Philippe Moerman

Net‐targeted mutant mice develop a vascular phenotype and up‐regulate egr‐1

The ternary complex factors (TCFs) Net, Elk‐1 and Sap‐1 regulate immediate early genes through serum response elements (SREs) in vitro, but, surprisingly, their in vivo roles are unknown. Net is a repressor that is expressed in sites of vasculogenesis during mouse development. We have made gene‐targeted mice that express a hypomorphic mutant of Net, Netδ, which lacks the Ets DNA‐binding domain. Strikingly, homozygous mutant mice develop a vascular defect and up‐regulate an immediate early gene implicated in vascular disease, egr‐1. They die after birth due to respiratory failure, resulting from the accumulation of chyle in the thoracic cage (chylothorax). The mice have dilated lymphatic vessels (lymphangiectasis) as early as E16.5. Interestingly, they express more egr‐1 in heart and pulmonary arteries at E18.5. Net negatively regulates the egr‐1 promoter and binds specifically to SRE‐5. Egr‐1 has been associated with pathologies involving vascular stenosis (e.g. atherosclerosis), and here egr‐1 dysfunction could possibly be associated with obstructions that ultimately affect the lymphatics. These results show that Net is involved in vascular biology and egr‐1 regulation in vivo.

Pulmonary sequestration: a comparison between pediatric and adult patients.

OBJECTIVE Modern large single institutional reports on pulmonary sequestration (PS) are extremely rare. We were interested in comparing patients with PS referred by our pediatric versus adult pulmonologists. METHODS Hospital notes of all patients operated on between 1978 and 1997 for a congenital broncho-pulmonary malformation were reviewed. In 28 patients, the parenchymal lesion was vascularized by a systemic artery and was separated from the bronchial tree, thus matching the strict definition of PS. Patient characteristics and outcome were analyzed comparing the pediatric group (< or =16 years: n=13; mean age, 3+/-5 years) versus the adult group (>16 years: n=15; mean age, 33+/-13 years). RESULTS No significant differences between both groups were observed in sex, side, type of sequestration, pulmonary venous drainage, associated anomalies, hospital and late outcome, and patients overall score. Patients (n=21) with the intralobar type of sequestration presented significantly more often with an infection when compared with patients (n=7) with the extralobar type (91 versus 14%; P=0.0033). When compared with the pediatric group, patients in the adult group had significantly more respiratory infections (87 versus 38%; P=0.016), and also required a lobectomy more often (67 versus 31%; P=0.056). CONCLUSIONS The extralobar type of sequestration often remains asymptomatic, and is usually an incidental finding during infancy. The intralobar type mostly presents with recurrent infections in adulthood resulting in more lobectomies. We believe these findings support our current policy to remove any pulmonary malformation whenever diagnosed in order to: (1), prevent infection and other potentially serious late complications which may compromise the surgical outcome; and (2), enhance the chance of a parenchymal-sparing resection.

Clinical study investigating the role of lymphadenectomy, surgical castration and adjuvant hormonal treatment in endometrial stromal sarcoma

The objective of this study is to assess the therapeutic importance of surgical castration, adjuvant hormonal treatment and lymphadenectomy in endometrial stromal sarcoma (ESS). A retrospective and multicentric search was performed. Clinicopathologic data were retrieved from cases that were confirmed to be ESS after central pathology review. The protocol was approved by the Ethical Committee. ESS was confirmed histopathologically in 34 women, but follow-up data were available in only 31 women. Surgical treatment (n=31) included hysterectomy with or without bilateral salpingo-oophorectomy (BSO) in 23 out of 31 (74%) and 8 out of 31 (26%) cases, respectively. Debulking surgery was performed in 6 out of 31 cases (19%). Stage distribution was as follows: 22 stage I, 4 stage III and 5 stage IV. Women with stage I disease recurred in 4 out of 22 (18%) cases. Among stage I women undergoing hormonal treatment with or without BSO, 3 out of 15 (20%) and 1 out of 7 (14%) relapsed, respectively. Among stages III–IV women receiving adjuvant hormonal treatment or not, 1 out of 5 (20%) and 3 out of 4 (75%) relapsed, respectively (differences=55.0%, 95% CI=−6.8–81.2%). Kaplan–Meier curves show comparable recurrence rates for stage I disease without adjuvant hormonal treatment when compared to stages III–IV disease treated with surgery and adjuvant hormonal treatment. Furthermore, women taking hormones at diagnosis have a better outcome when compared to women not taking hormonal treatment. Three out of 31 (9%) patients had a systematic lymphadenectomy whereas 3 out of 31 (9%) had a lymph node sampling. In one case, obvious nodal disease was encountered at presentation. Isolated retroperitoneal recurrence occurred in 1 out of 31 (3%) of all cases and in 1 out of 8 (13%) recurrences. This single woman later also developed lung and abdominal metastases. Leaving lymph nodes in situ does not appear to alter the clinical outcome of ESS. Although numbers are low, the retrospective data suggest that the need for surgical castration (BSO) in premenopausal women with early-stage disease should be discussed with the patient on an individual basis. The data support the current practice in some centres to administer adjuvant hormonal treatment.

