Endovascular Invasion Research Articles

The role of extravillous trophoblasts and uterine NK cells in vascular remodeling during pregnancy.

Successful embryo implantation requires both a receptive endometrium and competent blastocysts. After implantation, the maternal decidua undergoes a series of changes, including uterine spiral artery (SA) remodeling to accommodate the fetus and provide nutrients and oxygen for the fetus to survive. Uterine spiral arteries transform from small-diameter, high-resistance arteries to large-diameter and low-resistance arteries during pregnancy. This transformation includes many changes, such as increased permeability and dilation of vessels, phenotypic switching and migration of vascular smooth muscle cells (VSMCs), transient loss of endothelial cells (ECs), endovascular invasion of extravillous trophoblasts (EVTs), and presence of intramural EVT, which are regulated by uterine NK (uNK) cells and EVTs. In this review, we mainly focus on the separate and combined roles of uNK cells and EVTs in uterine SA remodeling in establishing and maintaining pregnancy. New insight into related mechanisms will help us better understand the pathogenesis of pregnancy complications such as recurrent pregnancy loss (RPL) and preeclampsia (PE).

VE-cadherin enables trophoblast endovascular invasion and spiral artery remodeling during placental development.

During formation of the mammalian placenta, trophoblasts invade the maternal decidua and remodel spiral arteries to bring maternal blood into the placenta. This process, known as endovascular invasion, is thought to involve the adoption of functional characteristics of vascular endothelial cells (ECs) by trophoblasts. The genetic and molecular basis of endovascular invasion remains poorly defined, however, and whether trophoblasts utilize specialized endothelial proteins in an analogous manner to create vascular channels remains untested. Vascular endothelial (VE-)cadherin is a homotypic adhesion protein that is expressed selectively by ECs in which it enables formation of tight vessels and regulation of EC junctions. VE-cadherin is also expressed in invasive trophoblasts and is a prime candidate for a molecular mechanism of endovascular invasion by those cells. Here, we show that VE-cadherin is required for trophoblast migration and endovascular invasion into the maternal decidua in the mouse. VE-cadherin deficiency results in loss of spiral artery remodeling that leads to decreased flow of maternal blood into the placenta, fetal growth restriction, and death. These studies identify a non-endothelial role for VE-cadherin in trophoblasts during placental development and suggest that endothelial proteins may play functionally unique roles in trophoblasts that do not simply mimic those in ECs.

Extensive Sclerosis ("mummification") in Lacrimal Gland Pleomorphic Adenoma May Indicate Neighboring Malignant Transformation.

Salivary gland pleomorphic adenomas not uncommonly show extensive sclerosis ("dense hyalinization," "coagulative necrosis," or "mummification"), which arise spontaneously or after prior surgery, and this change is considered a high-risk factor for malignant transformation of benign salivary adenomas. While minor hyalinization is common in lacrimal gland adenomas, massive sclerosis-where almost all (90% or more) of the tumor is replaced by an amorphous hyaline material-is extremely rare. Four patients (2 males) are described in whom, despite not having an acute inflammatory episode, their lacrimal gland tumor showed marked sclerotic necrosis within the majority of either the benign or malignant parts of the tumor. Three tumors had evidence of malignant change, 2 to adenocarcinoma, and 1 to mucoepidermoid carcinoma, but none of the malignant areas showed perineural or endovascular invasion. Extensive sclerosis in association with a lacrimal gland pleomorphic adenoma (LGPA) is rare (4/110 of the cases) and-as with salivary adenomas-appears to be associated with a high chance of associated malignant change. Both the surgeon and the histopathologist should regard extensive sclerotic necrosis as a harbinger for malignant change in association with benign pleomorphic adenomas of the lacrimal gland.

