERVENTION(S) Uterus transplantation procedure consisting of orthotopic replacement and fixation of the retrieved uterus, revascularization, end to site anastomoses of bilateral hypogastric arteries and veins to bilateral external iliac arteries and veins was performed. MAIN OUTCOME MEASURE(S) Resumption of menstrual cycles. RESULT(S) The patient had menarche 20 days after transplant surgery. She has had 12 menstrual cycles since the operation. CONCLUSION(S) We have described the longest-lived transplanted human uterus to date with acquirement of menstrual cycles.

Neoangiogenesis and expression of hypoxia-inducible factor 1α, vascular endothelial growth factor, and glucose transporter-1 in endometrioid type endometrium adenocarcinomas

OBJECTIVE Hypoxia Inducible Factor-1alpha (HIF-1alpha) is a transcriptional factor that activates multiple genes including Vascular Endothelial Growth Factor (VEGF) and glucose transporter-1 (GLUT-1) in response to hypoxia and promotes neoangiogenesis. METHODS Expression of HIF-1alpha VEGF, and GLUT-1 were analyzed by immunohistochemistry and microvessel density (MVD) was determined by CD 34 immunostaining in 100 endometrioid type endometrial adenocarcinoma, FIGO Stages I-IV. RESULTS High expression of HIF-1alpha, VEGF and GLUT-1 were significantly more prevalent in advanced stages than early stages (p<0.001). High expression of HIF-1alpha was found in 100% of Stage III-IV patients, whereas 50% of Stage II and 9% of Stage I patients had high HIF-1alpha expression. Similarly, high VEGF expression was determined in 4% of Stage I and 30% of Stage II patients, however 90% of Stage III-IV patients had high expression of VEGF. Comparing the GLUT-1 scores, it was found that increasing stages correlated with high GLUT-1 expression. Additionally, a statistically significant difference was also noted in MVD between stages (p<0.001). The average MVD of Stage I patients was 31.87+/-7.73. It was found 49.24+/-7.60 in Stage II, and 78.74+/-14.48 in Stage III-IV patients. On analyzing expression of HIF-1alpha, VEGF and GLUT-1 and MVD in pairs, statistically significant correlations were found between each other (p<0.001). CONCLUSION HIF-1alpha was increasingly expressed from early stages through advance stages of endometrioid adenocarcinoma, paralleled by activation of its downstream genes such as GLUT-1, VEGF and increased angiogenesis. These results highlight the importance of hypoxia and related pathways in progression of endometrial carcinoma.

Predictors of distant metastasis at presentation in breast cancer: a study also evaluating associations among common biological indicators

AbstractBackground. To investigate the correlation among some of the commonly used clinical, pathological factors and newer biological indicators, and to identify the independent predictors of distant metastasis at presentation in patients with breast cancer. Methods. The pathological specimens from 73 patients with breast cancer were retrospectively evaluated by immunohistochemistry. Data on 13 biological indicators; ER, PR, P53, c-erbB-2, PCNA, CEA, Ki-67, Vimentin, Ulex, Nm23, Cathepsin D, Factor VIII, PS2 together with clinical and pathological factors were collected. Results. A number of highly significant correlations were found among the biological indicators studied. By logistic regression analysis, the predictors of distant metastasis at presentation in univariate tests were tumor diameter, number of lymph nodes involved, P53, c-erbB-2 and grade. In multivariate analysis, tumor diameter (P=0.042, HR: 1.88(1.02–3.44)), c-erbB-2 expression (P=0.035, HR: 18.20 (1.23–268.66)) and grade (P=0.010, HR: 8.05(1.66–39.00)) retained their significance. Conclusion. Our findings show that inactivation of suppressor genes, expression of oncogenes, loss of differentiation, augmentation of proliferative activity, metastatic potential, angiogenesis and hormone receptor status are all interrelated facets of breast cancer pathogenesis. Patients with tumors overexpressing c-erbB-2 or with bigger or higher-grade tumors probably need to be more carefully evaluated for the presence of distant metastasis, thus be better staged, at presentation. This may be a new reason to test c-erbB-2 routinely in all patients with breast cancer in addition to its well-known prognostic and predictive uses.