The pedicle artery sign based on sonography with color Doppler imaging can replace second-stage tests in women with abnormal vaginal bleeding

Unenhanced transvaginal sonography is not accurate in the detection of endometrial polyps. Currently, second‐stage tests such as saline contrast sonohysterography and office hysteroscopy are used to diagnose endometrial lesions, but both have limitations and side effects. We proposed visualization of the pedicle artery on color Doppler imaging as a sign of polyps.

PATHOGENESIS OF CONGENITAL CYSTIC ADENOMATOID MALFORMATION OF THE LUNG

Congenital cystic adenomatoid malformation is a rare developmental abnormality of the lung. In most earlier reported cases, the anatomy of the bronchial tree was poorly documented. We describe four cases studied following autopsy. Post‐mortem bronchography or serial microscopical examination showed segmental bronchial absence or atresia in each of them. Our observations provide further evidence pointing to bronchial atresia as being the primary defect leading to the development of congenital cystic adenomatoid malformation. The morphology of the lesion, i.e. the type of malformation, is determined by the extent of dysplastic lung growth beyond the atretic segment. The aetiology of the bronchial atresia is probably heterogeneous and may either represent a primary malformation, or be the result of vascular disruption.

External Validation of Mathematical Models to Distinguish Between Benign and Malignant Adnexal Tumors: A Multicenter Study by the International Ovarian Tumor Analysis Group

Purpose: Several scoring systems have been developed to distinguish between benign and malignant adnexal tumors. However, few of them have been externally validated in new populations. Our aim was to compare their performance on a prospectively collected large multicenter data set. Experimental Design: In phase I of the International Ovarian Tumor Analysis multicenter study, patients with a persistent adnexal mass were examined with transvaginal ultrasound and color Doppler imaging. More than 50 end point variables were prospectively recorded for analysis. The outcome measure was the histologic classification of excised tissue as malignant or benign. We used the International Ovarian Tumor Analysis data to test the accuracy of previously published scoring systems. Receiver operating characteristic curves were constructed to compare the performance of the models. Results: Data from 1,066 patients were included; 800 patients (75%) had benign tumors and 266 patients (25%) had malignant tumors. The morphologic scoring system used by Lerner gave an area under the receiver operating characteristic curve (AUC) of 0.68, whereas the multimodal risk of malignancy index used by Jacobs gave an AUC of 0.88. The corresponding values for logistic regression and artificial neural network models varied between 0.76 and 0.91 and between 0.87 and 0.90, respectively. Advanced kernel-based classifiers gave an AUC of up to 0.92. Conclusion: The performance of the risk of malignancy index was similar to that of most logistic regression and artificial neural network models. The best result was obtained with a relevance vector machine with radial basis function kernel. Because the models were tested on a large multicenter data set, results are likely to be generally applicable.

Presymptomatic Identification of Cancers in Pregnant Women During Noninvasive Prenatal Testing.

IMPORTANCE Noninvasive prenatal testing (NIPT) for fetal aneuploidy by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a major prenatal genetic test. Similar to placental DNA, tumor DNA can be detected in the plasma, and analysis of cell-free tumor DNA can be used to characterize and monitor cancers. We show that plasma DNA profiling allows for presymptomatic detection of tumors in pregnant women undergoing routine NIPT. OBSERVATIONS During NIPT in over 4000 prospective pregnancies by parallel sequencing of maternal plasma cell-free DNA, 3 aberrant genome representation (GR) profiles were observed that could not be attributed to the maternal or fetal genomic constitution. A maternal cancer was suspected, and those 3 patients were referred for whole-body diffusion-weighted magnetic resonance imaging, which uncovered an ovarian carcinoma, a follicular lymphoma, and a Hodgkin lymphoma, each confirmed by subsequent pathologic and genetic investigations. The copy number variations in the subsequent tumor biopsies were concordant with the NIPT plasma GR profiles. CONCLUSIONS AND RELEVANCE We show that maternal plasma cell-free DNA sequencing for noninvasive prenatal testing also may enable accurate presymptomatic detection of maternal tumors and treatment during pregnancy.

Does Estrogen Receptor–Negative/Progesterone Receptor–Positive Breast Carcinoma Exist?

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Endometrial polyp: another benign tumor characterized by 12q13-q15 changes.

Clustering of aberrations to specific chromosome regions of benign tumors may indicate the location of genes related to the proliferative process. Although few endometrial polyps have been cytogenetically investigated, 6p21 band appears to be involved consistently in the chromosome changes. We report two cases of this type of benign tumor with chromosome rearrangements in 12q14-15, allowing identification of a second cytogenetic subgroup in endometrial polyps.

Ovarian borderline mucinous tumor in a premenarchal girl: Review on ovarian epithelial cancer in young girls

Ovarian tumors constitute the most common gynecological neoplasms during childhood. Unlike in adult women, ovarian epithelial tumors are uncommon in young girls and extremely rare prior to menarche. To our knowledge this is the first report of a borderline malignant mucinous tumor of the ovary in a premenarchal girl. It was successfully treated by conservative surgery. In our review of ovarian neoplasms in girls under 20 years of age, epithelial tumors were found in 19.3%, with a malignancy rate of 15.9%. Of these malignant tumors, 39.4% were of the mucinous type and 30.3% were borderline malignant. The occurrence of such a tumor at this age underscores the possibility of malignant transformation of the ovarian epithelium even prior to menarche. Its mucinous nature confirms the predominance of the mucinous subgroup in young girls. Hypotheses on the origin of mucinous tumors are discussed.