Maternal-Fetal Polybrominated Diphenyl Ether (PBDE) Levels and Biomarkers of Placental Development and Disease during Mid-gestation

While the mechanisms and periods of sensitivity remain undefined, in utero exposures to polybrominated diphenyl ethers (PBDEs) may be linked with placenta-mediated pregnancy complications. To define the relationship between PBDE exposure and placental development, we performed: 1) an evaluation of PBDE exposures in matched samples of maternal serum, placenta, and the fetal liver collected from healthy pregnant women undergoing elective terminations during mid-gestation (n=180; 2014-16); and 2) a semi-qualitative characterization of biomarkers of placental development in relation to placental PBDE levels (n=62). Study protocols were approved by the University of California, San Francisco institutional review board; written and verbal consent were obtained from each study participant. We used censored Kendall’s tau correlation and maximum likelihood regression to compare PBDE levels between maternal-fetal tissues and examine their associations with biomarkers of placental development and disease. We profiled placental cytotrophoblast (CTB) expression of integrin alpha 1 (ITGA1) and vascular endothelial-cadherin (CDH5) and metalloproteinase 1 (MMP1). In addition, we evaluated morphological features: leukocyte recruitment (basal plate), fibrinoid deposition (villous, basal plate), and CTB endovascular invasion. PBDEs were detected in all biomatrices. Prior to lipid adjustment, wet-weight PBDE levels were highest in the fetal liver compared to other compartments (p<0.001). In contrast, after lipid adjustment, PBDE levels were higher in maternal serum compared to the fetal liver and placenta (p<0.001). We observed associations between placental PBDE levels and endovascular CTB immunoreactivity of ITGA1 (inverse) and interstitial CTB immunoreactivity of CDH5 (positive), suggesting these markers of CTB invasion and development may be sensitive placental biomarkers of PBDE exposure. Our work suggests that PBDEs are widely detected and differentially distributed in maternal-fetal compartments. Furthermore, we propose specific biomarkers of placental development as potential barometers of PBDE exposure during mid-gestation. This paradigm could be extended to other environmental chemicals and placental biomarkers.

A CASE OF RUPTURED MYCOTIC ANEURYSM AFTER DISSEMINATED MYCOBACTERIUM BOVIS INFECTION

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Dissemination is a rare complication of intravesical bacille Calmette-Guerin (BCG) therapy for bladder malignancy. CASE PRESENTATION: An 86 year-old male with medical history of atrial fibrillation, cerebrovascular accident, and bladder carcinoma treated with intravesical BCG who initially presented with worsening lower back pain. A contrast CT showed left psoas abscess abutting posterior and left lateral wall of the infrarenal abdominal aorta without evidence of aneurysm formation or contrast extravasation. Culture from the left psoas abscess aspirate returned positive for mycobacterium tuberculosis complex with a monoresistance pattern for Pyrazinamide consistent with the diagnosis of Mycobacterium Bovis(M.Bovis). He was started on a multidrug antitubercular regimen with a plan for close-follow up with serial imaging. After 3 months, he developed worsening back pain and was brought to the emergency room with increasing somnolence. Vitals were remarkable for hypotension and tachycardia. On physical examination, the patient was disoriented and had mild abdominal tenderness. Rest of the exam was unremarkable. His blood work revealed hemoglobin 6.2mg/dl and creatinine 2.2mg/dl. Abdominal CT angiography showed large left retroperitoneal hematoma and contained rupture of the infrarenal aortic aneurysm. He was resuscitated with blood products and anticoagulation was held. He underwent emergent endovascular aneurysm repair. His postoperative period was complicated by the deterioration of renal functions resulting in anuric renal failure. He was transitioned to hospice as hemodialysis was not consistent with his goals of care. DISCUSSION: BCG contains a weak strain of M. Bovis which is used as a vaccination against mycobacterium tuberculosis infection in some parts of the world and also as intravesical immunotherapy for the treatment of bladder cancer. Common side effects of intravesical BCG treatment include transient fever, fatigue, dysuria, or hematuria. Rarely, it can lead to disseminated infection leading to pneumonitis, prostatitis, hepatitis, or endovascular involvement. The pathogenesis of endovascular invasion by BCG is unclear but it is postulated to be associated with instrumentation of the bladder. Presentation of endovascular involvement may be subtle and is usually discovered after the development of complications like a ruptured aneurysm. Mycotic aneurysm related to disseminated BCG infection should be suspected based on relevant history. Diagnosis requires imaging as well as a specimen collection for microscopic analysis and culture. Mycobacterium Bovis isolates are inherently resistant to pyrazinamide. On biopsy, there is usually evidence of granulomatous inflammation. Management involves multidrug antitubercular regimen and surgical repair of the aneurysm. CONCLUSIONS: Physicians should be aware of late complications of intravesicular BCG administration. Reference #1: A. Steg, S. Adjiman, B. Debre BCG therapy in superficial bladder tumors—complications and precautions Eur Urol, 21 (suppl 2) (1992), pp. 35-40 Reference #2: J.M. LaBerge, R.K. Kerlan Jr, L.M. Reilly, T.A. Chuter Diagnosis please: Case 9: mycotic pseudoaneurysm of the abdominal aorta in association with mycobacterial psoas abscess—a complication of BCG therapy Radiology, 211 (1999), pp. 81-85 Reference #3: D.L. Lamm, P.M. van der Meijden, A. Morales, S.A. Brosman, W.J. Catalona, H.W. Herr, et al. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer J Urol, 147 (1992), pp. 596-600 DISCLOSURES: No relevant relationships by Shahrukh Arif, source=Web Response No relevant relationships by Firas Jafri, source=Web Response