Heterotopic triplet pregnancy (twin tubal) in a natural cycle with tubal rupture: Case report and review of the literature

The incidence of heterotopic/ectopic pregnancy has risen in recent years, largely due to more frequent use of ovulatory medicine and increased incidence of pelvic inflammatory disease. In a natural cycle, it is a very rare event. Most heterotopic/ectopic pregnancies are localized in the uterine tube and, usually, it is diagnosed when symptoms develop. We report the case of a 37 year‐old, gravida 2, para 0, abortion 1 woman with no known risk factors for heterotopic pregnancy. The patient attended the emergency department because of acute abdominal pain. She was evaluated in our department and a heterotopic twin pregnancy in the tube was diagnosed by transvaginal sonography. Intrauterine pregnancy with positive fetal cardiac activity at 9 weeks of gestation according to crown‐rump length measurement was detected. Laparotomy was carried out because of acute abdominal syndrome. Right ruptured tubal ectopic/heterotopic pregnancy and hemoperitoneum were diagnosed. Right salpingectomy was carried out. Pathology revealed monochorionic twin tubal pregnancy. In a review of the literature, this is first case of twin tubal pregnancy in one uterine tube. In conclusion, heterotopic pregnancy in twin form in the uterine tube is possible in natural cycles. Intrauterine pregnancy does not exclude extrauterine pregnancy in natural cycles.

PTEN-mediated Akt activation in human neocortex during prenatal development.

Akt is a crucial factor for cell survival and migration. Phosphatase and tensin (PTEN) negatively regulates cell growth and survival by inhibiting PI3K-dependent signaling. PTEN also blocks Akt phosphorylation, a main downstream molecule of PI3K cascade. So far, no studies have shown PTEN expression and Akt phosphorylation levels in the developing human neocortex. Our hypothesis is that spatial and temporal expression of PTEN is likely to modulate developing human brain cortical modeling by regulating Akt activation. Therefore, our aim is to analyze the expression pattern of PTEN and phospho-Akt levels using immunohistochemistry, Western blot, and semiquantitative analysis in the developing human neocortex (n=13 fetuses from first, second, and third trimesters). PTEN expression was decreased parallel to development, but some cells revealed strong nuclear immunoreactivity in the developing neocortex while the active Akt level was increased. Double immunohistochemistry was performed for proliferating cell nuclear antigen (PCNA)-Tuj1 (as neuronal marker) and PCNA-GFAP (Glial marker) to the subsequent sections of PTEN and Akt-stained slides. PCNA (+) cells were mostly positive for glial fibrillary acidic protein (GFAP) and correlated with active-Akt immunoreactivity. Our results suggest that Akt-mediated signaling plays an active role in cell migration, survival, and cerebral cortical modeling throughout prenatal life and that PTEN is the most likely protein to regulate this signaling.

Reproducibility of endometrial intraepithelial neoplasia diagnosis is good, but influenced by the diagnostic style of pathologists

Endometrial intraepithelial neoplasia (EIN) applies specific diagnostic criteria to designate a monoclonal endometrial preinvasive glandular proliferation known from previous studies to confer a 45-fold increased risk for endometrial cancer. In this international study we estimate accuracy and precision of EIN diagnosis among 20 reviewing pathologists in different practice environments, and with differing levels of experience and training. Sixty-two endometrial biopsies diagnosed as benign, EIN, or adenocarcinoma by consensus of two expert subspecialty pathologists were used as a reference comparison to assess diagnostic accuracy of 20 reviewing pathologists. Interobserver reproducibility among the 20 reviewers provided a measure of diagnostic precision. Before evaluating cases, observers were self-trained by reviewing published textbook and/or online EIN diagnostic guidelines. Demographics of the reviewing pathologists, and their impressions regarding implementation of EIN terminology were recorded. Seventy-nine percent of the 20 reviewing pathologists’ diagnoses were exactly concordant with the expert consensus (accuracy). The interobserver weighted κ values of 3-class EIN scheme (benign, EIN, carcinoma) diagnoses between expert consensus and each of reviewing pathologists averaged 0.72 (reproducibility, or precision). Reviewing pathologists demonstrated one of three diagnostic styles, which varied in the repertoire of diagnoses commonly used, and their nonrandom response to potentially confounding diagnostic features such as endometrial polyp, altered differentiation, background hormonal effects, and technically poor preparations. EIN diagnostic strategies can be learned and implemented from standard teaching materials with a high degree of reproducibility, but is impacted by the personal diagnostic style of each pathologist in responding to potential diagnostic confounders.

Distribution of N-cadherin in human cerebral cortex during prenatal development.

An important subgroup of adhesion molecules is the superfamily of cadherins, which takes part in cell recognition and differentiation during development. To our knowledge only one study describing N-cadherin expression in developing human brain has been performed so far. Our aim is to identify N-cadherin expression to establish a relationship between its expression and function in human cerebral cortex during prenatal development. In the present study, localization and intensity of N-cadherin was investigated in developing cerebral cortex. Fetuses from spontaneous abortions (n=13) were obtained from first, second, and third trimesters. Western blot analysis revealed three bands and the third trimester samples showed the strongest bands for N-cadherin. Cell processes, axon bundles, and some of the developing neurons revealed immunoreactivity for N-cadherin throughout pregnancy. The immunoreactivity increased in the developing neocortex and expanded from the ventricular layer toward the marginal zone as development progressed. Moreover, the immunoreactivity was strong in vascular endothelium during all three trimesters. We conclude that N-cadherin is dynamically related to the organization of cerebral cortex layers during prenatal development. The dynamic expression pattern implicates N-cadherin as a potential regulator of cell migration, axon extension and fasciculation, the establishment of synaptic contacts, and neurovascular angiogenesis in the developing human cerebral cortex.