Association of polybrominated diphenyl ether (PBDE) levels with biomarkers of placental development and disease during mid-gestation

BackgroundPolybrominated diphenyl ether (PBDE) exposures have been associated with adverse pregnancy outcomes. A hypothesized mechanism is via alterations in placental development and function. However, we lack biomarkers that can be used as early indicators of maternal/fetal response to PBDE exposures and/or perturbations in placental development or function.MethodsTo evaluate the relationship between PBDE levels and placental biomarkers during mid-gestation of human pregnancy (n = 62), we immunolocalized three molecules that play key roles in cytotrophoblast (CTB) differentiation and interstitial/endovascular uterine invasion—integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and metalloproteinase-1 (MMP1)–and assessed three morphological parameters as potential indicators of pathological alterations using H&E-stained tissues–leukocyte infiltration, fibrinoid deposition, and CTB endovascular invasion. We evaluated associations between placental PBDE levels and of biomarkers of placental development and disease using censored Kendall’s tau correlation and linear regression methods.ResultsPBDEs were detected in all placental samples. We observed substantial variation in antigen expression and morphological endpoints across placental regions. We observed an association between PBDE concentrations and immunoreactivity of endovascular CTB staining with anti-ITGA1 (inverse) or interstitial CTBs staining with anti-CDH5 (positive).ConclusionsWe found several molecular markers that may be sensitive placental indicators of PBDE exposure. Further, this indicates that placental biomarkers of development and disease could be useful barometers of exposure to PBDEs, a paradigm that could be extended to other environmental chemicals and placental stage-specific antigens.

Galectin-1-Related Modulation of Trophoblast Endothelial Interactions by Integrins α1 and β1.

During normal trophoblast invasion, integrins α6β4 are downregulated, and α1β1 are upregulated in invasive cytotrophoblast cells. In preeclampsia both interstitial and endovascular invasion are shallow and cytotrophoblasts fail to upregulate α1β1 and downregulate α6β4. This study aims to investigate the role of integrins α1β1 and α6β4 on cellular pathways influencing trophoblast integration into endothelial cellular networks in vitro. Red fluorescent-labeled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on Matrigel to form endothelial networks. Green fluorescent-labeled trophoblastic HTR-8/SVneo cells pre-incubated with 20μg/ml of neutralizing antibodies (anti-α1, β1, α6, β4, α1+β1, or α6+β4) for 1h were then co-cultured with endothelial networks with the neutralizing antibodies for 24h. Fluorescent images were captured, and quantified utilizing Image J. Cells were retrieved to analyze mRNA expression of galectin-1, TIMP-1, and PAI-1 by quantitative PCR. MMP-2, MMP-9, free sFlt-1, and PlGF from conditioned media were measured by ELISA. The integration of trophoblast cells into endothelial cellular networks was inhibited by anti-β1(- 28± 3%, p< 0.0001), and increased by anti-α6(+ 19± 5%, p< 0.01). Galectin-1 mRNA expression was decreased by anti-α1(- 35± 7%, p< 0.001), anti-β1(-23± 5%, p< 0.05), and anti-α1+β1(- 35± 5%, p< 0.001). The mRNA expression of TIMP-1 was inhibited by anti-α1(- 59 ± 9%, p< 0.01) and anti-β1(- 63± 7%, p< 0.001) while PAI-1 mRNA expression was increased by anti-α1 + β1(+ 285 ± 70%, p< 0.0001). In the conditioned medium, anti-α1 reduced MMP-2(-28± 1%, p< 0.001), MMP-9(-27± 8%, p< 0.01), and sFlt-1(-27± 5%, p< 0.001) production. Anti-β1 reduced MMP-2(- 15± 2%, p< 0.05) production. There were no changes in PlGF. Appropriate integrins α1β1 modulate trophoblast cell integration into endothelial cellular networks in vitro through invasive pathways including galectin-1, TIMP-1, PAI-1, MMP-2, and MMP-9 production.

Effect of Placental Growth Factor on Trophoblast-Endothelial Cell Interactions In Vitro.

Placental growth factor (PlGF) is an important angiogenic factor which has an emerging role in the clinical management of suspected preeclampsia. The role of PlGF in normal placental development is not completely understood and it is uncertain whether PlGF influences trophoblast and endothelial cell interactions central to uterine spiral artery remodelling, especially in variable oxygen conditions. A two-cell model of endovascular invasion was used. Tissue culture plates were coated with Matrigel™, on which fluorescent-labelled uterine microvascular endothelial cells (1 × 105/well) and HTR8/SVNeo cells were co-cultured (1 × 105/well) for 20h. Co-cultures were treated with recombinant human PlGF (rhPlGF) (10 or 100ng/mL) and incubated at either 21% O2 or 2% O2. Images were captured by fluorescence microscopy and analysed using ImageJ (n = 7). Data was analysed using SPSSv24. Treatment with rhPlGF did not improve integration in co-cultures irrespective of oxygen conditions but increased proliferation in 2% O2 of both trophoblast and endothelial cells. Expression of angiogenic factors VEGF, sFLT-1, PlGF and CXCL12 in both co-cultures and in isolated trophoblast cells was not altered by rhPlGF treatment. Expression of TLR-3 mRNA in co-cultures was increased by rhPlGF 100ng/mL at 21% O2 (p = 0.03). PlGF contributes to trophoblast and endothelial cell proliferation in the setting of physiological hypoxia but does not influence trophoblast and endothelial cell interactions in an in vitro model of spiral artery remodelling. Upregulation of TLR-3 expression in co-cultures may indicate a role for PlGF in the placental inflammatory response.

Calcium deficient placental growth restriction is mediated by an increase in non-invasive integrin α5 and β4 phenotype.

Integrins are cell adhesion receptors that participated in endovascular invasion by cytotrophoblasts in preeclampsia. This study aimed to investigate the effect of calcium on cellular pathways influencing the trophoblast integration into endothelial cellular networks in vitro. Red fluorescent-labelled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on Matrigel. Green fluorescent-labelled HTR-8/SVneo trophoblast cells were then co-cultured with endothelial cells in different concentrations of calcium for 24h. The calcium effects on HTR-8/SVneo cell integration were quantified by Image J. Quantitative PCR was performed to measure mRNA expression of integrins α1, α5, α6, β1 and β4. The concentrations of interleukin IL-6, matrix metalloproteinase-2 (MMP-2), MMP-9, PlGF and sFlt-1 in the conditioned medium were measured by ELISA while levels of cytokines IL-1β, IL-8, IL-10, TNF-α and INF-γ were assessed by magnetic Luminex assays™. Both calcium depletion (0.4mM) and low calcium (1.8mM) groups demonstrated inhibited integration of trophoblast cells into endothelial cellular networks, compared with the normal calcium group (2.4mM). The IL-6 production was reduced from conditioned media in both calcium depletion and low calcium groups. In calcium depletion group, mRNA expression of integrin α5 and β4 in trophoblasts was increased while integrin α1 was decreased. The in vitro trophoblast cell integration into endothelial cellular networks could be modified by altering media calcium through integrin switch away from integrins α5 and β4 and towards integrin α1 which may be required for healthy early trophoblast integration.