Analysis of Metastatic Regional Lymph Node Locations and Predictors of Para-aortic Lymph Node Involvement in Endometrial Cancer Patients at Risk for Lymphatic Dissemination.

Objective The aim of this study was to provide detailed knowledge of the metastatic lymph node (LN) locations and to determine factors predicting para-aortic LN metastasis in endometrial cancer patients at risk (intermediate/high) for LN involvement. Methods A prospective case series with planned data collection was conducted in a total of 173 patients who treated with systematic pelvic para-aortic lymphadenectomy up to the renal vessels. All the LNs removed from pelvic and para-aortic basins—low or high according to the level of the inferior mesenteric artery—were evaluated separately. Logistic regression analyses were performed to determine the impact of variables on para-aortic metastasis. Results Lymph node metastasis was observed in 21.9% of the patients, pelvic LN involvement in 17.9%, para-aortic LN involvement in 15.0%, both pelvic and para-aortic LN involvement in 10.9%, and isolated para-aortic LN involvement in 4.0%. The most common metastatic LN locations were the external iliac (50.0%), obturator (50.0%), and low precaval regions (36.8%). The least common location of metastasis was the high precaval region (5.3%). Among patients with para-aortic LN metastasis, 42.3% had metastasis above the inferior mesenteric artery. The number of metastatic pelvic LNs greater than or equal to 2 was the only independent predictor of para-aortic metastasis in multivariate analysis (odds ratio, 23.38; 95% confidence interval, 1.35-403.99; P = 0.030), with 96.94% sensitivity, 95.87% specificity, 98.6% positive predictive value, and 97.0% negative predictive value. Conclusions The current study supports the idea that in patients at risk of LN involvement, the systematic lymphadenectomy should be performed up to the renal vessels due to the high rate of upper level involvement.

Expression of c-erbB-2 and p53 in breast carcinoma patients: comparison with traditional prognostic factors and survival.

We aimed to determine the correlations between standard clinicopathological factors and expression of c-erbB-2 and p53 proteins, and to investigate the significance of these variables in relapse and disease-free survival (DFS) in breast carcinoma patients. Data from 200 patients who had undergone mastectomy for breast carcinoma were evaluated. Significant correlations were found between c-erbB-2 positivity and high histological grade (grade 3) tumour, p53 positivity and high grade tumour, and age < 60 years and oestrogen receptor negativity. Twenty-six patients (13%) developed a recurrence. Disease relapse was more frequent in patients who had axillary lymph node (ALN) metastasis, high grade tumour, c-erbB-2 positivity and p53 positivity; these variables were also associated with a shorter DFS. The effects of ALN metastasis and p53 positivity were significant. In conclusion, ALN metastasis and p53 positivity were important factors for predicting disease relapse in mastectomy-treated breast carcinoma patients; other clinicopathological criteria and c-erbB-2 positivity were not predictive.

Detection of precancerous cervical conditions using elastic light single-scattering spectroscopy

We have investigated the potential application of elastic light single-scattering spectroscopy (ELSSS) as an adjunctive tool for screening of cervical precancerous lesions non-invasively and in real time. Ex-vivo measurements were performed on 95 cervix biopsy tissue of 60 patients. Normal cervix tissue from 10 patients after hysterectomy was used as a control group. Correlation between ELSSS spectra and histopathology results were investigated. It was found that the spectral slope was positive for all the spectra taken on normal cervix tissue samples from the control group. We assumed that if there is only one spectrum with a negative spectral slope among the all spectra taken on a biopsy specimen, the biopsy specimen is pathologically abnormal. This shows that pap smear and ELSSS results are in good agreement. Most biopsy tissue samples had both positive and negative spectral slopes. Therefore, we calculated the percentage of negative spectral slopes and hypothesized that this was correlated to dysplastic percentage of the epithelial tissue of the biopsy material. The ROC curve was calculated using the dysplastic percentage and high squamous intraepithelial lesion (HSIL) and low squamous intraepitherlial lesions (LSIL) biopsy specimens were differentiated from non HSIL and LSIL with a sensitivity and specificity of 70.4% and 66.7% respectively, with p < 0.05.