Spatiotemporal coordination of trophoblast and allantoic Rbpj signaling directs normal placental morphogenesis

The placenta, responsible for the nutrient and gas exchange between the mother and fetus, is pivotal for successful pregnancy. It has been shown that Rbpj, the core transcriptional mediator of Notch signaling pathway, is required for normal placentation in mice. However, it remains largely unclear how Rbpj signaling in different placental compartments coordinates with other important regulators to ensure normal placental morphogenesis. In this study, we found that systemic deletion of Rbpj led to abnormal chorioallantoic morphogenesis and defective trophoblast differentiation in the ectoplacental cone (EPC). Employing mouse models with selective deletion of Rbpj in the allantois versus trophoblast, combining tetraploid aggregation assay, we demonstrated that allantois-expressed Rbpj is essential for chorioallantoic attachment and subsequent invagination of allantoic blood vessels into the chorionic ectoderm. Further studies uncovered that allantoic Rbpj regulates chorioallantoic fusion and morphogenesis via targeting Vcam1 in a Notch-dependent manner. Meanwhile, we also revealed that trophoblast-expressed Rbpj in EPC facilitates Mash2’s transcriptional activity, promoting the specification of Tpbpα-positive trophoblasts, which differentiate into trophoblast subtypes responsible for interstitial and endovascular invasion at the later stage of placental development. Collectively, our study further shed light on the molecular network governing placental development and functions, highlighting the necessity of a spatiotemporal coordination of Rbpj signaling for normal placental morphogenesis.

Endovascular invasions for femoral-popliteal segment disorders of C andD-type according to TASC-II classification

Currently, direct re-vascularization for the management of critical limb ischemia (CLI) is effectuated through open and hybrid surgical treatments. At the same time, therapeutic recommendations for one of the methods appear as a subject of lasting discussions. Today TASC II (TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease) adopted in 2007 is the most popular document that provides justifications for endovascular and surgical treatment of peripheral arterial disease. Clinical practice provides evidence that there is a significant number of patients having critical limb ischemia who suffer from vascular bed disorders and are classified as C or D-type according to TASC classification. Meanwhile, there also are cases when these patients have no other alternative than re-vascularization by means of open surgery, which is why endovascular invasion appears as the only method of re-vascularization for them. The article presents some results of comparative studies within endovascular and surgical tools aimed at revascularization in the area of femoral-popliteal segment, including cases where patients are classified as C and D-type. The results of shunting operations are compared to angioplasty and remote endarterectomy, whereas technical methods for re-entry during subintimal angioplasty are regarded apart. Despite the fact that there are medical recommendations for the use of endovascular and surgical methods depending on TASC II classification, today there is no evidence that these tools can be efficient in revascularization of femoral-popliteal segment. In order to identify the efficiency of distinct methods in revascularization of femoral-popliteal segment there a need in a number of extended randomized studies designed to evaluate the role of such factors, as anatomic location of the vascular bed disorder, the extent of a disease, the location of purolo-necrotic areas as well as other pathologies on the results of the study.

88. Integrins (α1, β1 and α6, β4) differentially modulate trophoblast-endothelial interaction in vitro

Introduction During normal trophoblast invasion, integrin α6β4 are downregulated and α1β1 are upregulated in invasive cytotrophoblast cells. In preeclampsia, both interstitial and endovascular invasion are shallow and cytotrophoblast fail to upregulate α1β1 and downregulate α6β4. Objective This study aims to investigate role of integrin α1β1 and integrin α6β4 during trophoblast integration into endothelial cellular networks in vitro. Methods Red fluorescent-labeled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on Matrigel to form endothelial networks. Green fluorescent-labeled trophoblast HTR-8/SVneo cells pre-incubated with 20 μg/ml of neutralizing antibodies (anti-α1, β1, α6, β4, α1β1 or α6β4) for 1 h were then co-cultured with the endothelial networks with the neutralizing antibody for 24 h. Fluorescent images were captured and quantified by image J. Free soluble fms-like tyrosine kinase-1 (sFlt-1), placenta growth factor (PlGF), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) from conditioned media were measured by ELISA. Cells were retrieved to examine mRNA expression of invasion markers of tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor type 1 (PAI-1) by quantitative PCR. Results The integration of trophoblast cells into endothelial cellular networks was significantly inhibited by anti-β1 (72 ± 3%, p Discussion We have shown that anti-integrin β1, not anti-integrin a1 inhibited and anti-integrin a6, not anti-integrin β4 increased endothelial-trophoblast cellular integration in vitro. The matrix degradation enzymes (MMP-2 and MMP-9) and their associated inhibitors (TIMP-1 and PAI-1) may involve in this process.

THE FIRST EXPERIENCE IN THE EMBOLIZATION OF PROSTATIC ARTERIES IN PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA

Introduction. Our first experience in embolization of prostatic arteries at patients with benign prostatic hyperplasia had comprised patients with the symptoms of chronic urinary retention.Material and methods. The average age of patients (n=3) was 61.0±4 years. Among medical indications to embolization there were dysuria significantly degrading the patients’ life quality and their unwillingness to proceed to transurethral resection. Before the embolization of the prostatic artery, it is necessary to identify the place of its departure and its anastomosis by computed tomography. Successful operation was effectuated without microcatheter guides in 3 cases and with the application of microcatheter guides in 3 cases. For the purposes of embolization there were used spherical embolus HydroPearl sized 400 nm. No complications were reported neither in the operational nor in the post-operational periods.Results. All patients admitted a decrease in dysuria as well as the improvement in life quality already in 7–15 days after the endovascular invasion. Control ultrasound dopplerography was performed 3 months after intervention. Two patients with embolization showed decrease of prostate volume by 26%, and one patient — by 35%.Conclusions. Embolization of the prostatic arteries is a promising low-traumatic and safe method for treating patients with benign prostatic hyperplasia. It is necessary to further study its long-term results, to develop an optimized methodology — fast, simple and cheap, but not at the expense of efficiency and safety.

Superovulation alters the expression of endometrial genes critical to tissue remodeling and placentation.

Epidemiologic data suggest that in vitro fertilization (IVF) is associated with an increased risk of disorders of placentation including preeclampsia and fetal growth restriction. Specifically, studies have demonstrated that singleton pregnancies conceived following a fresh embryo transfer are at an increased risk of delivering an infant with low birth weight compared to those conceived following a frozen embryo transfer. The mechanism responsible for this association remains unclear. Procedures utilized in IVF have also been linked with epigenetic changes and gene expression changes in both fetal and maternal tissues. Data suggest that modifications in the maternal endometrium can lead to disordered trophoblast invasion and placentation. This study examines the effect of ovarian stimulation on endometrial gene expression and DNA methylation during the window of implantation to examine potential pathways playing a role in the adverse outcomes associated with IVF. Endometrial biopsies were obtained from oocyte donors and age-matched naturally cycling women 11days following oocyte retrieval in donors or 12days following luteinizing hormone (LH) surge in naturally cycling women. Global gene expression was analyzed via Affymetrix Human Gene 1.1 ST array and confirmed with RT-qPCR. DNA methylation was assessed with the Infinium DNA methylation 450K BeadChip. Analysis of endometrial gene expression from 23 women (11 oocyte donors and 12 controls) demonstrated 165 genes with a greater than twofold change in expression between donors and controls. While there were 785 genes with significant differential methylation in the endometrium of donors when compared with control subjects, none of the genes with altered expression showed significant changes in DNA methylation. Analysis of the differentially expressed genes showed enrichment for genes involved in endometrial remodeling including PLAT, HSPE2, MMP2, and TIMP1. Validation studies using RT-qPCR found a 73% reduction in expression of heparanase 2 (HSPE2) an enzyme associated with both angiogenesis and cell invasion, a greater than twofold increase in tissue-type plasminogen activator (PLAT), a serine protease participating in matrix degradation, and a 70% increase in MMP2, a gelatinase involved in collagen and fibronectin breakdown. Superovulation alters expression of genes critical to endometrial remodeling during early implantation. Such changes could lead to altered trophoblast migration and impaired endovascular invasion. These findings offer a potential mechanism for the adverse perinatal outcomes observed following embryo transfer during fresh IVF cycles.

Therapeutic lateral neck dissection in well-differentiated thyroid cancer: Analysis on factors predicting distribution of positive nodes and prognosis.

Neck dissection is considered the treatment of choice in patients with lateral neck metastases from well-differentiated thyroid cancer. A multicenter, retrospective review of patients who underwent therapeutic lateral neck dissection for well-differentiated thyroid carcinoma was carried out. The study included a total of 405 lateral neck dissections performed in 352 patients; 197 women (56%) and 155 men (44%). When considering ipsilateral neck metastases, levels IIa, IIb, III, IV, Va, Vb, and V (not otherwise specified) were involved in 42%, 6%, 73%, 67%, 11%, 31%, and 35% of cases, respectively. Five-year and 10-year overall survival (OS) were 93% and 81%, respectively. Age >55 years, pathologic T (pT)4 category, tumor diameter >4 cm, aggressive variants of well-differentiated thyroid carcinoma, endovascular invasion, and number of positive nodes >5 turned out to be the most important prognostic factors. Neck dissection is a valid treatment option in the presence of neck metastasis from well-differentiated thyroid carcinoma. Levels IIa, III, IV, and Vb should always be removed.

The role of arginine, homoarginine and nitric oxide in pregnancy.

Normal pregnancy leads to profound maternal hemodynamic changes, including increased blood volume and vasodilatation. Several vasodilator mediators are implicated, including prostaglandins, carbon monoxide and nitric oxide (NO). Pre-eclampsia (PE) affects 3-10 % of pregnancies and is associated with increased maternal and perinatal morbidity and mortality. Around 8 % of pregnancies are complicated by intra-uterine growth restriction (IUGR), also associated with increased perinatal mortality and morbidity. PE and IUGR often co-exist. NO is essential for the formation of healthy endothelium, and in pregnancy promotes endovascular invasion by the cytotrophoblast. As interstitial trophoblasts invade the maternal spiral arteries in the uterine wall, they produce NO which acts on artery walls to create a low-resistance, high-caliber uteroplacental unit. If this process fails, the result is a high-resistance uteroplacental circulation. The hypoperfused and ischemic placenta releases antiangiogenic factors which mediate generalized endothelial dysfunction, oxidative stress and inflammatory mediators. It is these mediators that are implicated in both the fetal and maternal syndromes of PE and IUGR. Studies of NO and its modulator amino acids, including the precursors arginine and homoarginine and the NO synthesis inhibitor asymmetric dimethylarginine (ADMA), have investigated their role in both normal and pathological pregnancies. Many studies of PE (and, to a lesser extent, IUGR) have investigated maternal circulating ADMA, arginine and homoarginine levels. This article reviews and discusses the role of these amino acids in pregnancy. The results have shed some light on their role in these pathologies, but some of the findings have been conflicting and more research is needed. Nevertheless, therapeutic interventions that manipulate these guanidine-amino acids and their interactions hold real promise for the management of pregnancies complicated by PE and/or IUGR, and the results of ongoing studies are eagerly awaited.

Clinical Significance of Portal-Superior Mesenteric Vein Resection in Pancreatoduodenectomy for Pancreatic Head Cancer

The purpose of this study was to determine the significance of portal vein-superior mesenteric vein (PV-SMV) invasion on survival in patients who underwent margin-negative pancreatoduodenectomy (PD) with PV-SMV resection for pancreatic adenocarcinoma. We retrospectively reviewed the records of 60 patients who underwent margin-negative PD with or without PV-SMV resection for pancreatic adenocarcinoma between August 2001 and December 2007. The depth of vessel invasion was investigated and was categorized into 3 groups: tunica adventitia, media, and intima. Clinicopathologic factors and survival were analyzed. Portal vein-superior mesenteric vein resection was performed on 19 patients, but only 15 patients (78.9%) had histologically true invasion and showed poorer survival (median survival, 14 vs 9 months; P < 0.05). Univariate analysis revealed that poorly differentiated tumor, lymphatic invasion, endovascular invasion, PV-SMV invasion, and invasion into the intima of PV-SMV were statistically significant. Poorly differentiated tumor and invasion into the intima of PV-SMV were significant in multivariate analysis. Aggressive surgical resection should be attempted in cases with suspected PV-SMV invasion because 21.1% of patients had no true invasion and showed better survival than those with true invasion. However, invasion into the tunica intima may be a poor prognostic factor for survival even after margin-negative PD for pancreatic adenocarcinoma.

MBL Interferes with Endovascular Trophoblast Invasion in Pre-Eclampsia

The spiral arteries undergo physiologic changes during pregnancy, and the failure of this process may lead to a spectrum of pregnancy disorders, including pre-eclampsia. Our recent data indicate that decidual endothelial cells (DECs), covering the inner side of the spiral arteries, acquire the ability to synthesize C1q, which acts as a link between endovascular trophoblast and DECs favouring the process of vascular remodelling. In this study, we have shown that sera obtained from pre-eclamptic patients strongly inhibit the interaction between extravillous trophoblast (EVT) and DECs, preventing endovascular invasion of trophoblast cells. We further demonstrated that mannose-binding lectin (MBL), one of the factor increased in pre-eclamptic patient sera, strongly inhibits the interaction of EVT with C1q interfering with the process of EVT adhesion to and migration through DECs. These data suggest that the increased level of MBL in pre-eclampsia may contribute to the failure of the endovascular invasion of trophoblast cells.

Mechanism of maternal vascular remodeling during human pregnancy.

Remodeling of maternal spiral arteries by invasion of extravillous trophoblast (EVT) is crucial for an adequate blood supply to the fetus. EVT cells that migrate through the decidual tissue destroy the arterial muscular lining from the outside (interstitial invasion), and those that migrate along the arterial lumen displace the endothelium from the inside (endovascular invasion). Numerous factors including cytokines/growth factors, chemokines, cell adhesion molecules, extracellular matrix-degrading enzymes, and environmental oxygen have been proposed to stimulate or inhibit the differentiation/invasion of EVT. Nevertheless, it is still difficult to depict overall pictures of the mechanism controlling perivascular and endovascular invasion. Potential factors that direct interstitial trophoblast towards maternal spiral artery are relatively high oxygen tension in the spiral artery, maternal platelets, vascular smooth muscle cells, and Eph/ephrin system. On the other hand, very little is understood about endovascular invasion except for the involvement of endothelial apoptosis in this process. Only small numbers of molecules such as polysialylated neural cell adhesion molecules and CCR1 have been suggested as specific markers for the endovascular trophoblast. Therefore, an initial step to approach the mechanisms for endovascular invasion could be more detailed molecular characterization of the endovascular trophoblast.

A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia

Placental trophoblasts (TBs) invade and remodel uterine vessels with an arterial bias. This process, which involves vascular mimicry, re-routes maternal blood to the placenta, but fails in pre-eclampsia. We investigated Notch family members in both contexts, as they play important roles in arterial differentiation/function. Immunoanalyses of tissue sections showed step-wise modulation of Notch receptors/ligands during human TB invasion. Inhibition of Notch signaling reduced invasion of cultured human TBs and expression of the arterial marker EFNB2. In mouse placentas, Notch activity was highest in endovascular TBs. Conditional deletion of Notch2, the only receptor upregulated during mouse TB invasion, reduced arterial invasion, the size of maternal blood canals by 30-40% and placental perfusion by 23%. By E11.5, there was litter-wide lethality in proportion to the number of mutant offspring. In pre-eclampsia, expression of the Notch ligand JAG1 was absent in perivascular and endovascular TBs. We conclude that Notch signaling is crucial for TB vascular invasion.